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.

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.

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.

TFPI2 and NDRG4 gene promoter methylation analysis in peripheral blood mononuclear cells are novel epigenetic noninvasive biomarkers for colorectal cancer diagnosis.

BACKGROUND: As a result of the growing prevalence of colorectal cancer (CRC), new screening and early detection methods are required. Among the novel biomarkers, DNA methylation has emerged as a high-potential diagnosis/screening molecular marker. The present study aimed to assess non-invasive early diagnosis of CRC by examining promoter methylation of TFPI2 and NDRG4 genes in peripheral blood mononuclear cells (PBMCs). METHODS: Fifty CRC patients and 50 normal controls were recruited to the present study. Quantitative methylation of the promoter region of the TFPI2 and NDRG4 genes was analyzed in DNA extracted from PBMCs of all cases and control subjects using a methylation-quantification endonuclease-resistant DNA (MethyQESD) method. RESULTS: The sensitivity and specificity of the TFPI2 gene for the diagnosis of CRC was 88% and 92%, respectively, and, for the NDRG4 gene, it was 86% and 92%, respectively. The methylation range for the TFPI2 gene was 43.93% and 11.56% in patients and controls, respectively, and, for the NDRG4 gene, it was 38.8% in CRC patients and 12.23% in healthy controls (p < 0.001). In addition, we observed that a higher percentage of methylation was correlated with the higher stage of CRC. CONCLUSIONS: The results of the present study reveal that PBMCs are reliable sources of methylation analysis for CRC screening. Furthermore, the TFPI2 and NDRG4 genes provide sufficiently high sensitivity and specificity to be nominated for use in a novel noninvasive CRC screening method in PBMCs.

Synthesis and translation of research and innovations from polio eradication (STRIPE): initial findings from a global mixed methods study.

BACKGROUND: Lessons from polio eradication efforts and the Global Polio Eradication Initiative (GPEI) are useful for improving health service delivery and outcomes globally. The Synthesis and Translation of Research and Innovations from Polio Eradication (STRIPE) is a multi-phase project which aims to map, package and disseminate knowledge from polio eradication initiatives as academic and training programs. This paper discusses initial findings from the knowledge mapping around polio eradication activities across a multi-country context. METHODS: The knowledge mapping phase (January 2018 - December 2019) encompassed four research activities (scoping review, survey, key informant interviews (KIIs), health system analyses). This paper utilized a sequential mixed method design combining data from the survey and KIIs. The survey included individuals involved in polio eradication between 1988 and 2019, and described the contexts, implementation strategies, intended and unintended outcomes of polio eradication activities across levels. KIIs were conducted among a nested sample in seven countries (Afghanistan, Bangladesh, the Democratic Republic of Congo, Ethiopia, India, Indonesia, Nigeria) and at the global level to further explore these domains. RESULTS: The survey generated 3955 unique responses, mainly sub-national actors representing experience in over 74 countries; 194 KIIs were conducted. External factors including social, political, and economic factors were the most frequently cited barriers to eradication, followed by the process of implementing activities, including program execution, planning, monitoring, and stakeholder engagement. Key informants described common strategies for addressing these barriers, e.g. generating political will, engaging communities, capacity-building in planning and measurement, and adapting delivery strategies. The polio program positively affected health systems by investing in system structures and governance, however, long-term effects have been mixed as some countries have struggled to institutionalize program assets. CONCLUSION: Understanding the implementing context is critical for identifying threats and opportunities to global health programs. Common implementation strategies emerged across countries; however, these strategies were only effective where organizational and individual capacity were sufficient, and where strategies were appropriately tailored to the sociopolitical context. To maximize gains, readiness assessments at different levels should predate future global health programs and initiatives should consider system integration earlier to ensure program institutionalization and minimize system distortions.

Factors influencing performance by contracted non-state providers implementing a basic package of health services in Afghanistan.

BACKGROUND: In 2002 Afghanistan's Ministry of Public Health (MoPH) and its development partners initiated a new paradigm for the health sector by electing to Contract-Out (CO) the Basic Package of Health Services (BPHS) to non-state providers (NSPs). This model is generally regarded as successful, but literature is scarce that examines the motivations underlying implementation and factors influencing program success. This paper uses relevant theories and qualitative data to describe how and why contracting out delivery of primary health care services to NSPs has been effective. The main aim of this study was to assess the contextual, institutional, and contractual factors that influenced the performance of NSPs delivering the BPHS in Afghanistan. METHODS: The qualitative study design involved individual in-depth interviews and focus group discussions conducted in six provinces of Afghanistan, as well as a desk review. The framework for assessing key factors of the contracting mechanism proposed by Liu et al. was utilized in the design, data collection and data analysis. RESULTS: While some contextual factors facilitated the CO (e.g. MoPH leadership, NSP innovation and community participation), harsh geography, political interference and insecurity in some provinces had negative effects. Contractual factors, such as effective input and output management, guided health service delivery. Institutional factors were important; management capacity of contracted NSPs affects their ability to deliver outcomes. Effective human resources and pharmaceutical management were notable elements that contributed to the successful delivery of the BPHS. The contextual, contractual and institutional factors interacted with each other. CONCLUSION: Three sets of factors influenced the implementation of the BPHS: contextual, contractual and institutional. The MoPH should consider all of these factors when contracting out the BPHS and other functions to NSPs. Other fragile states and countries emerging from a period of conflict could learn from Afghanistan's example in contracting out primary health care services, keeping in mind that generic or universal contracting policies might not work in all geographical areas within a country or between countries.

Genetic polymorphism of 8 Y-STR loci in native population of Isfahan province in central part of Iran.

BACKGROUND: Y-chromosome short tandem repeats (Y-STRs) are genetic markers with practical applications in human identification and population studies. AIM: Here we present the allelic and haplotype frequencies of 8 Y-STR loci most commonly used in forensic medicine in 103 unrelated native males of Isfahan province, central part of Iran. SUBJECTS AND METHODS: The cases were selected on the basis of strict criteria to assure pure native populations of Isfahan origin. DNA extracted from peripheral blood samples and PCR amplified for each marker. Y-specific STR loci DYS19, DYS385, DYS389I, DYS389II, DYS390, DYS391, DYS392 and DYS393 were included in this study. RESULTS: The most common alleles for each locus were: DYS19, allele 12; DYS385, allele 12; DYS389I, allele 13; DYS389II, allele 29; DYS390, allele 24; DYS391, allele 10; DYS392, allele 11; and DYS393, allele 13. Gene diversity value was calculated from the allelic frequency for each locus. The average gene diversity was 0.6518. A total of 101 haplotypes were observed in eight Y-specific STR loci, the haplotype diversity was raised to 0.986. CONCLUSION: The results revealed that a set of eight Y-specific STR loci were able to discriminate most of the male individuals in the population studied. A search through the Y Haplotype Reference Database demonstrated 21 matched haplotypes to 160,693 haplotypes, exclusively with Eurasian-European, Eurasian, and Eurasian-Indo Iranian populations.

GABAergic hyperinnervation of dentate granule cells in the Ts65Dn mouse model of down syndrome: Exploring the role of App.

It has been suggested that increased GABAergic innervation in the hippocampus plays a significant role in cognitive dysfunction in Down syndrome (DS). Bolstering this notion, are studies linking hyper-innervation of the dentate gyrus (DG) by GABAergic terminals to failure in LTP induction in the Ts65Dn mouse model of DS. Here, we used extensive morphometrical methods to assess the status of GABAergic interneurons in the DG of young and old Ts65Dn mice and their 2N controls. We detected an age-dependent increase in GABAergic innervation of dentate granule cells (DGCs) in Ts65Dn mice. The primary source of GABAergic terminals to DGCs somata is basket cells (BCs). For this reason, we assessed the status of these cells and found a significant increase in the number of BCs in Ts65Dn mice compared with controls. Then we aimed to identify the gene/s whose overexpression could be linked to increased number of BCs in Ts65Dn and found that deleting the third copy of App gene in Ts65Dn mice led to normalization of the number of BCs in these mice. Our data suggest that App overexpression plays a major role in the pathophysiology of GABAergic hyperinnervation of the DG in Ts65Dn mice. © 2016 Wiley Periodicals, Inc.

An equity analysis of utilization of health services in Afghanistan using a national household survey.

BACKGROUND: Afghanistan has made great strides in the coverage of health services across the country but coverage of key indicators remains low nationally and whether the poorest households are accessing these services is not well understood. METHODS: We analyzed the Afghanistan Mortality Survey 2010 on utilization of inpatient and outpatient care, institutional delivery and antenatal care by wealth quintiles. Concentration indexes (CIs) were generated to measure the inequality of using the four services. Additional analyses were conducted to examine factors that explain the health inequalities (e.g. age, gender, education and residence). RESULTS: Among households reporting utilization of health services, public health facilities were used more often for inpatient care, while they were used less for outpatient care. Overall, the utilization of inpatient and outpatient care, and antenatal care was equally distributed among income groups, with CIs of 0.04, 0.03 and 0.08, respectively. However, the poor used more public facilities while the wealthy used more private facilities. There was a substantial inequality in the use of institutional delivery services, with a CI of 0.31. Poorer women had a lower rate of institutional deliveries overall, in both public and private facilities, compared to the wealthy. Location was an important factor in explaining the inequality in the use of health services. CONCLUSIONS: The large gap between the rich and poor in access to and utilization of key maternal services, such as institutional delivery, may be a central factor to the high rates of maternal mortality and morbidity and impedes efforts to make progress toward universal health coverage. While poorer households use public health services more often, the use of public facilities for outpatient visits remains half that of private facilities. Pro-poor targeting as well as a better understanding of the private sector's role in increasing equitable coverage of maternal health services is needed. Equity-oriented approaches in health should be prioritized to promote more inclusive health system reforms.

Coverage and inequalities in maternal and child health interventions in Afghanistan.

BACKGROUND: Afghanistan has made considerable gains in improving maternal and child health and survival since 2001. However, socioeconomic and regional inequities may pose a threat to reaching universal coverage of health interventions and further health progress. We explored coverage and socioeconomic inequalities in key life-saving reproductive, maternal, newborn and child health (RMNCH) interventions at the national level and by region in Afghanistan. We also assessed gains in child survival through scaling up effective community-based interventions across wealth groups. METHODS: Using data from the Afghanistan Multiple Indicator Cluster Survey (MICS) 2010/11, we explored 11 interventions that spanned all stages of the continuum of care, including indicators of composite coverage. Asset-based wealth quintiles were constructed using standardised methods, and absolute inequalities were explored using wealth quintile (Q) gaps (Q5-Q1) and the slope index of inequality (SII), while relative inequalities were assessed with ratios (Q5/Q1) and the concentration index (CIX). The lives saved tool (LiST) modeling used to estimate neonatal and post-neonatal deaths averted from scaling up essential community-based interventions by 90 % coverage by 2025. Analyses considered the survey design characteristics and were conducted via STATA version 12.0 and SAS version 9.4. RESULTS: Our results underscore significant pro-rich socioeconomic absolute and relative inequalities, and mass population deprivation across most all RMNCH interventions studied. The most inequitable are antenatal care with a skilled attendant (ANCS), skilled birth attendance (SBA), and 4 or more antenatal care visits (ANC4) where the richest have between 3.0 and 5.6 times higher coverage relative to the poor, and Q5-Q1 gaps range from 32 % - 65 %. Treatment of sick children and breastfeeding interventions are the most equitably distributed. Across regions, inequalities were highest in the more urbanised East, West and Central regions of the country, while they were lowest in the South and Southeast. About 7700 newborns and 26,000 post-neonates could be saved by scaling up coverage of community outreach interventions to 90 %, with the most gains in the poorest quintiles. CONCLUSIONS: Afghanistan is a pervasively poor and conflict-prone nation that has only recently experienced a decade of relative stability. Though donor investments during this period have been plentiful and have contributed to rebuilding of health infrastructure in the country, glaring inequities remain. A resolution to scaling up health coverage in insecure and isolated regions, and improving accessibility for the poorest and marginalised populations, should be at the forefront of national policy and programming efforts.

Countdown to 2015 country case studies: what can analysis of national health financing contribute to understanding MDG 4 and 5 progress?

BACKGROUND: Countdown to 2015 (Countdown) supported countries to produce case studies that examine how and why progress was made toward the Millennium Development Goals (MDGs) 4 and 5. Analysing how health-financing data explains improvements in RMNCH outcomes was one of the components to the case studies. METHODS: This paper presents a descriptive analysis on health financing from six Countdown case studies (Afghanistan, Ethiopia, Malawi, Pakistan, Peru, and Tanzania), supplemented by additional data from global databases and country reports on macroeconomic, health financing, demographic, and RMNCH outcome data as needed. It also examines the effect of other contextual factors presented in the case studies to help interpret health-financing data. RESULTS: Dramatic increases in health funding occurred since 2000, where the MDG agenda encouraged countries and donors to invest more resources on health. Most low-income countries relied on external support to increase health spending, with an average 20-64 % of total health spending from 2000 onwards. Middle-income countries relied more on government and household spending. RMNCH funding also increased since 2000, with an average increase of 119 % (2005-2010) for RMNH expenditures (2005-2010) and 165 % for CH expenditures (2005-2011). Progress was made, especially achieving MDG 4, even with low per capita spending; ranging from US$16 to US$44 per child under 5 years among low-income countries. Improvements in distal factors were noted during the time frame of the analysis, including rapid economic growth in Ethiopia, Peru, and Tanzania and improvements in female literacy as documented in Malawi, which are also likely to have contributed to MDG progress and achievements. CONCLUSIONS: Increases in health and RMNCH funding accompanied improvements in outcomes, though low-income countries are still very reliant on external financing, and out-of-pocket comprising a growing share of funds in middle-income settings. Enhancements in tracking RMNCH expenditures across countries are still needed to better understand whether domestic and global health financing initiatives lead to improved outcomes as RMNCH continues to be a priority under the Sustainable Development Goals.

State-building and human resources for health in fragile and conflict-affected states: exploring the linkages.

BACKGROUND: Human resources for health are self-evidently critical to running a health service and system. There is, however, a wider set of social issues which is more rarely considered. One area which is hinted at in literature, particularly on fragile and conflict-affected states, but rarely examined in detail, is the contribution which health staff may or do play in relation to the wider state-building processes. This article aims to explore that relationship, developing a conceptual framework to understand what linkages might exist and looking for empirical evidence in the literature to support, refute or adapt those linkages. METHODS: An open call for contributions to the article was launched through an online community. The group then developed a conceptual framework and explored a variety of literatures (political, economic, historical, public administration, conflict and health-related) to find theoretical and empirical evidence related to the linkages outlined in the framework. Three country case reports were also developed for Afghanistan, Burundi and Timor-Leste, using secondary sources and the knowledge of the group. FINDINGS: We find that the empirical evidence for most of the linkages is not strong, which is not surprising, given the complexity of the relationships. Nevertheless, some of the posited relationships are plausible, especially between development of health cadres and a strengthened public administration, which in the long run underlies a number of state-building features. The reintegration of factional health staff post-conflict is also plausibly linked to reconciliation and peace-building. The role of medical staff as part of national elites may also be important. CONCLUSIONS: The concept of state-building itself is highly contested, with a rich vein of scepticism about the wisdom or feasibility of this as an external project. While recognizing the inherently political nature of these processes, systems and sub-systems, it remains the case that state-building does occur over time, driven by a combination of internal and external forces and that understanding the role played in it by the health system and health staff, particularly after conflicts and in fragile settings, is an area worth further investigation. This review and framework contribute to that debate.

Nest building is impaired in the Ts65Dn mouse model of Down syndrome and rescued by blocking 5HT2a receptors.

Down syndrome (DS) has an incidence of about 1/700 births, and is therefore the most common cause of cognitive and behavioral impairments in children. Recent studies on mouse models of DS indicate that a number of pharmacotherapies could be beneficial for restoring cognitive abilities in individuals with DS. Attention deficits that are present in DS account in part for learning and memory deficiencies yet have been scarcely studied in corresponding models. Investigations of this relevant group of behaviors is more difficult in mouse models because of the difficulty in homologizing mouse and human behaviors and because standard laboratory environments do not always elicit behaviors of interest. Here we characterize nest building as a goal-directed behavior that is seriously impaired in young Ts65Dn mice, a genetic model of DS. We believe this impairment may reflect in part attention deficits, and we investigate the physiological, genetic, and pharmacological factors influencing its expression. Nesting behavior in young Ts65Dn mice was severely impaired when the animals were placed in a novel environment. But this context-dependent impairment was transient and reversible. The genetic determinants of this deficiency are restricted to a ∼100 gene segment on the murine chromosome 16. Nest building behavior is a highly integrated phenotypic trait that relies in part on limbic circuitry and on the frontal cortex in relation to cognitive and attention processes. We show that both serotonin content and 5HT2a receptors are increased in the frontal cortex of Ts65Dn mice and that pharmacological blockage of 5HT2a receptors in Ts65Dn mice rescues their context dependent nest building impairment. We propose that the nest-building trait could represent a marker of attention related deficits in DS models and could be of value in designing pharmacotherapies for this specific aspect of DS. 5HT2a modulation may improve goal-directed behavior in DS.

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.

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.

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.

Increased efficiency of the GABAA and GABAB receptor-mediated neurotransmission in the Ts65Dn mouse model of Down syndrome.

Cognitive impairment in Down syndrome (DS) involves the hippocampus. In the Ts65Dn mouse model of DS, deficits in hippocampus-dependent learning and synaptic plasticity were linked to enhanced inhibition. However, the mechanistic basis of changes in inhibitory efficiency remains largely unexplored, and efficiency of the GABAergic synaptic neurotransmission has not yet been investigated in direct electrophysiological experiments. To investigate this important feature of neurobiology of DS, we examined synaptic and molecular properties of the GABAergic system in the dentate gyrus (DG) of adult Ts65Dn mice. Both GABAA and GABAB receptor-mediated components of evoked inhibitory postsynaptic currents (IPSCs) were significantly increased in Ts65Dn vs. control (2N) DG granule cells. These changes were unaccompanied by alterations in hippocampal levels of GABAA (α1, α2, α3, α5 and γ2) or GABAB (Gbr1a and Gbr1b) receptor subunits. Immunoreactivity for GAD65, a marker for GABAergic terminals, was also unchanged. In contrast, there was a marked change in functional parameters of GABAergic synapses. Paired stimulations showed reduced paired-pulse ratios of both GABAA and GABAB receptor-mediated IPSC components (IPSC2/IPSC1), suggesting an increase in presynaptic release of GABA. Consistent with increased gene dose, the level of the Kir3.2 subunit of potassium channels, effectors for postsynaptic GABAB receptors, was increased. This change was associated with enhanced postsynaptic GABAB/Kir3.2 signaling following application of the GABAB receptor agonist baclofen. Thus, both GABAA and GABAB receptor-mediated synaptic efficiency is increased in the Ts65Dn DG, thus likely contributing to deficient synaptic plasticity and poor learning in DS.

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.