End-of-Life Care for Individuals with Severe and Persistent Mental Illness

/in /by

This paper explores the intersection of individuals who struggle with severe and persistent mental illness (SPMI) and how palliative or end-of-life care is administered.  This exploration will also involve examining what impact this contextual intersection has on how decisions are made during end-of-life care and eligibility for medical assistance in dying (MAiD).  How much agency do individuals with severe mental health issues have regarding their health care and treatment options? Who determines the capacity of the individual to make sound decisions for their best benefit?  Are assumptions and stigmas at play in this intersection?  From the research conducted, there seems to be a hesitation among medical caregivers as to how much agency one who is afflicted with a serious mental illness can and are able to have over treatment.

A number of studies and articles report that there is a higher mortality rate among those with serious mental health challenges.  Trachsel (2018) states, “…patients with severe and persistent mental illness (SPMI) have a high mortality rate and die 10 to 20 years earlier than persons in the general population.” (Trachsel, 2018). Other studies report that the reasoning for this high mortality rate is varied, ranging from unsafe living conditions, such as homelessness; lack of access to quality medical care and unhealthy behaviours. (Elie et. al, 2018)

The complexity of this mental health issue is evident, combining legal and ethical implications of MAiD, alongside with societal stigma surrounding the capabilities of individuals who have serious mental health challenges and their ability to make medical decisions, particularly surrounding end-of-life, alongside with increased risk of developing serious physical illness.  All of this combined, produces a present day mental health issue whose resolution is anything but simple.

There are rare moments in one’s life where one is stripped to the core of themselves.  Their true nature and their truth.  One of those rare moments is when one faces their end-of-life.  To be there for the individual or to provide care that is anything but truthful, respectful and authentic is to diminish the humanity of the person we serve.  As professionals, there are moments the person is forgotten as symptoms are managed.  As end-of-life approaches, it is time for honesty about the type of care that can be provided, deserved and sought, for example, if MAiD is an option that one wishes to exercise, or there may be certain ways one wishes their pain symptoms to be managed.  End-of-life care, or physician assisted suicide is such a complex heated debate, I wondered how the wishes of an individual who has had serious or prolonged mental illness would be regarded by those providing care.  I advocate for the ability of those who suffer from any physical and/or mental ailments to pass away on their terms. Mandated by their wishes and beliefs, determined by them and not from another who may barely know them.


Paradigm

The social constructivist paradigm will be utilized as this theory follows the framework that we as humans and collectively in our societies, attribute meaning to events that impact our personalities, and behaviour.  Guided by the subjective experience and the subjective response. Alderson (1998) ), in her article, “The Importance of Theories in Health Care” explains, “There is no neutral, objective perspective; whatever the origins of the pain, the experience and the observers’ responses are deeply personal. The complex meanings of pain and disease can be seen as questions or problems instead of given facts.” (Alderson, 1998)  Due to the clinical nature of end-of-life care, the positivist paradigm tend to guide the medical model that care practitioners in this field conduct their work through.  Alderson (1998) points out, “In medicine, the emphasis on specific body parts, conditions, and treatments assumes that these are universally constant, replicable facts.” (Alderson, 1998)  In other words, the world is ordered by a natural set of rules that is true for everyone.  Objectively experienced and happens regardless of how one feels or believes.  The progression of physical death can be seen through this lens.

To discuss the intersection of  individuals who struggle with severe and prolong mental health issues and how palliative or end-of-life care is administered through strictly a positivist lens would inhibit the importance of how socially constructed perspectives around mental health effects the care that an individual receives. Through the social constructivist lens this paper aims to uncover if preconceived social perceptions underlie the positivist medical model.


Legislation

Although The Mental Health Act plays a large part in the intersection of mental health and end-of-life care, the largest legislative piece to mental health and decisions regarding end-of-life care is The Health Care Consent Act (HCCA).  The HCCA deals with the cognitive ability of a person in understanding information about their health and treatment, and the consequences of their decision(s).  It is up to a physician to determine if an individual is competent and able to make sound decisions for themselves.  The test for capacity is set out in subsection 4(1) of the

HCCA

and provides that:

“A person is capable with respect to a treatment, admission to a care facility… if the person is able to understand the information that is relevant to making a decision about the treatment, admission … as the case may be, and able to appreciate the reasonably foreseeable consequences of a decision or lack of decision.”  (Mental Health and the Law Toolkit Revised (2016))

The question lies in how medical personnel understands and perceives mental illness in light of the patients capacity to consent.  Hirsch (2016) argues and quotes Mishna et al. (2012), “The state of being depressed, mentally ill, or suicidal with feelings of hopelessness and despair can be thought of as impeding a person’s capacity to reason, make rational decisions, and to act autonomously. However, mental illness by definition does not mean someone is irrational or incompetent.” (Hirsch, 2016).  As it stands, the power of deciding if an individual has or lacks the ability to make end-of-their life care decisions, lies with medical professionals who may or may not be well-versed in the mental health field, and would make decisions based on their perceptions rather than on actual psychiatric knowledge of the mental illness the individual is diagnosed with.


Social Implications

It is a basic human right for each individual to live with self-agency and within an environment that is enriching, and encouraging, unfortunately that is utopist in thought.  Realistically, there are a number of factors that influence the mental health of an individual.  Alongside genetics and life choices, social determinants of health (i.e. social positioning, economic and environmental factors)  play a large part in the trajectory that a life takes.  Individuals with severe and persistent mental illness (SPMI) through no fault of their own are placed in a cycle where stigma and social determinants play a back and forth game of chicken with their health and quality of life.  In Butler and O’Brien’s (2018) article, they refer to a number of studies whose research has shown that individuals with severe and prolonged mental illness (SPMI),

“…are at increased risk of developing and dying from a life-limiting illness, and die at a younger age….at least 50% of people diagnosed with an SPMI have co-existing medical morbidities including higher rates of cardiovascular disease, infectious disease, including HIV; non-insulin-dependent diabetes mellitus; gastrointestinal disease; respiratory disease, and some forms of cancer.” (Butler & O’Brien, 2018)

At the heart of these health disparities, lies the societal stigma that is attached to those who are afflicted with a mental health disorder.  Corrigan et. al (2014) discusses how stigma that drives stereotypes go about, “…depicting people with mental illness as being dangerous, unpredictable, responsible for their illness, or generally incompetent can lead to active discrimination, such as excluding people with these conditions from employment and social or educational opportunities.” (Corrigan, Druss, & Perlick, 2014)

Stigma interweaves itself with social determinants of health, producing a dangerous cat and mouse game where individuals with SPMI hesitate to seek out health care services either voluntarily as they have internalized this societal stigma or involuntarily as the societal stigma becomes the impasse to accessing quality health care services, in this case, end-of-life care. The societal stigma surrounding the decision-making capabilities of individuals with SPMI, that is embedded within the medical profession keeps quality end-of-life care at arm’s length, producing substandard care levels as the person is not the primary focus but rather their mental illness is.  Elie et al. notes “…medical specialists rarely engage SPMI patients in end-of-life care discussion for various reasons….misconception that mental illness impairs decision-making capacity.” (Elie, et al., 2018)  What is most interesting is that there is a presumption that the individual due to their mental illness is not capable of making sound health decisions for themselves.  Hirsch (2016) comments, “..mental illness by definition does not mean someone is irrational or incompetent…there is a difference between…severe long-term illness who have deliberated carefully about ending their lives and those that are temporarily impaired whose wish to die might be a symptom of treatable illness such as being actively psychotic.” (Hirsch, 2016)  At the heart of the social implications of mental health and access to end-of-life care is stigma, reducing the stigma increases quality of life, and concurrently the social determinants that one’s quality of life is determined by.  Addressing the stigma, can begin to relieve some of the barriers to health care that individuals with SPMI face.


Historical Management

Historically, those who had any form of mental health disorder were institutionalized and closed off from society.  Seen as either an embarrassment to family or hopeless, these individuals were ignored, those afflicted with mental illness where feared and forgotten.  With no voice to be heard on care treatment plans, these individuals were seen to be a burden on society.  Hirsch (2016), “The perception of mental illness as a flaw or weakness obstructs our ability to empathize with those living with intractable and debilitating mental health issues.” (Hirsch, 2016).

At the intersection of this historical treatment of those with mental disorders and the current medical concept of end-of-life care we, as a society are left with a lot of uncertainty as to how to compassionately move forward.  “Our history of mistreatment of people with mental illness also creates a taboo against assisted suicide for these populations.” (Hirsch, 2016) Society’s generalized hesitation in addressing this intersection speaks to the misconceived notions still held about mental disorders, just as historically physicians made care decisions on behalf of the individual with a mental disorder, it feels like history is repeating itself in this juncture of mental health and end-of-life care, by deeming an individual lacking capacity to make their own decisions without having the discussion with the individual and moving forward with a care treatment plan that counters the individual’s wishes based on an old misguided assumption that the individual lacks ‘capacity’.


Current Research

Elie et. al (2018) designed a study to compare and assess patients who were either SPMI (severe and persistent mental illness) or CMI (chronic medically ill), and how they differed in their end-of-life care preferences and how comfortable they were in discussing their preferences.   What the researchers found was, “The percentage of patients supporting the use of pain medication, palliative sedation, MAiD, and artificial life support did not differ significantly between groups.” (Elie, et al., 2018)  Interestingly, SPMI patients “…were less likely to support its [MAiD] use before and after controlling for covariates….This contrasts with a controversial body of evidence suggesting that depressed and suicidal patients are more likely to support physician-assisted death and euthanasia” (Elie, et al., 2018)   What this body of research points to is that the misperception held by society that those individuals with SPMI would be more inclined to passive suicidal tendencies are falsely held.  Countering these misperceptions with scientific research may help turn the tide in the stigmatic thought that those in the SPMI population have suicidal ideation and would be inclined to choose end-of-life measures faster than the general population.  It goes to show how entrenched mental health stigma is within our culture.  As medical professionals with in-depth access to scientific knowledge, it is evident that the societal construction of mental illness has penetrated the ‘objective’ positivist mindset that the medical model prides itself to be.

Elie et. al (2018) did note that “…further studies are needed to carefully assess the impact of prominent psychiatric and cognitive symptoms on decision-making capacity about end-of-life care in vulnerable patients.”   Studies that can further de-stigmatize this line of thinking within the general public may help to navigate the complexity of mental illness and assist in understanding  that lack of rationality, capacity to consent nor end-of-life decisions are determined by mental illness, but rather by the individual themselves separate from their disorder.

In regards to access to and who qualifies for MAiD, this is a political, ethical and legal hot potato topic.  According to the Government of Canada website, to be eligible for MAiD, an individual needs to meet all of  the eligibility criteria, one criteria particularly stands out in relation to this paper’s topic, “…be at least 18 years old and mentally competent. This means being capable of making health care decisions for yourself.” (Medical Assistance in Dying, 2019) It was also noted that to be considered, the individual needs to, “…be in an advanced state of decline that

cannot

be reversed….[and]… experience unbearable physical or mental suffering from your illness, disease, disability or state of decline that

cannot

be relieved under conditions that you consider acceptable.” (Medical Assistance in Dying, 2019) This presents a quandary, if the mental disease that one suffers from affects the cognitive functioning of being considered mentally competent, how does one qualify for MAiD?   Who determines this lack of capacity?  As stated previously, individuals with SPMI seek out MAiD less than was perceived, perhaps as Trachsel et. al suggest, the answer then lies within, “An explicitly palliative approach within psychiatry has the potential to improve quality of care, person-centredness, outcomes, and autonomy for patients with severe persistent mental illness.” (Trachsel, Irwin, Biller-Andorno, Hoff, & Riese, 2016)

As can be seen, individuals with SPMI and end-of-life care and decision making is a complex issue that we all will be discussing for years to come.  What is clear, further research is required, a deeper analysis of parameters surrounding the determination of capacity and consent for those with SPMI and a recognition of the stigma that pervades the medical model.


Multicultural Context

Living in a multi-culturally diverse country such as Canada, it is important to understand the role culture plays in how mental health and end-of-life care is experienced, separately and together. Werth Jr. et. al points out that, “Although the majority culture…places great emphasis on autonomy, some cultures…place much less value on self-determination and instead emphasize collective decision-making.”   (Werth, Blevins, Toussaint, & Durham, 2012)  Within this context, the discussion this paper has had thus far on the autonomy of the individual with SPMI to choose for themselves the type of end-of-life care they would like to receive, must change to accommodate this cultural perspective.  It is important to be aware of the cultural lens that the individual lives through to ensure that their wishes are heard and understood.  Some cultures do not see mental illness the same way as western cultures, for some cultures mental illness is seen as a spiritual gift, and yet other cultures it is seen as possession of an unworldly spirit that needs to be exorcised. These perceptions shift how end of life care decisions are made.

Another cultural aspect to keep in mind in having these end-of-life discussions is that, “In addition, some cultures (e.g., some Native American tribes) believe that speaking of death at all, or telling the terminally ill person that she or he may die, is harmful” (Werth, Blevins, Toussaint, & Durham, 2012)  It is important to stay mindful and respectful of the space an individual occupies and how that space is filled with beliefs, values and cultural norms.


Critical Reflections

Reducing the stigma surrounding both mental illness and decisions about end-of-life care, that includes physician assisted suicide, literally is a life or death decision.  That is not said tongue in cheek, but rather quite seriously.  First, there must be an understanding of the correlation between mental health and concurrent physical ailments, that can reduce the lifespan of the individual by 10 to 20 years.  Stigma has a serious implication and role to play in one’s life.  Lastly, the debate around assisted dying.  if that is a choice the individual makes, the role that capacity and consent has on this decision is on its own, complex in nature, but add the complexity of SPMI individuals and one has a slew of questions and uncertainty that makes medical professionals run for the hills or avoid discussions at all costs.  But is that the type of care that is deserving to an individual, we are all complex human beings with a set of beliefs, values and understandings, informed by our cultural backgrounds, and lived experiences, regardless of our mental state.

It is also evident that the positivist skewed medical model is not sufficient enough to work with this intersection.  First of all, the objectivity of the medical model is thrown into question, the social construct of what it means to die a good death and the social construction of capacity in light of mental illness can prevent an individual to die that good death because society perceives them to be incapable of making their own decisions.  As Rentmeester (2014) comments, “we often focus too narrowly upon legal notions of competence and clinical notions of decision-making capacity and pay little attention to the patient’s actual illness experiences…recall that a person can have epistemic authority….seen as worthy of regard.” (Rentmeester, 2014)


References

  • Alderson, P. (1998, October 10). The Importance of Theories in Health Care.

    BMJ (Clinical Research Ed.)

    , pp. 1007-1010. doi:10.1136/bmj.317.7164.1007
  • Butler, H., & O’Brien, A. J. (2018). Access to specialist palliative care servies by people with severe and persistent mental illness: A retrospective cohort study.

    International Journel of Mental Health Nursing, 27

    , 737-746. doi:10.1111/inm.12360
  • Corrigan, P. W., Druss, B. G., & Perlick, D. A. (2014). The Impact of Mental Illness Stigma on Seeking and Participating in Mental Health Care.

    Association for Psychological Science

    . Retrieved June 21, 2019, from The Impact of Mental Illness Stigma on Seeking and Participating in Mental Health Care
  • Elie, D., Marino, A., Torres-Plata, S., Noohi, S., Semeniuk, T., Segal, M., . . . Rej, S. (2018, January). End-of-Life Care Preferences in Patients with Severe and Persistent Mental Illness and Chronic Medical Conditions: A Comparative Cross-Sectional Study.

    American Association for Geriatric Psychiatry, 26

    (1), 89-97. doi:https://doi.org/10.1016/j.jagp.2017.09.018
  • Hirsch, J. (2016). The Wish to Die: Assisted Suicide and Mental Illness.

    Journal of Social Work in End-of-Life & Palliative Care, 12

    (3), 231-235. doi:http://dx.doe.org/10.1080/15524256.2016.1200516

  • Medical Assistance in Dying

    . (2019, April 25). Retrieved from Government of Canada: https://www.canada.ca/en/health-canada/services/medical-assistance-dying.html

  • Mental Health and the Law Toolkit Revised (2016).

    (n.d.). Retrieved from Ontario Hospital Association: https://www.oha.com/Legislative%20and%20Legal%20Issues%20Documents1/OHA_Mental%20Health%20and%20the%20Law%20Toolkit%20-%20Revised%20(2016).pdf
  • Rentmeester, C. A. (2014). Regarding Refusals of Physically Ill People with Mental Illnesses at the End-of-Life.

    International Journal of Mental Health

    , 73-80.
  • Trachsel, M. (2018). The Ethical Importance of Assessing End-of-Life Care Preferences in Patients with Severe and Persistent Mental Illness.

    American Association for Geriatric Psychiatry

    , 98-99.
  • Trachsel, M., Irwin, S., Biller-Andorno, N., Hoff, P., & Riese, F. (2016). Palliative psychiatry for severe persistent mental illness as a new approach to psychiatry? Definition, scope, benefits and risks.

    BMC Psychiatry

    . doi:http://doi.10.1186/s12888-016-0970-y
  • Werth, J., Blevins, D., Toussaint, K., & Durham, M. (2012). The Influence of Cultural Diversity on End-of-Life Care and Decisions.

    American Behavioral Scientist

    , pp. 204-210. doi:https://doi.org/10.1177/000276402236673

Interleukin-6 Levels in Early Diagnosis of Neonatal Sepsis

/in /by


Study of Interleukin-6 Levels in Early Diagnosis of Neonatal Sepsis

Dr.

Sonawane

Vijay B., Dr.

Mehkarkar

Nitin S., Dr.

Jadhav

Pradnya B., Dr.

Gaikwad

Sonali U., Dr.

Kadam

Nitin N.

Department of Pediatrics, MGM Medical College and Hospital, Navi Mumbai, Maharashtra, INDIA


ABSTRACT


Introduction:

Neonatal septicemia is one of the commonest causes of neonatal mortality and morbidity. Interleukin-6 Levels appears to be one of the most promising candidate cytokine for early diagnosis of neonatal septicemia. The aim and objectives of this study was to study the role of IL-6 levels as an early marker for diagnosis of neonatal sepsis and to compare IL-6 levels with other septic markers.


Materials and Methods:

This is a hospital based prospective study to evaluate the efficacy of IL-6 as an early diagnostic marker of neonatal sepsis. Eighty neonates, delivered in the hospital, having risk factors for neonatal sepsis, along with those coming to hospital with signs and symptoms of sepsis up to 28 days of life (as study group ) along with normal newborns admitted to the postnatal ward without high risk factors (control group) were enrolled for this study

.


Results:

IL-6 Levels has shown maximum Sensitivity of 95.83%, Specificity of 87.50%, Positive Predictive Value of 92 %, Negative Predictive Value of 93.33 % and Accuracy of 92.50 %. E.Coli was the most common organism responsible for sepsis. CRP was reported to be highly sensitive(84.21%), and CBC was highly specific (75.00%), IT ratio has sensitivity of 62.5% and specificity of 56.25% while Micro-ESR has shown sensitivity of 50.0% and specificity of 62.5%, Out of 80 cases, blood culture (BacTalert) showed growth in 48 cases in study group while two cases in control group. Thus blood culture positivity was 60%.


Conclusion:

IL-6 test has maximum sensitivity as well as specificity in comparison with other septic markers. Blood culture is the gold standard for the diagnosis of septicemia.CRP is most sensitive while CBC is most specific marker in neonatal sepsis.


KEY WORDS:

Neonatal Sepsis, Diagnostic Markers, Mortality, IL-6 Levels.


INTRODUCTION

Neonatal Septicemia is the leading cause neonatal mortality and morbidity in India. It is estimated that 20% of all neonates develop sepsis


1


and is responsible for 30-50% of total neonatal death in developing countries


2


. Accurate and timely diagnosis of neonatal sepsis still remains a major challenge to the pediatricians and neonatologists. Mortality due to neonatal sepsis is preventable and if diagnosed early the outcome is better. Several indicators have been evaluated as septic screen for the early diagnosis of neonatal sepsis like CBC, CRP, Micro-ESR, IT ratio, and Blood Culture. There is a constant search for better and ideal diagnostic marker. Ideal marker should be sensitive, specific and easily available. Its results should be immediate and reproducible. Recently various new markers are being studied such as IL-6, TNF-α, Procalcitonin, G-CSF etc. IL-6 is an inducer of hepatic protein synthesis which promotes production and liberation of CRP and can be detected early when there is bacterial bloodstream invasion. It appears to be one of the most promising candidate cytokine for early diagnosis of neonatal septicaemia.


3,4

In the present study conducted at Mahatma Gandhi Mission Medical College and Hospital, Navi Mumbai, IL-6 levels were assessed in normal healthy newborns as well as newborns with high risk factors for sepsis and the usefulness of IL-6 was evaluated as an early marker for sepsis detection and its effectiveness was compared with other septic markers.


MATERIALS AND METHODS


Study Design:

A prospective study design was used to evaluate the efficacy of IL-6 as an early diagnostic marker of neonatal sepsis. This is a hospital based study conducted in M.G.M Medical College and Hospital, Navi Mumbai.


Study Period

: July-2005 to August-2007


Sample Size

:

Eighty neonates, delivered in the hospital, having risk factors for neonatal sepsis, along with those coming to hospital with signs and symptoms of sepsis up to 28 days of life (as Study Group) also normal newborns admitted to the postnatal ward without high risk factors (Control Group) were enrolled for this study. Newborns were treated with antibiotics for clinical evidence of sepsis & positive septic score as per neonatal sepsis score system (Table 1).

Table 1: Neonatal sepsis score system

5


Score 1
 Maternal fever in 3

rd

trimester, instrumental delivery, intubations, exchange transfusion, LBW, outside delivery, abdominal distention, irritability, lethargy, convulsion, apnea

Score 2
 Hypothermia, fever, local infection, refusal to feed, feed Intolerance, vomiting, loose stools, meconium aspiration

Score 3
 LPV >12 hrs, chorioamnionitis, cord erythema, foul smelling (cord)

Score 4
 Sclerema, meningitis, DIC, NEC


Score1=risk of infection, Score2=need septic work up to exclude, Score 3 or more=investigate and treat

A detailed history was taken and examination was done. Following laboratory tests were done as soon as presumptive diagnosis of sepsis was made based on septic score system and on clinical grounds. All investigations were done within 24 hours of birth or at presentation before starting antibiotics like IL-6 levels, CBC, CRP with titer, Micro ESR, Immature to Total (IT) ratio, peripheral smear for toxic granules and band forms, blood culture (BacTalert), x-ray chest, CSF whenever indicated etc. Soon after birth, 1 ml of venous blood was drawn for blood culture. Also 5 ml of venous blood was collected for TLC, DLC, peripheral blood smear, micro-ESR and CRP. CRP was sent at 12 hours of life in newborns with high risk factors for sepsis. This study was approved by Ethical Committee of this hospital. Informed Written Consent was obtained from parents before entry into this study. Information of selected neonates including detailed history and clinical examination was recorded on a predesigned proforma.


Interleukin-6 Levels Determination



3,4



:

1 ml blood was collected in plain bulb and serum was tested by Chemiluminescent Immunometric technique in IMMULITE Machine1000 (Table 2). IMMULITE 1000 IL-6 is a solid phase, enzyme labeled, Chemiluminescent sequential immunometric assay. The use of an ultracentrifuge is recommended to clear lipemic samples. Volume required – 100 µL serum, EDTA or Heparinized Plasma (Sample cup must contain at least 250 µL more than the total volume required).


Interpretation



6,7



:

Table 2 – Interpretation Guide for Immune Monitoring


Parameter
Group
Concentration
Interpretation Guide

IL-6
 Low Level < 100 pg/ml Infection unlikely

Patient may be tested again if clinical sign persists
High Level > 100 pg/ml Patient most likely needs treatment

IL-6 levels correlate with the severity of the disease


DATA ANALYSIS

Data was collected, classified, tabulated and analyzed. Tests of significance were applied at appropriate places and interpretation was done accordingly. To evaluate the difference between the categories, McNemar Chi Square test was used as a test of significance. A p-value of less than 0.05 was considered statistically significant.


RESULTS AND DISCUSSION

Of total of 80 cases, with risk factor and clinical signs and symptoms of sepsis (40 cases as study group) and normal healthy newborns without risk factors (40 cases as control group). The study group consists of 28 males (70%) and 12 females (30%) while control group consists of 21 males (52.50%) and 19 females (47.50%). Among 40 babies of study group, 24(60%) are blood culture (BacTalert) positive and 16 (40%) are blood culture (BacTalert) negative while in control group, 1(2.50%) is blood culture (BacTalert) positive and 39(97.50%) are blood culture(BacTalert) negative (Fig. 1).

Fig. 1: Bar Chart Showing Distribution of Cases According to Blood Culture

In study group, E-coli comprised the maximum number of cases accounting for sepsis i.e. 7 (17.5%) followed by 5 cases (12.5%) of Acinetobacter baumanii, 5 cases (12.5%) of Klebsiella Pneumoniae, 2 cases(5%) each for Citrobacter and Staphylococcus aureus and 1 case (2.5%) has shown Pseudomonous Sp., Burkholderia cepacia and Fungus while no growth in 16 (40% ) cases. In control group, only 1 case (2.5%) shows growth of Acinetobacter baumanii and 39 cases (97.5%) are sterile (Fig. 2). Bhargava et al

8

noted in their study that the incidence of E.Coli as the causative organism of neonatal sepsis was 45%. Mirfet al

9

in their study of 50 cases also showed similar results. McCraken

10

, Faridi and Gupta

11

, Kumar GD et al

12

have also reported that gram negative septicemia is more common than gram positive septicemia


Study Group


Control Group

Fig. 2: Pie Chart Showing Distribution of Cases According to Microbiological Growth on Blood Culture

Out of 40 cases in study group, CBC is abnormal in 13 cases (32.5%), Blood Culture (BacTalert) was positive in 24 cases (60%) and 4 cases (10%) has CBC abnormal with sterile blood culture. In this study CBC had low sensitivity (37.50%) and high specificity ( 75.00%). Chan and Ho

13

revealed in their study that abnormal CBC had the lowest sensitivity and PPV while abnormal ANC had the lowest specificity and NPV among them. (Fig. 3)


Fig. 3: Bar Chart Showing Distribution of Cases According to CBC

Out of 40 cases in study group, CRP is reactive in 31 cases (77.5%), Blood culture is positive in 24 cases (60%) and 15 cases (37.5%) are having CRP reactive with sterile blood culture. In this study CRP was reported most sensitive (84.21%) but low specific(28.57%), Franz AR et al


14


showed that there is generally a delay of up to 24 hours between onset of symptoms of infection and a rise in serum CRP. Sensitivity of the test at presentation is only 40% that is, 60% of subsequently proven sepsis episodes will have a normal initial CRP. (Fig. 4).

Fig. 4: Bar Chart Showing Distribution of Cases According to CRP

Out of 40 cases in study group, IT Ratio is abnormal in 22 cases (55%), Blood Culture is positive in 24 cases (60%) and 7 cases (17.5%) are having IT Ratio abnormal with sterile blood culture. In our study IT ratio was reported NPV of 50.0%. Ghosh et al

15

studied 103 high risk neonates having predisposing perinatal factors or clinical suspicion of sepsis and found that an abnormal immature to total neutrophil (IT) ratio were the most sensitive indicators in identifying neonates with sepsis showing high negative predictive value over 94%. (Fig. 5)


Fig. 5: Bar Chart Showing Distribution of Cases According to IT Ratio

Out of 40 cases in study group, Micro-ESR is abnormal in 18 cases (45%), Blood Culture is positive in 24 cases (60%) and 6 cases (15%) has Micro ESR abnormal with sterile blood culture. In our study Micro-ESR has shown sensitivity of 50.0%, specificity of 62.5. K.K. Diwakarand Rosul G

16

studied on 114 term neonates for early neonatal sepsis. The sensitivity and specificity of the ‘revised’ Micro-ESR was 62.5% and 60.9% respectively in diagnosing culture proven sepsis. (Fig. 6)


Fig. 6: Bar Chart Showing Distribution of Cases According to Micro-ESR

Among 40 babies of study group, 25 (62.50%) has IL-6 Test positive and 15 (37.50%) has IL-6 Test negative while in control group, 3 (7.5%) has IL-6 Test positive and 37 (92.5%) has IL-6 Test negative. In present study, neonatal mortality is seen in 4 cases (5%) of the total 80 cases. Of these 4 cases, all cases have shown elevated IL-6 levels. Hence, strongly elevated IL-6 levels in this study have found to be associated with bad prognosis as indicated by death. Statistical analysis of IL-6 levels concentration >100 pg/ml in this study of 40 cases (study group) yielded a sensitivity of 95.83% and specificity of 87.50 % whereas Positive predictive value and the Negative predictive value is 92% and 93.33% respectively. Many studies have also reported similar results. The recent study of IL-6 in early neonatal sepsis by Silveira et al

17

using normal newborns as controls, showed similar sensitivity of 96%. Recently, Silveira and Procianoy

18

reported that IL-6 and TNF-α are likely candidate cytokines for use in early diagnosis of neonatal sepsis. (Fig. 7)

Fig. 7: Bar Chart Showing Distribution of Cases According to IL-6 Assay

Out of 40 cases in study group, blood culture is positive in 24 cases (60%), IL-6 is positive in 25 cases (62.5%) and 2 cases (5%) have IL-6 positive with sterile blood culture. (Fig. 8)



Fig. 8: Bar Chart Showing IL-6 Levels in Sepsis

Same group of patients are tested with both Blood Culture (BacTalert) as well as IL-6 levels. Therefore McNemar’s (ChiSquare) test is used to evaluate whether results of these tests vary significantly from each other. It is observed that the results of both tests are not statistically significant from each other with x

2

= 0.083, p-value equal to 1.00 and degree of freedom equal to 1. There is no statistically significant difference between Blood Culture (BacTalert) and IL-6 assay (p=1). Hence use of IL-6 levels for early diagnosis of neonatal sepsis can be justified. (Table 3)

Table 3 – IL-6 Parameters: Sensitivity, Specificity, PPV, NPV and Accuracy

Sensitivity 95.83%
Specificity 87.50%
Positive Predictive Value (PPV) 92.00%
Negative Predictive Value (NPV) 93.33%
Accuracy 92.50%

Chi-square (X

2

) = 0.083, Degree of Freedom = 1, p-value = 1.00

Thus, IL-6 test has maximum sensitivity as well as specificity in comparison with other septic markers in early detection of neonatal sepsis. (Table 4)

Table 4 – Comparative Parameters: Sensitivity, Specificity, PPV, NPV and Accuracy

Tests Sensitivity Specificity PPV NPV Accuracy
CBC 37.50% 75.00% 69.23% 44.44% 52.50%
Micro-ESR 50.00% 62.50% 66.67% 45.45% 55.00%
IT Ratio 62.50% 56.25% 68.18% 50.00% 60.00%
CRP 84.21% 28.57% 51.61% 66.67% 55.00%
IL-6 Assay 95.83% 87.50% 92.00% 93.33% 92.50%

Hence, it can be concluded that IL-6 concentration increases to significant level in the patient having bacterial septicemia. IL-6 test has maximum sensitivity as well as specificity in comparison with other septic markers. Therefore, IL-6 levels can be used as an early diagnostic marker for neonatal sepsis.


SUMMARY AND CONCLUSION

  • Thus, IL-6 has shown Sensitivity of 95.83%, Specificity of 87.5%, Positive Predictive Value of 92%, Negative Predictive Value of 93.33% and Accuracy of 92.5%.
  • Neonatal mortality was seen in 4(5%) of the 80 cases studied. Of these 4 mortalities, all 4 cases showed IL-6 levels strongly positive. Hence, strongly elevated IL-6 levels, in this study, are found to be associated with bad prognosis as indicated by death.
  • The result of the present study appears to emphasize that serum IL-6 levels increases to a significant level in the patients having bacterial septicemia. The level of rise depends upon the severity of the sepsis.
  • Hence, it can be concluded that IL-6 levels can be used as an early diagnostic marker of neonatal sepsis.


ACKNOWLEDGEMENTS

Authors are thankful Dr. V. Kotrashetti for guidance during study period. We also express thanks to Mr. Dattatray Parle and Dr. Tabish Pathan for editing this study.

Funding: None

Conflict of Interest: None

Permission from IRB: Yes


REFERENCES

  1. “NNF Teaching Aids: Newborn Care” –

    www.newbornwhocc.org/pdf/

    teaching-aids/neonatalsepsis.pdf.
  2. Siegel J, McCracken G, “Sepsis Neonatarum” NEJM, 1981(304):642-646.
  3. “IMMULITE: IL-6” Manual on IMMULITE Published by Siemens Medical Solutions and Diagnostics, Los Angels, CA, USA, 2006.
  4. Saunders, B. M., Z. Liu, Y. Zhan and C. Cheers, “Interleukin- 6 production during chronic experimental infection” Immunol. Cell Biol. 1993(71):275-280
  5. Gupte S., “The Short Text Book of Paediatrics” 9

    th

    Ed., Jaypee Brothers, New Delhi, 2001:559-561.
  6. “Milenia QuickLine IL-6” Published by Milenia Biotec, USA SepsisNeoEnglish, 2005.
  7. de Bont, E., A. Martens, J. van Raan, G. Samson, W. P. Fetter, A Okken and L. H. F. M. de Lei, “Tumor necrosis factor-alpha, interleukin-1 beta and interleukin-6 plasma levels in neonatal sepsis” Pediatr. Res., 1993(33):380-383.
  8. Bhargav SK, Gupta A, Bhargav M. Bacterial Infections in Newborn. Newer Development in

    Pediatric

    [A1]
    Research 1977; 1.

  9. MirfAmans and Khan SR. Neonatal sepsis; a review with study of 50 cases.

    Journal

    [A2]
    of – Tropical Pediatrics 1987; 33(3):131-5.

  10. McCraken and Shinefield. Changes in the pattern of neonatal septicemia and meningitis. Am J Dis. Child 1966; 112:33.
  11. Faridi et

    al

    [A3]
    . Chest radiograph in neonatal sepsis. Ind.

    Ped

    [A4]
    . 1972; 29:871.

  12. Kumar GD et

    al

    [A5]
    . Bacteriological analysis of blood culture isolates from neonate in tertiary care hospital in India. J Health, Population and Nutrition, 2002; 20(4): 343-347.

  13. Chan DK and Ho LY. Usefulness of C-reactive protein in the diagnosis of neonatal sepsis. Singapore Medical

    Journal

    [A6]
    1997; 38(6): 252-5.

  14. Franz AR, et al. Reduction of unnecessary antibiotic therapy in newborn infants using interleukin-8 and C-reactive protein as markers of bacterial infections. Pediatrics 1999; 104:447-53.
  15. .Ghosh S, Mittal M, Jaganathan G. Early diagnosis of neonatal sepsis using a hematological scoring system 2000;54(9):495-500.
  16. Diwakar KK, Rosul G, “Revised Look at Micro-Erythrocyte Sedimentation Rate in Neonates” Indian

    Pediatrics

    [A7]
    1999; 36:703-705.

  17. Silveira RC, Procianoy RS, “Evaluation of interleukin-6, tumour necrosis factor-a and interleukin-1 for early diagnosis of neonatal sepsis” Acta. Paediatr ,1999(88): 647-650.
  18. Renato S. Procianoy, Rita C. Silveira, “The role of sample collection timing on interleukin-6 levels in early-onset neonatal sepsis” J Pediatr (Rio J), 80(5):407-10, 2004.


[A1]
AS ABOVE


[A2]
BBR


[A3]
ET AL ONLY IF THERE ARE MORE THAN SIX AUTHORS, PLEASE CHECK


[A4]
CORRECT AS ABOVE; NO FULL STOPS AND CORRECTLY ABBREVIATED NAMES OF JOURNALS.


[A5]
CHECK ET AL


[A6]
Sing Med J


[A7]
Abbr??

Nursing as a profession- science- and discipline

/in /by

Instructions:

Nurse scholars have claimed that nursing is both a discipline and a profession. In order to understand these claims, we must first know what it means for nursing to have a “unique body of knowledge.” If we assume that nursing does, indeed, possess a unique body of knowledge, we can claim that nursing is a “basic science” rather than an “applied science.” Despite these claims, debate continues about nursing as discipline, profession, and science. Is nursing a discipline? A profession? Is nursing a basic science and/or applied science? In your initial post, state what you think about nursing as discipline, profession, and science. Explore the literature beyond that assigned to you for this week’s readings to help you formulate your position. You should include the following:

What is a discipline? What is a profession? What’s the difference? What are examples of each?

Does nursing fit the criteria for a “discipline” and “profession”?

What is a “basic science”? What is an “applied science”? What’s the difference?

Is nursing a “basic” or “applied” science?

Support your statements with scholarly references. You may use those from the assigned readings for this module, but you must also select and use (via your literature search) a minimum of one scholarly reference outside of assigned readings in your initial post.

Present your posts and replies in a professional, scholarly manner. Use the APA publication manual to format citations and references.

Use 3 scholarly articles within the past 5 years

WRITE 1–3 SENTENCES IN EACH CELL OF THE TABLE (SEE ATTACHED FILE) DESCRIBE THE IMPORTANCE, GOAL, OR INFLUENCE OF EACH ITEM.

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WRITE 1–3 SENTENCES IN EACH CELL OF THE TABLE (SEE ATTACHED FILE) DESCRIBE THE IMPORTANCE, GOAL, OR INFLUENCE OF EACH ITEM.

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There have been many influential publications, agencies, and people in the field of nursing research. Write 1–3 sentences in each cell of the table (SEE ATTACHED FILE) describe the importance, goal, or influence of each item.

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Therapeutic goals and how you would decide upon goals

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Therapeutic goals and how you would decide upon goals

Career Counseling- Outline for Sessions

Required Materials:
Zunker, V.G. (2016). Career counseling: A holistic approach (9th ed.). Pacific Grove, CA: Brooks/Cole Publishing Company.

PLEASE REFER TO TEXTBOOK

ASSIGNMENT DETAILS:

Three Sessions of Career Counseling
• Develop a three-session outline. Your paper should deal with aspects such as: • key concepts of your approach • view of your role as a counselor • therapeutic goals and how you would decide upon goals • relationship issues you are likely to consider • central techniques you are likely to employ • how you would address issues of cultural diversity
• I suggest you take a primary theory (one that comes closest to your beliefs and your theory of choice from textbook) and develop your outline based on it. Be sure to explain why you selected a particular theory as your main theory.

: Social and Cultural Diversity Issues and Co-Occurring Disorders.Some clients ask clinicians to share details of their daily life or history. How would you answer these queries? Do you believe that more or less self-disclosure is appropriate? Why?

/in /by

: Social and Cultural Diversity Issues and Co-Occurring Disorders.Some clients ask clinicians to share details of their daily life or history. How would you answer these queries? Do you believe that more or less self-disclosure is appropriate? Why?

As a counselor, why is it important to consider the client perspective in a counseling session? Reflect on your previous learning in your Social and Cultural Diversity Issues and Co-Occurring Disorders courses as you respond to this question. Share your insights with your classmates.

Many times, clients have waited a long time to come into counseling due to feelings of fear of the unknown or fears of disclosing. In what ways can counselors overcome client apprehension in the counseling session? Identify ways in which you can help build a healthy client/therapist relationship. What type of client may challenge you the most? Share your insights with your classmates.

A stone falls from rest from the top of a cliff. a second stone is

/in /by

A stone falls from rest from the top of a cliff.

A second stone is thrown downward from the

same height 3.4 s later with an initial speed of

66.64 m/s. They hit the ground at the same

time.

How long does it take the first stone to hit

the ground? The acceleration of gravity is

9.8 m/s2 .

Answer in units of s

Cost-Effectiveness Analysis of Breast Cancer Treatments

/in /by


Cost-Effectiveness Analysis of Pertuzumab With Trastuzumab and Chemotherapy Compared to Trastuzumab and Chemotherapy in the Adjuvant Treatment of HER2-Positive Breast Cancer in the United States


Introduction

Throughout the past decades, burden of cancer has increased globally. As per WHO report in 2018, the burden has risen to 18 million new cases diagnosed and almost 9.6 million deaths. From each six females, one would develop cancer and from each 11 females, one would die from cancer. The most commonly diagnosed cancer in females is breast cancer (24.2%), as well as the leading cause of cancer deaths in females (15%).

Since the introduction of anti-HER2 therapies, there has been noticed a great improvements in survival for patients with HER2 positive breast cancer in both early and advanced states. Use of combinations of anti-HER2 therapies has been studied in different clinical trials, and it is suggested that these combinations can potentially improve outcomes however, in some patients may also allow de-escalation of therapy and sparing needless therapies with their related side effects and costs. In this essay, we will review a recently published economic evaluation for combination of Pertuzumab with Trastuzumab and chemotherapy against Trastuzumab and chemotherapy (Pernas & Tolaney, 2019).


Study Overview and Recommendation:

There are four HER-2 targeting therapies and Pertuzumab is one of them. When used alone, it has limited activity with Trastuzumab-resistant patients. When used in combination with Trastuzumab and chemotherapy, complementary effect is noticed. Based on that, it is recommended by the National Comprehensive Cancer Network (NCCN) guidelines to use dual HER-2 targeting therapies (Pertuzumab + Trastuzumab) (Garrison et al., 2019).

Several studies have been conducted to demonstrate the extra benefit of using duo HER-2 therapies. In Cleopatra, using the duo plus docetaxel (TPH) resulted in improved overall survival by 15.7 months versus the use of Trastuzumab with chemotherapy (TH). In APHINITY, treatment of HER-2 positive in early breast cancer was evaluated using TPH and TH. When 4-year invasive-disease-free survival, was evaluated, it was shown to be 90.6% in TPH arm compared to 92.3% in the TH arm. This study had three subgroups; ITT population, node-positive tumors and hormone receptor negative tumor, where there was risk reduction of recurrence or death compared to control arm (Swain et al., 2015).

The objective of this economic evaluation was clearly mentioned in the title “Cost-Effectiveness Analysis of Pertuzumab With Trastuzumab and Chemotherapy Compared to Trastuzumab and Chemotherapy in the Adjuvant Treatment of HER2-Positive Breast Cancer in the United States”. The perspective is also clearly mentioned targeting US payers and different stakeholders to facilitate decision making of the new treatment coverage and reimbursement. The Markov model was built to cover six different health states: invasive-disease-free survival, non-metastatic recurrence, remission, first line metastatic, subsequent line metastatic and death. Primary outcomes of the model were life-years (LY), quality-adjusted life years (QALYs) and ICERs (Garrison et al., 2019)

For the results, they detailed them into the three subgroups; ITT population, where the analysis projected improved outcomes by 0.5 LYs and 0.45 QALYs and increased costs for ICERs of 147,774$/LY gained and 167,185$/QALY gained for THP versus TH patients respectively. Second group was the node positive patients, where the analysis projected improved outcomes by 0.86 LYs and 0.76 QALYs and increased costs for ICERs of 77,684$/LY gained and 87,929$/QALY gained for THP versus TH patients respectively. Third group was the hormone receptor negative patients, where the analysis projected improved outcomes by 0.52 LYs and 0.47 QALYs and increased costs for ICERs of 147,022$/LY gained and 166,518$/QALY gained for THP versus TH patients respectively (Garrison et al., 2019).

They used 50,000$ as the lower limit and 200,000$ as the upper limit for cost-effectiveness, and mentioned briefly that these results were most sensitive to time horizon. Accordingly, they concluded that addition of Pertuzumab to standard therapy of TH in high risk of recurrence HER-2 positive early breast cancer patients would

“likely”

be cost-effective (Garrison et al., 2019).

Looking at clinical evidence, it is clear that there is an added benefit when adding Pertuzumab to TH, however there is an uncertainty about the size of this clinical benefit. The trial shows that 1.7% fewer patients had invasive disease at 4 years using Pertuzumab as adjuvant (in the ITT group). Whereas there was much better evidence for patients with node positive disease with 3.2% fewer patients had invasive disease at 4 years using Pertuzumab as adjuvant. With these results, it would be difficult to assume whether overall survival is better when using Pertuzumab as adjuvant (NICE appraisal, 2019)

There is an argument whether disease-free survival can be a substitute to overall survival in those high-risk patients, where in most recent studies the use of invasive-disease-free survival has been widely accepted. Despite the fact that there might be a 10% difference in outcomes between invasive-disease-free and disease-free survival, it is acknowledged that obtaining overall survival data would be challenging for adjuvant treatments. Based on the APHINITY, patients with node positive HER-2 as well as patients with residual disease after neo-adjuvant chemotherapy are likely the most benefited from addition of Pertuzumab, despite the trial was not intended to evaluate treatment outcomes in different subgroups of interest. It is also worthwhile mentioning that these benefits shown in APHINITY trial are very similar to that in ALLTO trial, when Lapatinib was added to adjuvant Trastuzumab and chemotherapy, which showed a hazard ratio of 0.84 (Stanton & Davidson, 2017).


Additional information needed:

Apart from APHINITY, it would have been useful to use other studies like Cleopatra in the analysis, to cover different populations and to consider different permutations of second and third line therapies. In this analysis, Pertuzumab was compared to placebo, which would have been more robust if compared with other HER-2 targeting therapies (Durkee et al., 2016). Basing all assumptions on a single trial would fail to take into consideration different factors like selection bias, different demographics, patients’ variations and probability in staying in each stage (Miller, 2017).

There was un-clarity in the model on the cost effectiveness threshold used on US. Back in 2010, Permera Blue cross has developed a guidance on a value based drug formulary tiers based on ICERs. This was developed because of rising premiums and concerns about affordability of higher value therapies and it has four Tiers where Tier 4: (ICER >$150,000/QALY) – insufficient evidence. Rare conditions with no effective treatments were considered special cases (Dubois, 2016).

Based on literature, policymakers will have to consider the research; however, they would also need to balance population level assessments with individual patients’ needs. The question is whether cost-effectiveness thresholds are likely to come to US and be of wider use. One of the points that was not covered in this study was the mode of administration of Pertuzumab, which is administered intravenously, while Trastuzumab is administered subcutaneosly. Accordingly, Trastuzumab has to be administered intravenously and patients has to stay more time at the hospital and incur extra costs. Furthermore, the use of bio-similar of Trastuzumab would steeply affect the results and show much better cost-effectiveness. (NICE appraisal, 2019)


Key data sources used:

In this model, different data sources were considered, however results were mainly based on APHINITY trial. They referenced

National Comprehensive Cancer Network (NCCN) guidelines,

for the use of dual HER-2 targeting therapies. They also used

Akaike Information Criterion (AIC)

and the

Bayesian Information Criterion (BIC),

in addition to conformity tothe original

Kaplan-Meier

survival curves, to assess the log-logistic distribution for the base-case analysis. Recurrence rates were adjusted using

HERA and BCIRG-006 studies

(Garrison et al., 2019).

To make sure model has resulted in valid death rates matching the general population mortality, they used

US life tables. Hamilton et al.

study was used to measure the probabilities of transition between the remission state and the first line metastatic breast cancer.

Cleopatra

trial was used to evaluate the monthly probability of progression in metastatic breast cancer. They used

Average Sale Price (ASP)(Genentech data)

for Pertuzumab and Trastuzumab costs while costs of other chemotherapy drugs were gathered from

Centers for Medicare and Medicaid (CMS) Average Sales Price in 2017(ASP).

They have assumed that patients who advanced into local recurrence will receive an additional round of adjuvant treatment, for the purpose of cost estimation. They used published literature to estimate end of life healthcare costs (Garrison et al., 2019).


Quality of Life Data:

The main objective of the analysis is to compare the outcomes of the TPH arm compared to TH arm and reflect that on life years (LYs) and quality adjusted life years (QALYs). Utility values were estimates from APHINITY trial where they used EQ-5D to gather patient reported outcomes. Utilities estimates were calculated separately for patients whether on or off treatments and across different disease states. They also used published literature to generate utilities for metastatic states (Garrison et al., 2019).

These estimates were then used to calculate utility values for patients and health states based on a specific scoring mechanism, which was gathered from a survey on the non-institutionalized general population in the US. Furthermore, the model took into consideration, long-term utilities of patients in general population to account for increased comorbidity with age. A limitation for this survey is that it is not a robust source (Garrison et al., 2019).


Comparators, outcomes and Model:

In this analysis, despite the fact that the dual HER-2 therapies is recommended by guidelines, there are some other therapies like Lapatinib were not mentioned in the analysis, which may have had very similar outcomes. In general, comparators and outcomes were well detailed either clinical outcomes for the APHINITY or economic outcomes of cost-effectiveness per subgroup of patients.

Markov model was used and an illustrative figure was presented to show the six states and transition in each state. Authors did not explain the reason behind choosing Markov model neither they explained other modelling choices. Of course, all models are just simplification of the reality and the main objective of such models is to facilitate decision-making. May be it would have been more robust if they used a Markov model using TreeAge Pro software (TreeAge,Williamstown, MA), like the one used in the paper of CEA of Cleopatra (Durkee et al., 2016).

Authors had a conservative assumption, assuming that Pertuzumab treatment effect would last for 7 years and totally fade away at 10 years. It was considered conservative since authors neglected the fact of observed efficacy of Trastuzumab in adjuvant setting and Pertuzumab in metastatic setting. Accordingly predicting treatment effect duration would be impossible given the uncertainty in estimation of treatment benefit (Garrison et al., 2019).


Uncertainty:

In the model, based on the trial extrapolation that the risk of recurrence would drop to 10% if the patients were disease-free after 120 months, in both treatment arms. As mentioned by the authors, when performing a univariate sensitivity analysis, ICERs for ITT patients, node-positive patients or hormone-negative population were most sensitive to time horizon of the model (variation from 25-52 years) as well as the timing of onset of increasing cure proportion (variation from 48-120 months). For example, at a time horizon of 25 years, the ICER of node-positive patients increased by almost 35% (Garrison et al., 2019).

Authors have also worked on a probabilistic sensitivity analysis to show proportion of simulations that treatment with PTH was cost-effective. At a willingness to pay of $162,500, cost-effectiveness acceptability curve for the ITT patients in PHT and TH arms were cost-effective. If a threshold of $150,000/QALY was considered, only 45% of simulations would show that PHT is more cost-effective than TH. Based on that, it would be very difficult to draw a conclusion, because of the uncertainty of clinical effectiveness across the three subgroups, where the maximum benefit was shown in node-positive patients (Garrison et al., 2019).


Discounting:

Costs and outcomes was discounted at 3% per annum, and they referred to Cortes J paper, which has not shown a clear rationale why these figures were selected. The US Panel and Cost-Effectiveness in Health and medicine proposed 3% as a discount rate given the fact that QALY is not stable over time. On the other hand, Paulden et al argued that 3% discount rate is quite high, especially from healthcare perspective (Attema, Brouwer, & Claxton, 2018).

If discount rates for both costs and outcomes were not the same, it could have impacted the overall study results. Discount rates were not considered in sensitivity analysis, which is a limitation for this model. Based on Discounting article, that department of health is recommending that health benefits should not be discounted however many others argue that discounting health benefits should be as low as 1.5-2.5%. In most economic evaluations, choice of different discount rates will not only affect the final result of the analysis, it might also mislead decision makers. It is a good practice to evaluate the outcomes of using different discount rates using a sensitivity analysis (which is a limitation of this analysis) (Attema, Brouwer, & Claxton, 2018).


Future research:

As mentioned by the authors, a limitation of the analysis is the extrapolation of clinical trial data to a lifetime horizon, where there is uncertainty whether there is an additional benefit after the follow up period. In other words, the median follow up period in the clinical trial was 45.4 months, however the model projected a treatment effect of up to 84 months and reaching zero effect at 120 months where they relied on data from HERA and BCIRG-006. Accordingly, long-term efficacy data is needed from ongoing follow up of the APHINITY to estimate the cost-effectiveness of Pertuzumab as well as longer follow-up on the adverse-events profile (Garrison et al., 2019).

Another direction is focusing more on less-intensive therapies and searching for predictive biomarkers (including immunological markers) that would identify patient population benefiting from therapies, through randomized larger studies (e.g. ongoing trial (NCT01037117) to evaluate value of PET-CT in prediction of PCR to Peruzumab and Trastuzumab in HER2+ patients). Up until now, there is very limited data on identifying biomarkers in response to anti-HER therapies. Furthermore, with the satisfying outcomes of the standard therapy, additive therapies are expected to show limited benefits in general population (Stanton & Davidson, 2017).


External Validity:

(Mahmoud) Based on how authors presented the results, this model can be applied for US payers, with very limited external validity in other countries. The model setup, design, methodology followed and perspective can be valid in other countries, however other countries cannot take decisions or build assumptions based on these results unless they considered localizing some elements. Interventions vary in price, so costs should be localized (treatments, administrations, adverse events and utility costs). Which standard of care used and whether they use the brand or its biosimilar can be an element. EQ-5D estimates should be obtained from a more robust source since benefits and costs accrue differently to different constituents (patients, physicians, caregivers and society) (Durkee et al., 2016)


Conclusion:

In conclusion, there is a massive role on oncologists on how to advise their patients on different treatment options given their clinical effectiveness, safety and tolerability profile, economic burden and patients’ preferences for risk tolerance (Garrison et al., 2019). Based on the data presented, Pertuzumab seems to be cost-effective only in node-positive HER2+ patients with debatable cost-effectiveness in other subgroups. Further long-term data is needed with a follow up on safety and tolerability profile to be able to draw a conclusion of the most appropriate approach to use Pertuzumab.




References:


  1. Attema, A. E., Brouwer, W. B. F., & Claxton, K. (2018). Discounting in Economic Evaluations.

    PharmacoEconomics

    ,

    36

    (7), 745–758.


    https://doi.org/10.1007/s40273-018-0672-z
  2. Dubois, R. W. (2016). Cost–effectiveness thresholds in the USA: are they coming? Are they already here?

    Journal of Comparative Effectiveness Research

    ,

    5

    (1), 9–12.


    https://doi.org/10.2217/cer.15.50
  3. Durkee, B. Y., Qian, Y., Pollom, E. L., King, M. T., Dudley, S. A., Shaffer, J. L., … Horst, K. C. (2016). Cost-Effectiveness of Pertuzumab in Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer.

    Journal of Clinical Oncology

    ,

    34

    (9), 902–909.


    https://doi.org/10.1200/JCO.2015.62.9105
  4. Garrison, L. P., Babigumira, J., Tournier, C., Goertz, H.-P., Lubinga, S. J., & Perez, E. A. (2019). Cost-Effectiveness Analysis of Pertuzumab With Trastuzumab and Chemotherapy Compared to Trastuzumab and Chemotherapy in the Adjuvant Treatment of HER2-Positive Breast Cancer in the United States.

    Value in Health

    ,

    22

    (4), 408–415.


    https://doi.org/10.1016/j.jval.2018.11.014
  5. Miller, K. D. (2017). Questioning Our APHINITY for More.

    New England Journal of Medicine

    ,

    377

    (2), 186–187.


    https://doi.org/10.1056/NEJMe1706150
  6. NICE appraisal, Pertuzumab for adjuvant treatment of HER2-positive early stage breast cancer. Technology appraisal guidance, 20 March 2019


    www.nice.org.uk/guidance/ta569
  7. Pernas, S., & Tolaney, S. M. (2019). HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance.

    Therapeutic Advances in Medical Oncology

    ,

    11

    , 175883591983351.


    https://doi.org/10.1177/1758835919833519
  8. Stanton, S. E., & Davidson, N. E. (2017). What lies beyond APHINITY for HER2-positive breast cancer?

    Nature Reviews Clinical Oncology

    ,

    14

    (12), 715–716.


    https://doi.org/10.1038/nrclinonc.2017.125
  9. Swain, S. M., Baselga, J., Kim, S.-B., Ro, J., Semiglazov, V., Campone, M., … Cortés, J. (2015). Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer.

    New England Journal of Medicine

    ,

    372

    (8), 724–734.


    https://doi.org/10.1056/NEJMoa1413513
  10. WHO report, 2018, Online GLOBOCAN 2018 database, accessible at http://gco.iarc.fr/, part of IARC’s Global Cancer Observatory.

Scenario: An 83-year-old resident of a skilled nursing facility presents to the emergency department with generalized edema of extremities and abdomen. History obtained from staff reveals the patient

/in /by

Scenario:

An 83-year-old resident of a skilled nursing facility presents to the emergency department with generalized edema of extremities and abdomen. History obtained from staff reveals the patient has a history of malabsorption syndrome and difficulty eating due to lack of dentures. The patient has been diagnosed with protein malnutrition.

Post an explanation of the disease highlighted in the scenario you were provided. Include the following in your explanation, usually a paragraph with citation(s) should suffice to cover each point. Citations would reflect classroom textbook, primary, current peer-reviewed journal articles (published in last 5 yr) usually, 3 will support your points.

  • The role genetics plays in the disease.
  • Why the patient is presenting with the specific symptoms described.
  • The physiologic response to the stimulus presented in the scenario and why you think this response occurred.
  • The cells that are involved in this process.
  • How another characteristic (e.g., gender, genetics) would change your response.

Alzheimers Disease Research on the Effects of Exercise

/in /by

Alzheimer’s Disease is a disease that affects the nervous system, specifically the brain. It is a disease that attacks the connective tissues in the brain, causing the tissue to die and affecting how the brain functions. The brain shrinks naturally with age, but typically does not lose a large number of neurons. In Alzheimer’s disease the neurons lose connections with other neurons; the connections are usually destroyed in parts of the brain that are used in memory function such as the hippocampus and the entorhinal cortex. The formation of amyloid plaques and neurofibrillary tangles are a cause to the degeneration of the neurons. The disease then wide spreads to the cerebral cortex, which is in control of speech, reasoning, learning and social behavior. Eventually a person with Alzheimer’s loses their ability to live independently. Because Alzheimer’s is a disease that cannot be cured, actions such as integrating more social contact and changing lifestyle patterns could delay the progression of the disease or even help prevent it.

Alzheimer’s disease takes place in the central nervous system (CNS), which contains the brain, spinal cord, and neurons. In the CNS, the brain is responsible for most of the sensory information and coordination in the body both conscious and unconscious. The brain takes on complex actions like thinking and feeling. There are two types of tissues in the brain, grey and white matter. Grey matter consists of the nerve cell bodies, dendrites and axons. The white matter mostly consists of axons. The hypothalamus is critical for homeostasis in the brain and the body’s internal environment. The cerebrum is responsible for the brains conscious sensations and voluntary movement and also functions like thinking, learning, problem solving and emotion (Newman, 2017). It is no wonder that the symptoms of Alzheimer’s disease affect memory and cognition.

Amyloid plaques are said to be a direct cause of neuron death. Amyloid is a term for the protein fragments that the body produces naturally. Alzheimer’s disease is the accumulation of these proteins between nerve cells, specifically the beta amyloid fragments. Normally the beta amyloids are broken down in a healthy brain, but in a diseased brain the pieces form together and create hard plaques that cannot

be broken down. Neurofibrillary tangles are hard twisted fibers found in the brain cells these tangles form a microtubule. In a healthy brain the microtubules help transport nutrients to other nerve cells, but in a brain with Alzheimer’s the microtubule structures are collapsed. It is not known if the formation of these plaques and neurofibrillary tangles are the earliest form of the disease process and their role in the direct

Normal Beta-amyloid vs. Alzheimer’s Beta-amyloid Kwon, D. (2018, July 24)

Cause of the disease is controversial (Hardy, 2013).

Oxidative stress causing neuroinflammation is thought to play a large role in a number of central nervous system disorders including Alzheimer’s. The microglia function is necessary for the brain’s homeostasis and the microglia show exaggerated responses to systemic inflammation, which impairs cognitive function (D’Avila, 2018). The Microglia are key in the brain’s immune system and are a first line of defense in neuronal insults (Suridjan, 2015). Neuroinflammation is thought to progress the disease by increasing the build up of beta amyloid plaques and causes the neurodegeneration of microglial activation. The release of these inflamed cytokines reduce the clearance of the beta amyloid plaques and increases its production (Alasmari, 2018). Tangle formations directly result in the deprivation of the hippocampus and the entorhinal cortex.


Aging is a natural process that affects the brain and cognitive decline as well as function and social impairments. It is normal to see decline in the hippocampal function in memory consolidation and also behavior and mood regulation. In fact, oxidative stress, neuroinflamation, altered intracellular signaling; reduced synaptic plasticity and altered gene expression are believed to be natural processes of the aging brain (Bettio, 2017). The hippocampus is a part of the brain the directly correlates with memory and when, in a diseased state, such as a brain with Alzheimer’s, the hippocampus is affected mostly in size. The hippocampus is located under the medial temporal lobes. The hippocampus’ job is to help us make new memories and be able to retrieve old memories in the long-term memory bank. Research shows that the hippocampus is one of the first areas affected by Alzheimer’s. The hippocampus shrinks and atrophies which causes the impairment of developing new memory and recalling old memory. Image analysis of the hippocampus has recently become an interest in diagnosing Alzheimer’s through MRIs. This allows professionals to see the hippocampal shapes and the symmetry and volume. Volumetric variations are one of the primary indicators in differentiating a healthy aging brain and a diseased brain (Suksuphew, 2017).

Healthy brain vs. shrinking brain in advanced Alzheimer’s disease. Alzheimer’s Brain. (2017).

The entorhinal cortex is located in the medial temporal lobe and is in charge of memory, navigation and perception of time, which can be damaged in the progression of Alzheimer’s disease. In recent studies the volume of the entorhinal cortex has been tested along side the size of the hippocampus in healthy aging adults and adults with early onset of Alzheimer’s disease. The results, through imaging, based on postmortem studies, concluded that the entorhinal cortex is the first site and location that the disease occurs and then moves on to the hippocampus. This study was conducted with patients with mild cognitive impairment and not all mildly impaired individuals have Alzheimer’s disease (Suksuphew, 2017). The destruction of the hippocampus and entorhinal cortex in the progressive disease is the cause of memory deficiency at higher rates than normal or healthy aging in the brain.

The general stages of Alzheimer’s disease can vary in different patients and can vary over the time period in which it progresses. The first 2-7 years are mild stages of the disease. In the first stage, there is usually no impairment and the patient seems to have normal cognition; typically other people don’t notice. Stage two has a mild cognitive decline such as forgetting words or misplacing things. Stage three consists of early confusion and mild impairment. This is usually when patients try to hide their symptoms; they cannot recall what was just said, and they have problems planning. Stage three is usually when the symptoms of Alzheimer’s starts to have an affect on daily living. Stage four is considered mild Alzheimer’s disease and lasts about 2 years. In these two years, financials and math start to become difficult and the ability to remember events or recall memories is a challenge. The patient may have issues performing tasks that require stages like cooking or driving. A diagnosis at this stage is usually accurate. Stage five is moderate Alzheimer’s disease. Cognitive decline becomes more drastic, the patient is more likely to become disoriented and need assistance. This is usually the stage where decision making and reasoning is affected. In stage six, the patient is considered to have moderately severe Alzheimer’s, where they have lack of awareness and ability to remember the past and cannot carry on a conversation. Basic daily tasks will be something that the patient will now need help in and remembering names of family members is rare. Stage seven is the final stage of progressive Alzheimer’s and it is considered sever. Speech becomes limited and even movement becomes limited and difficult because the disease has spread to those parts of the brain. Total assistance is necessary at this stage because the patient will no longer be able to discern when they are hungry and thirsty and no longer be able to carry out the daily living tasks. Not all patients will experience these stages in this timeline or even time period (Marshall, 2018).


Memory isn’t the only symptom of Alzheimer’s though; social behavior and social cognition are also impaired in the progression of the disease. Patients with Alzheimer’s disease are typically not able to socialize like a healthy aging person. They’re confused and less trusting and mood swings are a part of their disease. Being as it is that the cerebral cortex, which is directly affiliated with emotion, is affected in Alzheimer’s, it is not surprising that patients suffer social disabilities. In a recent study, twenty-seven patients with Alzheimer’s and their significant others were studied in their relationships and how the disease affects the interaction between the partners. Because patients with the disease have severe deficits with emotional processing and emotional recognition the relationships started to suffer causing changes in social behavior and being apathetic towards the other. Behavior changes such as apathy, and agitation in participants with dementia were significantly related to relationship continuing (Poveda, 2017).

Some studies have shown that social environment and social relationships can affect a patient’s behavior and mental health. There has been a study that analyzed the correlation between loneliness and the risk of developing Alzheimer’s disease and the progression of it as well. The study revealed that people who were lonely had higher risks of developing the disease compared to other people who were not lonely. It was also shown that the disease progression in cognitive decline could be prevented and even delays the onset of the disease if patients keep mentally active and frequently participate in social activities. Social isolation exasperates cognitive impairment and memory and also causes psychosocial stress, which in turn increased oxidative stress and inflammatory reactions in the brain. Social isolation aggravates Alzheimer’s associated memory decline (Hsiao, 2018).

Social isolation in Alzheimer’s disease. Institute. (2016, April 21).

Social interaction rescues Alzheimer patients’ memory by increasing Brain-derived neurotropic factor (BDNF). The BDNF increases synaptic plasticity and enhances cognitive function; it also decreased depressive episodes in patients (Hsiao, 2018). Clinicians and medical reports advise us that patients can reduce the cognitive rundown and delay the onset of the disease by maintaining strong social connections and frequent activities. An easy intervention to the memory decline in patients is to have daily meetings either with family members, or if in a facility, with members of the community. Doing activities such as card games or talking or listening to music in the company of other human beings can delay the progression of the disease.               Alzheimer’s disease inhibits the ability to communicate or participate in social interaction and as a consequence can cause a feeling of loneliness and isolation. Research as shown that constant isolation and social depression can cause hallucinatory experiences, which is a frequent happening in patients with the disease. To test this hypothesis that social isolation causes depression and hallucinations, a sample of twenty-two patients with mild Alzheimer’s and twenty-four healthy elderly participants were assessed using the Launay-Slade Hallucination Scale. The scale explores contact and social participation. The Results showed that more hallucinatory experiences and social isolation were found in the Alzheimer’s group as apposed to the healthy group of elders. The discussion following the study between researches suggested that the hallucinations were a mechanism to fulfill communication needs and escape a cycle of boredom (El Haj, 2016). Verbal play early on in the beginning stages of Alzheimer’s such as creative language to make puns, jokes, and rhymes could help maintain speech abilities as the disease progresses. Speech therapy throughout the disease could help prevent the impact of social isolation the disease leaves on the patient, which in turn could prevent or lower the hallucination rate (Shune, 2013).

Though a disease like Alzheimer’s is irrevocable, lifestyle interventions like diet and exercise have played a large role in the prevention and slowing of the progression. Specific dietary patterns such as the Mediterranean diet, which is based on the high consumption of omega-3 fatty acids and polyphenol-rich foods such as olive oil, nuts and vegetables and fruits has been associated with a reduced risk in cognitive decline. In Japan, Alzheimer’s has greatly increased due to the incorporation of the western diet as compared to the normal diet of fish and vegetables. To test these outcomes, two pilot studies have reported outcomes from individual lifestyle interventions consisting of high nutrient and low carbohydrate diets, resulting in a reduction of the Alzheimer’s symptoms based on neuropsychological tests and neuroimaging (D’Cunha, 2017).

Another aspect of nutrition is micronutrients. Research has shown that micronutrients such as a vitamin B-12, vitamin D and folic acid are pivotal in brain function and mental and emotional health as adult’s age. In a cross sectional study done with adults age 60-75 over 17 months, proved that the deficiency in these vitamins have a positive correlation in the serum evaluated in the study in patients with senile dementia of Alzheimer’s Type. One hundred and ten patients suffering from the disease were evaluated. Two groups were studied. One group of 110 patients was given the supplements and another group of 55 patients were given a placebo. The results in the serum were higher by average in the group given the supplementation by 23% as compared to the control group. The study concluded that adults who were deficient in vitamin D, vitamin B-12, and folic acid were at higher risk of senile dementia of Alzheimer’s type than those who supplemented the vitamins (Vashistha, 2018). Adding simple supplementation of vitamins and micronutrients is an easy way to prevent Alzheimer’s disease, enhance brain function and help aid healthy aging in the brain.

Not only is diet and micronutrients an important to nutrition when it comes to nuerodegenerating disease like Alzheimer’s, but also implementing calorie restriction. In laboratory animals, such as rats, calorie restriction was proven to protect against aging, oxidative stress, and neurodegenerative pathologies. Reduced levels of growth hormone, which mediate some of the positive effects of a calorie restricted diet, can also extend longevity and protect against the neurodegenerative diseases in the rodents and even humans. Severely restricted diets were difficult to maintain and are associated with chronic low weight and major side effects such as bone mass decreasing. The study with laboratory rodents showed four months of periodic protein restriction and supplementing essential amino acids showed significant cognitive improvement with the mice already displaying impairment. This study showed that implementing a protein restricted diet on cycles would protect against age-related neuropathology (Parrella, 2013). Reducing the amount of meat a person intakes drastically changes the amount of calories put into the body. There are not many interventions that have been proven to significantly change results incurred with Alzheimer’s, except for calorie restriction and exercise.


There have been numerous large cohort studies that have been conducted that indicated that physical activity or exercise could enhance cognitive function and delay the onset of Alzheimer’s disease and other dementias. Preventative strategies have been the only way to help the disease since a cure has not been found. Therapeutic trials focusing on the effects of physical activity and exercise and how the factors are associated with healthy brain aging is a way to investigate these preventative strategies. The evidence from the epidemiological studies have found better reaction time in older men who participate in racket sports, such as tennis or running compared to men who have sedentary lifestyles. Verbal memory, executive functioning and attention were all categories that active aging men scored higher in. There have not been any follow up studies on whether the amount of physical activity and exercise is correlated with the amount of cognitive domains; however, in contradiction to the theory that the amount of time does not correlate to the domains in cognition, a study that used an exercise questionnaire on 1324 subjects and it was found that light, not vigorous exercise at mid- life to late-life was associated with reduced risk of memory impairment (Brown, 2013).

Senior Fitness: A Key to Healthy Aging. (2013, November 25)

In a study that supervised the aerobic activity on an exercise program over six months, 68 individuals with early onset of Alzheimer’s were tested to see if their cognition improved. The study was randomized and monitored by trained exercise specialists. The program consisted of 150 minutes of aerobic exercise a week versus non-aerobic stretching and toning control intervention. Neuropsychological tests were conducted at the start, the thirteenth week and the final week to access memory and functional ability and depressive symptoms. The aerobic exercise was associated with a slight gain in functional ability compared to the group that did non-aerobic activity and analyses revealed that enhancing cardiorespiratory fitness positively correlated with memory performance and hippocampus volume. The conclusion of this study was that cardiovascular exercise might be an important key in brain benefits and reduced hippocampal atrophy (Morris, 2017).

Based on research and findings with exercise and Alzheimer’s disease, a healthy intervention with early onset Alzheimer’s is to take up a passive sport for recreation or to introduce cardiovascular exercise as a part of daily routine. Depending on age and ability to move, walking briskly everyday for twenty- five minutes could also be a great way to supplement for exercise. In the later stages of Alzheimer’s walking may be the only physical activity a patient can take on. It takes activity in the brain to make functional movement or any physical activity at all, which could suggest why activity improves verbal memory, executive functioning and attention.

In conclusion, Alzheimer’s disease is incurable. It affects the regions of the brain such as the entohrinal cortex, the cerebral cortex (temporal lobes) and the hippocampus. The main findings and diagnosis are based on size and atrophy of these areas. Another root cause to the disease is the beta-amyloid protein plaques building up and blocking nerve cells in the brain and causing them to die off. Alzheimer’s is a disease affects people at different rates and progresses in patients uniquely. The disease has affected more people presently than ever in the past due to the longevity of age now; its rapid incline in the population has left health experts with no choice but to find a cure. It leaves patients and peoples no choice, but to be proactive and implement interventions into their daily living. In the researched findings, the earlier an individual changed their lifestyle behavior, the less likely they were to experience cognitive decline early on. Social behavior is a major debilitation in the disease and can be taken into account in preventative way such as joining a social group and aging alongside people of the same age as well as setting up patient’s with Alzheimer’s with a group of people on a regular basis and implementing a speech therapist. Changing lifestyle such as diet and exercise are great ways to age healthily and take care of the brain by giving it proper nutrients and oxygen.


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