Programmed cell death 50 (and beyond)

In the 50 years since we described cell death as ‘programmed,'' we have come far, thanks to the efforts of many brilliant researchers, and we now understand the mechanics, the biochemistry, and the genetics of many of the ways in which cells can die. This knowledge gives us the resources to alter the fates of many cells. However, not all cells respond similarly to the same stimulus, in either sensitivity to the stimulus or timing of the response. Cells prevented from dying through one pathway may survive, survive in a crippled state, or die following a different pathway. To fully capitalize on our knowledge of cell death, we need to understand much more about how cells are targeted to die and what aspects of the history, metabolism, or resources available to individual cells determine how each cell reaches and crosses the threshold at which it commits to death.     

Family Preference for Place of Death Mediates the Relationship between Patient Preference and Actual Place of Death: A Nationwide Retrospective Cross-Sectional Study

Background

Discrepancy between preferred and actual place of death is common in cancer patients. While previous research has elucidated the factors associated with congruence between patients'' preferred and actual place of death, it is not known how the perspective of the family influences the place of death. This study examined whether family preference for place of death mediates the relationship between patient preference and actual place of death.

Methods

A total of 258 cancer patients (home death, n = 142; hospital death, n = 116) who had received terminal care in Japan were analyzed. Measures included patients'' demographic variables, patient and family preferences for place for death, actual place of death, patients'' functional status, use and intensity of home care, availability of inpatient bed, living arrangement, and amount of extended family support.

Results

Patient-family congruence on preferred place of death was 66% in patients who died at home and 47% in patients who died at other places (kappa coefficient: 0.20 and 0.25, respectively). In a multiple logistic regression model, patients were more likely to die at home when patients were male (odds ratio [OR], 95% confidence interval [CI]: 2.53, 1.06–6.05) and when their family preferred death at home (OR, 95% CI: 37.37, 13.82–101.03). A Sobel test revealed that family preference mediated the relationship between patient preference and place of death (p<0.05).

Conclusions

This study is, to our knowledge, the first to unveil the role of the family in the relationship between patient preference and place of death in Japan. In order to honor patients'' wishes to die at home, supporting caregivers in the family may be an essential component of terminal care.     

Out of hours service: the Danish solution examined.

In Denmark the provision of out of hours care by general practitioners came under increasing pressure in the 1980s because of growing demand for services by the public and increasing complaints from rural doctors about their heavy workload and disproportionately low remuneration in comparison with urban doctors. As a result, the out of hours service was reformed at the start of 1992: locally negotiated rota systems were replaced with county based services. Each county now has a coordination centre, where all patients'' calls are received by a team of doctors. The doctors may give a telephone consultation, advise the patient to attend one of the emergency clinics strategically placed about the county, or arrange for a home visit. Doctors on home visiting duty are located at bases throughout the county and keep in touch with the coordination centre with mobile telephones. Graded fees mean that doctors are encouraged to give telephone consultations rather than arrange for clinic consultations or home visits. The reforms have reduced doctors'' out of hours workload and the number of home visits made and have proved acceptable to patients, doctors, and administrators.     

Organ Donation After Acute Brain Death: Addressing Limitations of Time and Resources in the Emergency Department

It is not unusual for emergency physicians to quickly identify whether a patient would have wanted to be resuscitated or intubated in a cardiac arrest situation, but patients’ other preferences for end-of-life care or organ donation are less commonly ascertained in the emergency department. Typically, the decision process regarding such goals at end of life may be “deferred” to the intensive care unit. We present a case illustrative of the complexity of discussing organ donation in the emergency department and suggest that patients who die in the emergency department should be afforded the respect and consideration provided in other parts of the hospital, including facilitation of organ transplantation. As circulatory determination of death becomes a more common antecedent to organ transplantation, specific questions may arise in the emergency department setting. When in the emergency department, how should organ donation be addressed and by whom? Should temporary organ preservation be initiated in the setting of uncertainty regarding a patient’s wishes? To better facilitate discussions about organ donation when they arise in emergency settings, we propose increased coordination between organ procurement organizations and emergency physicians to improve awareness of organ transplantation.     

Randomised controlled trial of effects of coordinating care for terminally ill cancer patients.

OBJECTIVES--To measure effects on terminally ill cancer patients and their families of coordinating the services available within the NHS and from local authorities and the voluntary sector. DESIGN--Randomised controlled trial. SETTING--Inner London health district. PATIENTS--Cancer patients were routinely notified from 1987 to 1990. 554 patients expected to survive less than one year entered the trial and were randomly allocated to a coordination or a control group. INTERVENTION--All patients received routinely available services. Coordination group patients received the assistance of two nurse coordinators, whose role was to ensure that patients received appropriate and well coordinated services, tailored to their individual needs and circumstances. MAIN OUTCOME MEASURES--Patients and carers were interviewed at home on entry to the trial and at intervals until death. Interviews after bereavement were also conducted. Outcome measures included the presence and severity of physical symptoms, psychiatric morbidity, use of and satisfaction with services, and carers'' problems. Results from the baseline interview, the interview closest to death, and the interview after bereavement were analysed. RESULTS--Few differences between groups were significant. Coordination group patients were less likely to suffer from vomiting, were more likely to report effective treatment for it, and less likely to be concerned about having an itchy skin. Their carers were more likely to report that in the last week of life the patient had had a cough and had had effective treatment for constipation, and they were less likely to rate the patient''s difficulty swallowing as severe or to report effective treatment for anxiety. Coordination group patients were more likely to have seen a chiropodist and their carers were more likely to contact a specialist nurse in a night time emergency. These carers were less likely to feel angry about the death of the patient. CONCLUSIONS--This coordinating service made little difference to patient or family outcomes, perhaps because the service did not have a budget with which it could obtain services or because the professional skills of the nurse-coordinators may have conflicted with the requirements of the coordinating role.     

Terminal cancer care and patients' preference for place of death: a prospective study.

OBJECTIVE--To assess the preference of terminally ill patients with cancer for their place of final care. DESIGN--Prospective study of randomly selected patients with cancer from hospital and the community who were expected to die within a year. Patients expected to live less than two months were interviewed at two week intervals; otherwise patients were interviewed monthly. Their main carer was interviewed three months after the patient''s death. SETTING--District general hospital, hospices, and patients'' homes. MAIN OUTCOME MEASURE--Stated preferred place of final care; actual place of death; reason for final hospital admission for those in hospital; community care provision required for home care. RESULTS--Of 98 patients approached, 84 (86%) agreed to be interviewed, of whom 70 (83%) died during the study and 59 (84%) stated a preferred place of final care: 34 (58%) wished to die at home given existing circumstances, 12 (20%) in hospital, 12 (20%) in a hospice, and one (2%) elsewhere. Their own home was the preferred place of care for 17 (94%) of the patients who died there, whereas of the 32 patients who died in hospital 22 (69%) had stated a preference to die elsewhere. Had circumstances been more favourable 67% (41) of patients would have preferred to die at home, 16% (10) in hospital, and 15% (9) in hospice. CONCLUSION--With a limited increase in community care 50% more patients with cancer could be supported to die at home, as they and their carers would prefer.     

“Closer‐to‐home” strategy benefits juvenile survival in a long‐distance migratory bird

Human‐induced changes in the climate and environment that occur at an unprecedented speed are challenging the existence of migratory species. Faced with these new challenges, species with diverse and flexible migratory behaviors may suffer less from population decline, as they may be better at responding to these changes by altering their migratory behavior. At the individual level, variations in migratory behavior may lead to differences in fitness and subsequently influence the population's demographic dynamics. Using lifetime GPS bio‐logging data from 169 white storks (Ciconia ciconia), we explore whether the recently shortened migration distance of storks affects their survival during different stages of their juvenile life. We also explore how other variations in migratory decisions (i.e., time, destination), movement activity (measured using overall body dynamic acceleration), and early life conditions influence juvenile survival. We observed that their first autumn migration was the riskiest period for juvenile white storks. Individuals that migrated shorter distances and fledged earlier experienced lower mortality risks. In addition, higher movement activity and overwintering “closer‐to‐home” (with 84.21% of the tracked individuals stayed Europe or North Africa) were associated with higher survival. Our study shows how avian migrants can change life history decisions over only a few decades, and thus it helps us to understand and predict how migrants respond to the rapidly changing world.     

Reproductive Capability Is Associated with Lifespan and Cause of Death in Companion Dogs

Reproduction is a risky affair; a lifespan cost of maintaining reproductive capability, and of reproduction itself, has been demonstrated in a wide range of animal species. However, little is understood about the mechanisms underlying this relationship. Most cost-of-reproduction studies simply ask how reproduction influences age at death, but are blind to the subjects'' actual causes of death. Lifespan is a composite variable of myriad causes of death and it has not been clear whether the consequences of reproduction or of reproductive capability influence all causes of death equally. To address this gap in understanding, we compared causes of death among over 40,000 sterilized and reproductively intact domestic dogs, Canis lupus familiaris. We found that sterilization was strongly associated with an increase in lifespan, and while it decreased risk of death from some causes, such as infectious disease, it actually increased risk of death from others, such as cancer. These findings suggest that to understand how reproduction affects lifespan, a shift in research focus is needed. Beyond the impact of reproduction on when individuals die, we must investigate its impact on why individuals die, and subsequently must identify the mechanisms by which these causes of death are influenced by the physiology associated with reproductive capability. Such an approach may also clarify the effects of reproduction on lifespan in people.     

Which physicians make home visits and why? A survey

BACKGROUND: Recent changes in the North American health care system and certain demographic factors have led to increases in home care services. Little information is available to identify the strategies that could facilitate this transformation in medical practice and ensure that such changes respond adequately to patients'' needs. As a first step, the authors attempted to identify the major factors influencing physicians'' home care practices in the Quebec City area. METHODS: A self-administered questionnaire was sent by mail to all 696 general practitioners working in the Quebec City area. The questionnaire was intended to gather information on physicians'' personal and professional characteristics, as well as their home care practice (practice volume, characteristics of both clients and home visits, and methods of patient assessment and follow-up). RESULTS: A total of 487 physicians (70.0%) responded to the questionnaire, 283 (58.1%) of whom reported making home visits. Of these, 119 (42.0%) made fewer than 5 home visits per week, and 88 (31.1%) dedicated 3 hours or less each week to this activity. Physicians in private practice made more home visits than their counterparts in family medicine units and CLSCs (centres locaux des services communautaires [community centres for social and health services]) (mean 11.5 v. 5.8 visits per week), although the 2 groups reported spending about the same amount of time on this type of work (mean 5.6 v. 5.0 hours per week). The proportion of visits to patients in residential facilities or other private residences was greater for private practitioners than for physicians from family medicine units and CLSCs (29.7% v. 18.9% of visits), as were the proportions of visits made at the patient''s request (28.0% v. 14.2% of visits) and resulting from an acute condition (21.4% v. 16.0% of visits). The proportion of physicians making home visits at the request of a CLSC was greater for those in family medicine units and CLSCs than for those in private practice (44.0% v. 11.3% of physicians), as was the proportion of physicians making home visits at the request of a colleague (18.0% v. 4.5%) or at the request of hospitals (30.0% v. 6.8%). Physicians in family medicine units and CLSCs did more follow-ups at a frequency of less than once per month than private practitioners (50.9% v. 37.1% of patients), and they treated a greater proportion of patients with cognitive disorders (17.2% v. 12.6% of patients) and palliative care needs (13.7% v. 8.6% of patients). Private practitioners made less use of CLSC resources to assess home patients or follow them. Male private practitioners made more home visits than their female counterparts (mean 12.8 v. 8.3 per week), although they spent an almost equal amount of time on this activity (mean 5.7 v. 5.2 hours per week). INTERPRETATION: These results suggest that practice patterns for home care vary according to the physician''s practice setting and sex. Because of foreseeable increases in the numbers of patients needing home care, further research is required to evaluate how physicians'' practices can be adapted to patients'' needs in this area.     

How neurons die in Alzheimer's disease: Implications for neuroinflammation

Despite the long-standing observation of vast neuronal loss in Alzheimer's disease (AD) our understanding of how and when neurons are eliminated is incomplete. While previous investigation has focused on apoptosis, several novel forms of cell death (i.e. necroptosis, parthanatos, ferroptosis, cuproptosis) have emerged that require further investigation. This review aims to collect evidence for different modes of neuronal cell death in AD and to also discuss how these different forms of cell death may impact the neuroinflammatory environment that prevails in the AD brain. Improved understanding of how neurons die may help to delineate disease pathogenesis, provide insights toward treatment, and aid in the development of improved animal models of AD.     

Health care cost effects of public use of a regional poison control center.

Poison control centers in the United States are threatened with closure, and attempts at a cost-benefit analysis of these services have been indeterminate. The purpose of this study was to compare the operating costs of a regional poison control center resulting from public use of its telephone hotline services with those of hypothetical alternative sources of advice and care. We conducted a follow-up telephone survey among 589 public callers to the San Francisco Bay Area Regional Poison Control Center who had been managed at home without medical referral after an unintentional poisoning. All survey respondents were asked what alternative action they would have taken had the poison control center not been available to assist them by telephone consultation. We then surveyed emergency departments and physicians'' offices cited as alternatives by the callers to determine their response and charges for evaluating a suspected poisoning case. A total of 464 (79%) of the callers surveyed would have sought assistance from their local emergency health care system had the poison control center not been available. We conservatively estimated that the total charges for such evaluations would be +71,900. Comparatively, the total actual operating cost of services provided by the poison control center for all 589 poisoning cases was +13,547. Most of the study subjects (429 [73%]) had private insurance coverage. Direct public access to these services probably reduces the use of emergency health care resources, thus lowering health care costs.     

Are elderly people living alone an at risk group?

OBJECTIVE--To test the hypothesis that elderly people living alone are an at risk group with a high level of morbidity that makes high demands on health and social services. DESIGN--Secondary analysis of data from a community survey of 239 people aged 75 and over, identified from general practitioners'' age-sex registers. SETTING--Nine practices in the London boroughs of Brent and Islington. MAIN OUTCOME MEASURES--Scores on the mini-mental state examination; stated satisfaction with life; assessment of mobility; numbers of diagnoses of major physical problems; numbers of prescribed drugs taken; urinary incontinence; alcohol consumption; contacts with general practitioners and hospital outpatient and inpatient services; contact with community health and social services. RESULTS--There were significantly more women among those living alone (93/120 (78%) v 63/119 (53%); p < 0.0005) and the median age of elderly people living alone was higher (81 v 80; p < 0.04). Those living alone and those living with others showed no significant differences in measures of cognitive impairment, numbers of major physical diagnoses, impaired mobility, or use of general practitioner or hospital services. Stated satisfaction with life was somewhat higher in those living alone. Elderly people living alone were significantly more likely to have contact with chiropody, home help, and meals on wheels services and less likely to have someone they could contact in an emergency or at night. Living alone increased the likelihood of contact with one or more community health professionals (district nurses, health visitors, or chiropodists) considered as a group and also increased the likelihood of contact with social services as a whole. There was a tendency for more of those living alone than those living with others to have home visits from their general practitioners, but there were no significant differences in contact with hospital services between the two groups. CONCLUSIONS--Elderly people living alone do not have an excess of morbidity compared with those living with others and do not seem to be an at risk group requiring specifically targeted assessments. More help is needed to provide elderly people living alone with a point of contact in case of emergency.     

Do Patients Want to Die at Home? A Systematic Review of the UK Literature,Focused on Missing Preferences for Place of Death

Background

End-of-life care policy has a focus on enabling patients to die in their preferred place; this is believed for most to be home. This review assesses patient preferences for place of death examining: the extent of unreported preferences, the importance of patient factors (place of care and health diagnosis) and who reports preferences.

Methods and Findings

Systematic literature review of 7 electronic databases, grey literature, backwards citations from included studies and Palliative Medicine hand search. Included studies published between 2000–2015, reporting original, quantifiable results of adult UK preferences for place of death. Of 10826 articles reviewed, 61 met the inclusion criteria. Summary charts present preferences for place of death by health diagnosis, where patients were asked and who reported the preference. These charts are recalculated to include ‘missing data,’ the views of those whose preferences were not asked, expressed or reported or absent in studies. Missing data were common. Across all health conditions when missing data were excluded the majority preference was for home: when missing data were included, it was not known what proportion of patients with cancer, non-cancer or multiple conditions preferred home. Patients, family proxies and public all expressed a majority preference for home when missing data were excluded: when included, it was not known what proportion of patients or family proxies preferred home. Where patients wished to die was related to where they were asked their preference. Missing data calculations are limited to ‘reported’ data.

Conclusions

It is unknown what proportion of patients prefers to die at home or elsewhere. Reported preferences for place of death often exclude the views of those with no preference or not asked: when ‘missing data’ are included, they supress the proportion of preferences for all locations. Caution should be exercised if asserting that most patients prefer to die at home.     

Evaluation of a palliative care service: problems and pitfalls.

OBJECTIVE--To evaluate a palliative care home support team based on an inpatient unit. DESIGN--Randomised controlled trial with waiting list. Patients in the study group received the service immediately, those in the control group received it after one month. Main comparison point was at one month. SETTING--A city of 300,000 people with a publicly funded home care service and about 200 general practitioners, most of whom provide home care. MAIN OUTCOME MEASURES--Pain and nausea levels were measured at entry to trial and at one month, as were quality of life for patients and care givers'' health. RESULTS--Because of early deaths, problems with recruitment, and a low compliance rate for completion of questionnaires, the required sample size was not attained. CONCLUSION--In designing evaluations of palliative care services, investigators should be prepared to deal with the following issues: attrition due to early death, opposition to randomisation by patients and referral sources, ethical problems raised by randomisation of dying patients, the appropriate timing of comparison points, and difficulties of collecting data from sick or exhausted patients and care givers. Investigators may choose to evaluate a service from various perspectives using different methods: controlled trials, qualitative studies, surveys, and audits. Randomised trials may prove to be impracticable for evaluation of palliative care.     

Multi-purpose HealthCare Telemedicine Systems with mobile communication link support

The provision of effective emergency telemedicine and home monitoring solutions are the major fields of interest discussed in this study. Ambulances, Rural Health Centers (RHC) or other remote health location such as Ships navigating in wide seas are common examples of possible emergency sites, while critical care telemetry and telemedicine home follow-ups are important issues of telemonitoring. In order to support the above different growing application fields we created a combined real-time and store and forward facility that consists of a base unit and a telemedicine (mobile) unit. This integrated system: can be used when handling emergency cases in ambulances, RHC or ships by using a mobile telemedicine unit at the emergency site and a base unit at the hospital-expert's site, enhances intensive health care provision by giving a mobile base unit to the ICU doctor while the telemedicine unit remains at the ICU patient site and enables home telemonitoring, by installing the telemedicine unit at the patient's home while the base unit remains at the physician's office or hospital. The system allows the transmission of vital biosignals (3–12 lead ECG, SPO2, NIBP, IBP, Temp) and still images of the patient. The transmission is performed through GSM mobile telecommunication network, through satellite links (where GSM is not available) or through Plain Old Telephony Systems (POTS) where available. Using this device a specialist doctor can telematically "move" to the patient's site and instruct unspecialized personnel when handling an emergency or telemonitoring case. Due to the need of storing and archiving of all data interchanged during the telemedicine sessions, we have equipped the consultation site with a multimedia database able to store and manage the data collected by the system. The performance of the system has been technically tested over several telecommunication means; in addition the system has been clinically validated in three different countries using a standardized medical protocol.     

Secondary care beyond Tomlinson: an opportunity to be seized or squandered?

The Tomlinson report''s emphasis on primary care and its essentially quantitative analysis of hospital care in London leaves little space for a picture of how secondary care for Londoners should look. In this article Fiona Moss and Martin McNicol argue that most outpatient work does not need to be done in hospitals. With proper organisation and better premises a genuinely specialist consultative service can be provided in primary health care centres, with benefit to patients and communication between primary and secondary care doctors. Hospitals would then house those outpatient services that needed major investigative facilities and much reduced inpatient capacity. It may no longer be necessary for each acute unit to offer a full range of services. Such a pattern of secondary care will have implications for the organisation of accident and emergency services and for postgraduate training. Above all Moss and McNicol argue that Tomlinson''s recommendations demand that general practitioners and specialists should re-examine the services hospitals provide and agree on the best settings for different sorts of health care and the most appropriate skills to provide it.     

Cultural considerations in forgoing enteral feeding: A comparison between the Hong Kong Chinese,North American,and Malaysian Islamic patients with advanced dementia at the end‐of‐life

Cultural competence, a clinical skill to recognise patients' cultural and religious beliefs, is an integral element in patient‐centred medical practice. In the area of death and dying, physicians' understanding of patients' and families' values is essential for the delivery of culturally appropriate care. Dementia is a neurodegenerative condition marked by the decline of cognitive functions. When the condition progresses and deteriorates, patients with advanced dementia often have eating and swallowing problems and are at high risk of developing malnutrition. Enteral tube feeding is a conventional means of providing artificial nutrition and hydration to meet nutritional needs, but its benefits to the frail population are limitedly shown in the clinical evidence. Forgoing tube feeding is ethically challenging when patients are mentally incompetent and in the absence of an advance directive. Unlike some developed countries, like the United States of America, death and dying is a sensitive issue or even a taboo in some cultures in developing countries that forgoing enteral tube feeding is clinically and ethically challenging, such as China and Malaysia. This article in three parts 1) discusses the clinical and ethical issues related to forgoing tube feeding among patients with advanced dementia, 2) describes how Hong Kong Chinese, North American, and Malaysian Islamic cultures respond differently in the decision‐making patterns of forgoing tube feeding for patients with advanced dementia, and 3) reiterates the clinical implications of cultural competence in end‐of‐life care.     

The habitat functional response links seasonal third‐order selection to second‐order landscape characteristics

Determining how animals respond to differences in resource availabilities across spatiotemporal extents is critical to our understanding of organism distributions. Variations in resource distribution leading to changes in spatial arrangements across landscapes are indicative of a habitat functional response. Our goal was to assess how resource availabilities influenced both second‐order (i.e., home ranging behavior) and third‐order (i.e., habitat or resource selection) selection by feral pigs (Sus scrofa) in an agricultural landscape. We defined agriculturally based seasons to estimate home range characteristics using autocorrelated kernel density estimation within each season. We then modeled home range size as a function of resource availability (i.e., resource selection analyses) to determine whether individual behaviors were predicted by shifts in home ranging behavior. Both home range analyses and resource selection analyses indicated seasonal differences in selection for agricultural resources as availabilities changed, suggesting second‐ and third‐order selection is mechanistically linked through a habitat functional response.     

Mature neurons: equipped for survival

Neurons completely transform how they regulate cell death over the course of their lifetimes. Developing neurons freely activate cell death pathways to fine-tune the number of neurons that are needed during the precise formation of neural networks. However, the regulatory balance between life and death shifts as neurons mature beyond early development. Mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. This dramatic shift from permitting cell death to ensuring cellular survival is critical, as these post-mitotic cells must provide neuronal circuitry for an organism''s entire lifetime. Importantly, as many neurodegenerative diseases afflict adult neuronal populations, the survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Examining the adaptations for inhibiting apoptosis during neuronal maturation is key to comprehending not just how neurons survive long term, but may also provide insight for understanding how neuronal toxicity in various neurodegenerative diseases may ultimately lead to cell death.     

RIP1, a kinase on the crossroads of a cell's decision to live or die

Binding of inflammatory cytokines to their receptors, stimulation of pathogen recognition receptors by pathogen-associated molecular patterns, and DNA damage induce specific signalling events. A cell that is exposed to these signals can respond by activation of NF-kappaB, mitogen-activated protein kinases and interferon regulatory factors, resulting in the upregulation of antiapoptotic proteins and of several cytokines. The consequent survival may or may not be accompanied by an inflammatory response. Alternatively, a cell can also activate death-signalling pathways, resulting in apoptosis or alternative cell death such as necrosis or autophagic cell death. Interplay between survival and death-promoting complexes continues as they compete with each other until one eventually dominates and determines the cell's fate. RIP1 is a crucial adaptor kinase on the crossroad of these stress-induced signalling pathways and a cell's decision to live or die. Following different upstream signals, particular RIP1-containing complexes are formed; these initiate only a limited number of cellular responses. In this review, we describe how RIP1 acts as a key integrator of signalling pathways initiated by stimulation of death receptors, bacterial or viral infection, genotoxic stress and T-cell homeostasis.