Donor Electrocardiogram Associations With Cardiac Dysfunction, Heart Transplant Use, and Survival: The Donor Heart Study.

BACKGROUND: Potential organ donors often exhibit abnormalities on electrocardiograms (ECGs) after brain death, but the physiological and prognostic significance of such abnormalities is unknown. OBJECTIVES: This study sought to characterize the prevalence of ECG abnormalities in a nationwide cohort of potential cardiac donors and their associations with cardiac dysfunction, use for heart transplantation (HT), and recipient outcomes. METHODS: The Donor Heart Study enrolled 4,333 potential cardiac organ donors at 8 organ procurement organizations across the United States from 2015 to 2020. A blinded expert reviewer interpreted all ECGs, which were obtained once hemodynamic stability was achieved after brain death and were repeated 24 ± 6 hours later. ECG findings were summarized, and their associations with other cardiac diagnostic findings, use for HT, and graft survival were assessed using univariable and multivariable regression. RESULTS: Initial ECGs were interpretable for 4,136 potential donors. Overall, 64% of ECGs were deemed clinically abnormal, most commonly as a result of a nonspecific St-T-wave abnormality (39%), T-wave inversion (19%), and/or QTc interval >500 ms (17%). Conduction abnormalities, ectopy, pathologic Q waves, and ST-segment elevations were less common (each present in ≤5% of donors) and resolved on repeat ECGs in most cases. Only pathological Q waves were significant predictors of donor heart nonuse (adjusted OR: 0.39; 95% CI: 0.29-0.53), and none were associated with graft survival at 1 year post-HT. CONCLUSIONS: ECG abnormalities are common in potential heart donors but often resolve on serial testing. Pathologic Q waves are associated with a lower likelihood of use for HT, but they do not portend worse graft survival.

CD68 Antigen and Cerebral Aneurysms: A Case-Control Study.

BACKGROUND: Intracranial aneurysms are more commonly associated with inflammation as a cause of their development, progression, and rupture. Macrophages and other cells can express the CD68 antigen. The aim of this study was to assess the CD68 antigen levels in cerebral aneurysm (CA) patients compared to a control group at a referral center in Iran. METHODS: A case-control investigation was undertaken on 88 individuals (44 of whom were cases and 44 were controls). Individuals with CA as the case group consisted of 28 ruptured and 16 unruptured subgroups. Clinical, radiographic, and CD68 levels were evaluated and registered. RESULTS: The average age of the participants was 49 years. Males comprised 43.2% of the patients, while 56.8% were females (p = 0.002). There was a statistically significant difference in the CD68 levels between the two groups. There was no significant difference (p = 0.42) between the ruptured and unruptured subgroups (23.66 and 20.47, respectively) in this comparison. No significant correlation was seen between the patients' CD68 and Glasgow Coma Scale (GCS) levels and their aneurysm diameter (p = 0.74 and 0.45, respectively). A link between CD68 levels and age was found, but it was not statistically significant (r = 0.44 and p = 0.002). CONCLUSIONS: A possible involvement of CD68 as an inflammatory agent in the development of CAs but not in aneurysm rupture has been suggested. Inflammation and CD68 were positively associated with age. The CD68 antigen should be studied further in population-based cohort studies.

Third party monitoring for health in Afghanistan: the good, the bad and the ugly.

Third party monitoring (TPM) is used in development programming to assess deliverables in a contract relationship between purchasers (donors or government) and providers (non-governmental organisations or non-state entities). In this paper, we draw from our experience as public health professionals involved in implementing and monitoring the Basic Package of Health Services (BPHS) and the Essential Package of Hospital Services (EPHS) as part of the SEHAT and Sehatmandi programs in Afghanistan between 2013 and 2021. We analyse our own TPM experience through the lens of the three parties involved: the Ministry of Public Health; the service providers implementing the BPHS/EPHS; and the TPM agency responsible for monitoring the implementation. Despite the highly challenging and fragile context, our findings suggest that the consistent investments and strategic vision of donor programmes in Afghanistan over the past decades have led to a functioning and robust system to monitor the BPHS/EPHS implementation in Afghanistan. To maximise the efficiency, effectiveness and impact of this system, it is important to promote local ownership and use of the data, to balance the need for comprehensive information with the risk of jamming processes, and to address political economy dynamics in pay-for-performance schemes. Our findings are likely to be emblematic of TPM issues in other sectors and other fragile and conflicted affected settings and offer a range of lessons learnt to inform the implementation of TPM schemes.

Lessons from the development process of the Afghanistan integrated package of essential health services.

In 2017, in the middle of the armed conflict with the Taliban, the Ministry of Public Health decided that the Afghan health system needed a well-defined priority package of health services taking into account the increasing burden of non-communicable diseases and injuries and benefiting from the latest evidence published by DCP3. This leads to a 2-year process involving data analysis, modelling and national consultations, which produce this Integrated Package of Essential health Services (IPEHS). The IPEHS was finalised just before the takeover by the Taliban and could not be implemented. The Afghanistan experience has highlighted the need to address not only the content of a more comprehensive benefit package, but also its implementation and financing. The IPEHS could be used as a basis to help professionals and the new authorities to define their priorities.

Left Ventricular Dysfunction Associated With Brain Death: Results From the Donor Heart Study.

BACKGROUND: Left ventricular dysfunction in potential donors meeting brain death criteria often results in nonuse of donor hearts for transplantation, yet little is known about its incidence or pathophysiology. Resolving these unknowns was a primary aim of the DHS (Donor Heart Study), a multisite prospective cohort study. METHODS: The DHS enrolled potential donors by neurologic determination of death (n=4333) at 8 organ procurement organizations across the United States between February 2015 and May 2020. Data included medications administered, serial diagnostic tests, and transthoracic echocardiograms (TTEs) performed: (1) within 48 hours after brain death was formally diagnosed; and (2) 24±6 hours later if left ventricular (LV) dysfunction was initially present. LV dysfunction was defined as an LV ejection fraction <50% and was considered reversible if LV ejection fraction was >50% on the second TTE. TTEs were also examined for presence of LV regional wall motion abnormalities and their reversibility. We assessed associations between LV dysfunction, donor heart acceptance for transplantation, and recipient 1-year survival. RESULTS: An initial TTE was interpreted for 3794 of the 4333 potential donors by neurologic determination of death. A total of 493 (13%) of these TTEs showed LV dysfunction. Among those donors with an initial TTE, LV dysfunction was associated with younger age, underweight, and higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and troponin levels. A second TTE was performed within 24±6 hours for a subset of donors (n=224) with initial LV dysfunction; within this subset, 130 (58%) demonstrated reversibility. Sixty percent of donor hearts with normal LV function were accepted for transplant compared with 56% of hearts with reversible LV dysfunction and 24% of hearts with nonreversible LV dysfunction. Donor LV dysfunction, whether reversible or not, was not associated with recipient 1-year survival. CONCLUSIONS: LV dysfunction associated with brain death occurs in many potential heart donors and is sometimes reversible. These findings can inform decisions made during donor evaluation and help guide donor heart acceptance for transplantation.

The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans.

Molecular characterization of cell types using single-cell transcriptome sequencing is revolutionizing cell biology and enabling new insights into the physiology of human organs. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. Using multiple tissues from a single donor enabled identification of the clonal distribution of T cells between tissues, identification of the tissue-specific mutation rate in B cells, and analysis of the cell cycle state and proliferative potential of shared cell types across tissues. Cell type-specific RNA splicing was discovered and analyzed across tissues within an individual.

A Blockchain Framework to Secure Personal Health Record (PHR) in IBM Cloud-Based Data Lake.

The health system in today's real world is significant but difficult and overcrowded. These hurdles can be diminished using improved health record management and blockchain technology. These technologies can handle medical data to provide security by monitoring and maintaining patient records. The processing of medical data and patient records is essential to analyze the earlier prescribed medicines and to understand the severity of diseases. Blockchain technology can improve the security, performance, and transparency of sharing the medical records of the current healthcare system. This paper proposed a novel framework for personal health record (PHR) management using IBM cloud data lake and blockchain platform for an effective healthcare management process. The problem in the blockchain-based healthcare management system can be minimized with the utilization of the proposed technique. Significantly, the traditional blockchain system usually decreases the latency. Therefore, the proposed technique focuses on improving latency and throughput. The result of the proposed system is calculated based on various matrices, such as F1 Score, Recall, and Confusion matrices. Therefore, the proposed work scored high accuracy and provided better results than existing techniques.

Challenges encountered in conducting donor-based research: Lessons learned from the Donor Heart Study.

Solid organ transplantation continues to be constrained by a lack of suitable donor organs. Advances in donor management and evaluation are needed to address this shortage, but the performance of research studies in deceased donors is fraught with challenges. Here we discuss several of the major obstacles we faced in the conduct of the Donor Heart Study-a prospective, multi-site, observational study of donor management, evaluation, and acceptance for heart transplantation. These included recruitment and engagement of participating organ procurement organizations, ambiguities related to study oversight, obtaining authorization for donor research, logistical challenges encountered during donor management, sustaining study momentum, and challenges related to study data management. By highlighting these obstacles encountered, as well as the solutions implemented, we hope to stimulate further discussion and actions that will facilitate the design and execution of future donor research studies.

Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model.

INTRODUCTION: People with Down syndrome (DS) are predisposed to Alzheimer's disease (AD). The amyloid hypothesis informs studies of AD. In AD-DS, but not sporadic AD, increased APP copy number is necessary, defining the APP gene dose hypothesis. Which amyloid precursor protein (APP) products contribute needs to be determined. METHODS: Brain levels of full-length protein (fl-hAPP), C-terminal fragments (hCTFs), and amyloid beta (Aß) peptides were measured in DS, AD-DS, non-demented controls (ND), and sporadic AD cases. The APP gene-dose hypothesis was evaluated in the Dp16 model. RESULTS: DS and AD-DS differed from ND and AD for all APP products. In AD-DS, Aß42 and Aß40 levels exceeded AD. APP products were increased in the Dp16 model; increased APP gene dose was necessary for loss of vulnerable neurons, tau pathology, and activation of astrocytes and microglia. DISCUSSION: Increases in APP products other than Aß distinguished AD-DS from AD. Deciphering AD-DS pathogenesis necessitates deciphering which APP products contribute and how.

Enlargement of early endosomes and traffic jam in basal forebrain cholinergic neurons in Alzheimer's disease.

While a handful of neurotransmitter systems including cholinergic, norepinephrinergic, and serotonergic undergo significant degeneration in Alzheimer's disease, the cholinergic system has been the prime target for research and therapy. The cholinergic system in the basal forebrain is strategically located to impose significant modulatory effects on vast cortical and subcortical regions of the brain. Numerous studies have established a strong link between neurotrophin signaling and basal forebrain cholinergic neuron degeneration in several neurodegenerative disorders. Evidence presented during the last few years points to the effects of endosomal pathology and primarily unidirectional traffic jam. Hence, formulating new therapies, e.g., to reduce local production of ß C-terminal fragments and preventing changes in endosomal morphology have become attractive potential therapeutic strategies to restore cholinergic neurons and their neuromodulatory function. While it is not expected that restoring the cholinergic system function will fully mitigate cognitive dysfunction in Alzheimer's disease, pivotal aspects of cognition including attention-deficit during the prodromal stages might well be at disposal for corrective measures.

The effects of polio eradication efforts on health systems: a cross-country analysis using the Develop-Distort Dilemma.

Vertical disease control programmes have enormous potential to benefit or weaken health systems, and it is critical to understand how programmes' design and implementation impact the health systems and communities in which they operate. We use the Develop-Distort Dilemma (DDD) framework to understand how the Global Polio Eradication Initiative (GPEI) distorted or developed local health systems. We include document review and 176 interviews with respondents at the global level and across seven focus countries (Afghanistan, Bangladesh, Democratic Republic of Congo, Ethiopia, India, Indonesia and Nigeria). We use DDD domains, contextual factors and transition planning to analyse interactions between the broader context, local health systems and the GPEI to identify changes. Our analysis confirms earlier research including improved health worker, laboratory and surveillance capacity, monitoring and accountability, and efforts to reach vulnerable populations, whereas distortions include shifting attention from routine health services and distorting local payment and incentives structures. New findings highlight how global-level governance structures evolved and affected national actors; issues of country ownership, including for data systems, where the polio programme is not indigenously financed; how expectations of success have affected implementation at programme and community level; and unresolved tensions around transition planning. The decoupling of polio eradication from routine immunization, in particular, plays an outsize role in these issues as it removed attention from system strengthening. In addition to drawing lessons from the GPEI experience for other efforts, we also reflect on the use of the DDD framework for assessing programmes and their system-level impacts. Future eradication efforts should be approached carefully, and new initiatives of any kind should leverage the existing health system while considering equity, inclusion and transition from the start.

Political economy analysis of the performance-based financing programme in Afghanistan.

BACKGROUND: Performance-based financing (PBF) has attracted considerable attention in recent years in low and middle-income countries. Afghanistan's Ministry of Public Health (MoPH) implemented a PBF programme between 2010 and 2015 to strengthen the utilisation of maternal and child health services in primary health facilities. This study aimed to examine the political economy factors influencing the adoption, design and implementation of the PBF programme in Afghanistan. METHODS: Retrospective qualitative research methods were employed using semi structured interviews as well as a desk review of programme and policy documents. Key informants were selected purposively from the national level (n = 9), from the province level (n = 6) and the facility level (n = 15). Data analysis was inductive as well as deductive and guided by a political economy analysis framework to explore the factors that influenced the adoption and design of the PBF programme. Thematic content analysis was used to analyse the data. RESULTS: The global policy context, and implementation experience in other LMIC, shaped PBF and its introduction in Afghanistan. The MoPH saw PBF as a promise of additional resources needed to rebuild the country's health system after a period of conflict. The MoPH support for PBF was also linked to their past positive experience of performance-based contracting. Power dynamics and interactions between PBF programme actors also shaped the policy process. The PBF programme established a centralised management structure which strengthened MoPH and donor ability to manage the programme, but overlooked key stakeholders, such as provincial health offices and non-state providers. However, MoPH had limited input in policy design, resulting in a design which was not well tailored to the national setting. CONCLUSIONS: This study shows that PBF programmes need to be designed and adapted according to the local context, involving all relevant actors in the policy cycle. Future studies should focus on conducting empirical research to not only understand the multiple effects of PBF programmes on the performance of health systems but also the main political economy dynamics that influence the PBF programmes in different stages of the policy process.

Targeting increased levels of APP in Down syndrome: Posiphen-mediated reductions in APP and its products reverse endosomal phenotypes in the Ts65Dn mouse model.

OBJECTIVE: Recent clinical trials targeting amyloid beta (Aß) and tau in Alzheimer's disease (AD) have yet to demonstrate efficacy. Reviewing the hypotheses for AD pathogenesis and defining possible links between them may enhance insights into both upstream initiating events and downstream mechanisms, thereby promoting discovery of novel treatments. Evidence that in Down syndrome (DS), a population markedly predisposed to develop early onset AD, increased APP gene dose is necessary for both AD neuropathology and dementia points to normalization of the levels of the amyloid precursor protein (APP) and its products as a route to further define AD pathogenesis and discovering novel treatments. BACKGROUND: AD and DS share several characteristic manifestations. DS is caused by trisomy of whole or part of chromosome 21; this chromosome contains about 233 protein-coding genes, including APP. Recent evidence points to a defining role for increased expression of the gene for APP and for its 99 amino acid C-terminal fragment (C99, also known as ß-CTF) in dysregulating the endosomal/lysosomal system. The latter is critical for normal cellular function and in neurons for transmitting neurotrophic signals. NEW/UPDATED HYPOTHESIS: We hypothesize that the increase in APP gene dose in DS initiates a process in which increased levels of full-length APP (fl-APP) and its products, including ß-CTF and possibly Aß peptides (Aß42 and Aß40), drive AD pathogenesis through an endosome-dependent mechanism(s), which compromises transport of neurotrophic signals. To test this hypothesis, we carried out studies in the Ts65Dn mouse model of DS and examined the effects of Posiphen, an orally available small molecule shown in prior studies to reduce fl-APP. In vitro, Posiphen lowered fl-APP and its C-terminal fragments, reversed Rab5 hyperactivation and early endosome enlargement, and restored retrograde transport of neurotrophin signaling. In vivo, Posiphen treatment (50 mg/kg/d, 26 days, intraperitoneal [i.p.]) of Ts65Dn mice was well tolerated and demonstrated no adverse effects in behavior. Treatment resulted in normalization of the levels of fl-APP, C-terminal fragments and small reductions in Aß species, restoration to normal levels of Rab5 activity, reduced phosphorylated tau (p-tau), and reversed deficits in TrkB (tropomyosin receptor kinase B) activation and in the Akt (protein kinase B [PKB]), ERK (extracellular signal-regulated kinase), and CREB (cAMP response element-binding protein) signaling pathways. Remarkably, Posiphen treatment also restored the level of choline acetyltransferase protein to 2N levels. These findings support the APP gene dose hypothesis, point to the need for additional studies to explore the mechanisms by which increased APP gene expression acts to increase the risk for AD in DS, and to possible utility of treatments to normalize the levels of APP and its products for preventing AD in those with DS. MAJOR CHALLENGES FOR THE HYPOTHESIS: Important unanswered questions are: (1) When should one intervene in those with DS; (2) would an APP-based strategy have untoward consequences on possible adaptive changes induced by chronically increased APP gene dose; (3) do other genes present on chromosome 21, or on other chromosomes whose expression is dysregulated in DS, contribute to AD pathogenesis; and (4) can one model strategies that combine the use of an APP-based treatment with those directed at other AD phenotypes including p-tau and inflammation. LINKAGE TO OTHER MAJOR THEORIES: The APP gene dose hypothesis interfaces with the amyloid cascade hypothesis of AD as well as with the genetic and cell biological observations that support it. Moreover, upregulation of fl-APP protein and products may drive downstream events that dysregulate tau homeostasis and inflammatory responses that contribute to propagation of AD pathogenesis.