Defining the ethical considerations surrounding kidney transplantation for frail and cognitively impaired patients: a Delphi study of geriatric transplant experts.

BACKGROUND: Among adult kidney transplant (KT) candidates, 21% are frail and 55% have cognitive impairment, increasing the risk of pre- and post-KT mortality. Centers often assess frailty status and cognitive function during transplant evaluation to help identify appropriate candidate. Yet, there are no ethical guidelines regarding the use of frailty and cognitive function during this evaluation. We seek to develop a clinical consensus on balancing utility and justice in access to KT for frail and cognitively impaired patients. METHODS: Twenty-seven experts caring for ESRD patients completed a two-round Delphi panel designed to facilitate consensus (> 80% agreement). RESULTS: Experts believed that denying patients transplantation based solely on expected patient survival was inequitable to frail or cognitively impaired candidates; 100% agreed that frailty and cognitive impairment are important factors to consider during KT evaluation. There was consensus that health related quality of life and social support are important to consider before waitlisting frail or cognitively impaired patients. Experts identified important factors to consider before waitlisting frail (likely to benefit from KT, frailty reversibility, age, and medical contraindications) and cognitively impaired (degree of impairment and medication adherence) patients. CONCLUSIONS: Clinical experts believed it was ethically unacceptable to allocate organs solely based on patients' expected survival; frailty and cognitive impairment should be measured at evaluation when weighed against other clinical factors. Ethical guidelines regarding the use of frailty and cognitive function during KT evaluation ought to be developed.

Comparability of family planning quality of care measurement tools in low-and-middle income country settings: a systematic review.

BACKGROUND: In low-and-middle income countries (LMICs), accurate measures of the elements of quality care provided by a health worker through family planning services (also known as process quality) are required to ensure family's contraceptives needs are being met. There are many tools used to assess family planning process quality of care (QoC) but no one standardized method. Those measuring QoC in LMICs should select an appropriate tool based the program context and financial/logistical parameters, but they require data on how well each tool measures routine clinical care. We aim to synthesize the literature on validity/comparability of family planning process QoC measurement tools through a quantitative systematic review with no meta-analysis. METHODS: We searched six literature databases for studies that compared quality measurements from different tools using quantitative statistics such as sensitivity/specificity, kappa statistic or absolute difference. We extracted the comparative measure along with other relevant study information, organized by quality indicator domain (e.g. counseling and privacy), and then classified the measure by low, medium, and high agreement. RESULTS: We screened 8172 articles and identified eight for analysis. Studies comparing quality measurements from simulated clients, direct observation, client exit interview, provider knowledge quizzes, and medical record review were included. These eight studies were heterogenous in their methods and the measurements compared. There was insufficient data to estimate overall summary measures of validity for the tools. Client exit interviews compared to direct observation or simulated client protocols had the most data and they were a poor proxy of the actual quality care received for many measurements. CONCLUSION: To measure QoC consistently and accurately in LMICs, standardized tools and measures are needed along with an established method of combining them for a comprehensive picture of quality care. Data on how different tools proxy quality client care will inform these guidelines. Despite the small number of studies found during the review, we described important differences on how tools measure quality of care.

Accurate measures of process quality of care­or how well clinicians deliver services according to standards of care­are important to monitor, evaluate and improve service quality. Periodic surveys of health facilities or provider are the main source of national or regional quality of care data in many low- and middle-income countries. Many tools are used for these surveys: exit interviews with patients, observations of the visits by a clinician-assessor, simulated or mystery patients, and others. Implementers must select the appropriate and feasible tools for their program, context and setting but there is little information on how well different tools measure the same quality of care indicators.This review summarizes the current literature on the validity of measurements from different family planning quality of care tools. We found only eight studies, but we were able to see some differences important to consider when selecting the most appropriate tool. For instance, patients reported different events through an exit interview than what was documented by the assessor during the same visit. Exit interviews may be more appropriate to measure client experience or satisfaction rather than specifics of the care received. Knowing these differences will help implementers choose an appropriate tool depending on the focus of the quality assessment. This review contributes to the body of knowledge on improving quality of care measurements, resulting in better data to improve family planning services for patients.

Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen.

BACKGROUND/PURPOSE: High serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE. METHODS: We previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture. RESULTS: We find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10-6). We also find SNPs in the PPM1H, PTPRM, and NRGN regions associated with IFN-α levels in European-American, Amerindian, and African-American SLE patients respectively. Many of these associations are within regulatory regions of the gene, suggesting an impact on transcription. CONCLUSION: This study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.

Racial differences in inflammation and outcomes of aging among kidney transplant candidates.

BACKGROUND: Inflammation is more common among African Americans (AAs), and it is associated with frailty, poor physical performance, and mortality in community-dwelling older adults. Given the elevated inflammation levels among end-stage renal disease (ESRD) patients, inflammation may be associated with adverse health outcomes such as frailty, physical impairment, and poor health-related quality of life (HRQOL), and these associations may differ between AA and non-AA ESRD patients. METHODS: One thousand three ESRD participants were recruited at kidney transplant evaluation (4/2014-5/2017), and inflammatory markers (interleukin-6 [IL-6], tumor necrosis factor-a receptor-1 [TNFR1], C-reactive protein [CRP]) were measured. We quantified the association with frailty (Fried phenotype), physical impairment (Short Physical Performance Battery [SPPB]), and fair/poor HRQOL at evaluation using adjusted modified Poisson regression and tested whether these associations differed by race (AA vs. non-AA). RESULTS: Non-AAs had lower levels of TNFR1 (9.7 ng/ml vs 14.0 ng/ml, p < 0.001) and inflammatory index (6.7 vs 6.8, p < 0.001) compared to AAs, but similar levels of IL-6 (4.5 pg/ml vs 4.3 pg/ml, p > 0.9) and CRP (4.7 µg/ml vs 4.9 µg/ml, p = 0.4). Non-AAs had an increased risk of frailty with elevated IL-6 (RR = 1.58, 95% CI:1.27-1.96, p < 0.001), TNFR1 (RR = 1.60, 95% CI:1.25-2.05, p < 0.001), CRP (RR = 1.41, 95% CI:1.10-1.82, p < 0.01), and inflammatory index (RR = 1.82, 95% CI:1.44-2.31, p < 0.001). The associations between elevated inflammatory markers and frailty were not present among AAs. Similar results were seen with SPPB impairment and poor/fair HRQOL. CONCLUSIONS: Non-AAs with elevated inflammatory markers may need closer follow-up and may benefit from prehabilitation to improve physical function, reduce frailty burden, and improve quality of life prior to transplant.

Strengthening primary health care through community health workers in South Asia.

The growing health challenges in South Asia require further adaptations of community health worker (CHW) programs as a key element of primary health care (PHC). This paper provides a comparative analysis of CHW programs in five countries (Bangladesh, India, Nepal, Pakistan, and Sri Lanka), examines successes and challenges, and suggests reforms to better ensure highly performing CHW programs. To examine CHW programs in the region, we conducted a narrative review of the peer-reviewed and grey literatures, as well as eliciting opinions from experts. Common roles of CHWs include health education, community mobilization, and community-based services, particularly related to reproductive, maternal, neonatal, and child health. Some countries utilize CHWs for non-communicable diseases and other emerging health issues. To maximize the potential contribution of CHWs to achieving Universal Health Coverage, we recommend future research and policy focus on strengthening existing health systems to support the expansion of CHWs roles and better integrating of CHWs into national PHC systems. This is Paper 4 in the Series on Primary Health Care in South Asia, addressing areas that have the potential to revitalize health systems in South Asian countries. Funding: The authors received financial support from the Department of Health Systems Development, WHO South-East Asia Regional Office (WHO SEAR).

Patient Perspectives on the Use of Aging Metrics for Kidney Transplant Decision-Making.

INTRODUCTION: Frailty and cognitive function are often measured during kidney transplant evaluation. However, patient perspectives on the ethical considerations of this practice are unclear. RESEARCH QUESTION: What are patient perspectives on the use of aging metrics in kidney transplant decision-making? DESIGN: One hundred participants who were evaluated for kidney transplantation and were enrolled in an ongoing prospective cohort study (response rate = 61.3%) were surveyed. Participants were informed of the definitions of frailty and cognitive impairment and then asked survey questions regarding the use of these measures of aging to determine kidney transplant candidacy. RESULTS: Participants (75.6%) thought it was unfair to prevent older adults from receiving a kidney transplant based on age, but there was less agreement on whether it was fair to deny frail (46.5%) and cognitively impaired (45.9%) patients from accessing kidney transplantation. Compared to older participants, younger participants had 5.36-times (95%CI:1.94-14.81) the odds of choosing a hypothetical younger, frail patient to list for kidney transplantation than an older, non-frail patient; they also had 3.56-times (95%CI:1.33-9.56) the odds of choosing the hypothetical frail patient with social support rather than a non-frail patient without social support. Participants disagreed on the use of patient age as a listing criterion; 19.5% ranked it as the fairest and 28.7% as the least fair. CONCLUSION: The patient views highlighted in this study are an important step toward developing ethical guidelines to ensure fair use of frailty, cognitive function, and chronological age for kidney transplant decision-making.

Recruiting hard-to-reach populations via respondent driven sampling for mobile phone surveys in Colombia: a qualitative study.

BACKGROUND: Uptake of mobile phone surveys (MPS) is increasing in many low- and middle-income countries, particularly within the context of data collection on non-communicable diseases (NCDs) behavioural risk factors. One barrier to collecting representative data through MPS is capturing data from older participants.Respondent driven sampling (RDS) consists of chain-referral strategies where existing study subjects recruit follow-up participants purposively based on predefined eligibility criteria. Adapting RDS strategies to MPS efforts could, theoretically, yield higher rates of participation for that age group. OBJECTIVE: To investigate factors that influence the perceived acceptability of a RDS recruitment method for MPS involving people over 45 years of age living in Colombia. METHODS: An MPS recruitment strategy deploying RDS techniques was piloted to increase participation of older populations. We conducted a qualitative study that drew from surveys with open and closed-ended items, semi-structured interviews for feedback, and focus group discussions to explore perceptions of the strategy and barriers to its application amongst MPS participants. RESULTS: The strategy's success is affected by factors such as cultural adaptation, institutional credibility and public trust, data protection, and challenges with mobile phone technology. These factors are relevant to individuals' willingness to facilitate RDS efforts targeting hard-to-reach people. Recruitment strategies are valuable in part because hard-to-reach populations are often most accessible through their contacts within their social network who can serve as trust liaisons and drive engagement. CONCLUSIONS: These findings may inform future studies where similar interventions are being considered to improve access to mobile phone-based data collection amongst hard-to-reach groups.

Towards achieving transnational research partnership equity: lessons from implementing adaptive platform trials in low- and middle-income countries.

Background: Use of adaptive clinical trials, particularly adaptive platform trials, has grown exponentially in response to the coronavirus disease (COVID-19) pandemic. Implementation of these trials in low- and middle-income countries (LMICs) has been fostered through the formation or modification of transnational research partnerships, typically between research groups from LMICs and high-income countries (HICs). While these partnerships are important to promote collaboration and overcome the structural and economic disadvantages faced by LMIC health researchers, it is critical to focus attention on the multiple dimensions of partnership equity. Methods: Based on informal literature reviews and a meeting with leaders of one of the multinational COVID-19 adaptive platform trials, we describe some important considerations about research partnership equity in this context. Results: We organize these considerations into eight thematic categories: 1) epistemic structures, 2) funding, 3) ethics oversight, 4) regulatory oversight, 5) leadership, 6) post-trial access to interventions, data, and specimens, 7) knowledge translation and dissemination, and 8) research capacity strengthening and maintenance. Within each category we review normative claims that support its relevance to research partnership equity followed by discussion of how adaptive platform trials highlight new dimensions, considerations, or challenges. Conclusion: In aggregate, these observations provide insight into procedural and substantive equity-building measures within transnational global health research partnerships more broadly.

Challenges in Providing Reproductive and Gynecologic Care to Women With Intellectual Disabilities: A Review of Existing Literature.

Objective: Our review aims to focus on identifying challenges faced by intellectually disabled women (IDW) in receiving gynecological and reproductive care and also highlights evidence based strategies to overcome those challenges. Materials and methods: We conducted a literature review discussing challenges faced by IDW in obtaining healthcare services by thorough search on various electronic databases (PubMed, Google Scholar, and Scopus) starting from 2000 to 28 August 2021 excluding all non-english articles, reviews, editorials and letters to editor. The keywords used for search were "reproductive care", "gynecologic care", "intellectual disability", "mental handicap", and "mental retardation". Results: The existing literature review showed that IDW have difficulty maintaining menstrual hygiene and lack knowledge regarding contraception use and sexual health resulting in violations of their reproductive rights. Sexually transmitted diseases and cervical cancer are common among IDW due to their vulnerability to sexual abuse. Nulliparity in IDW increases their suspectibility to even breast cancer. Moreover, they face problems with sexually transmitted infection (STI) and cancer screening due to physical barriers for assessment, low socio-economic status, physician-patient communication issues and deficit in skilled providers. Short acting sedatives such as ketamine or midazolam can be used to overcome challenges faced with gynecological and obstetric examination. Finally forced sterilization and institutionalization has been a habitual practice as menstrual hygiene and pregnancy in IDW raise concerns on psychosocial challenges along with associated obstetric complications. Conclusion: Reproductive and sexual health education including contraception use can be provided by using evidence based strategies involving use of pictures, animations and models by adequately trained healthcare providers including midwives. Further research involving IDW is needed to allow state-wise laws and policies to be created to mitigate the challenges and improve health outcomes in this population.

Portal vein thrombosis as a thrombotic complication of COVID-19 mRNA vaccine: A case report and literature review.

Thrombosis following COVID-19 vaccination commonly occurs with vector-based vaccines. The proposed mechanism is vaccine-induced thrombotic thrombocytopenia (VITT), with thrombocytopenia as principal manifestation. We present a 51-year-old male who came with isolated portal vein thrombosis (PVT) one day after Moderna vaccination, without associated thrombocytopenia, challenging VITT as being the only patho-mechanism. Further exploration of these possible alternative mechanisms is needed for COVID-19 vaccine-related thrombotic complications.

Characteristics of COVID-19 Breakthrough Infections among Vaccinated Individuals and Associated Risk Factors: A Systematic Review.

We sought to assess breakthrough SARS-CoV-2 infections in vaccinated individuals by variant distribution and to identify the common risk associations. The PubMed, Web of Science, ProQuest, and Embase databases were searched from 2019 to 30 January 2022. The outcome of interest was breakthrough infections (BTIs) in individuals who had completed a primary COVID-19 vaccination series. Thirty-three papers were included in the review. BTIs were more common among variants of concern (VOC) of which Delta accounted for the largest number of BTIs (96%), followed by Alpha (0.94%). In addition, 90% of patients with BTIs recovered, 11.6% were hospitalized with mechanical ventilation, and 0.6% resulted in mortality. BTIs were more common in healthcare workers (HCWs) and immunodeficient individuals with a small percentage found in fully vaccinated healthy individuals. VOC mutations were the primary cause of BTIs. Continued mitigation approaches (e.g., wearing masks and social distancing) are warranted even in fully vaccinated individuals to prevent transmission. Further studies utilizing genomic surveillance and heterologous vaccine regimens to boost the immune response are needed to better understand and control BTIs.

The Past, Present and Future of COVID-19 Associated Mucormycosis: A Rapid Review.

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, which is known for the multiple mutations and forms that have rapidly spread across the world. With the imminent challenges faced by low- and middle-income countries in curbing the public health fallbacks due to limited resources, mucormycosis emerged as a fungal infection associated with high mortality. In this rapid review, we explored MEDLINE, Cochrane, Web of Science, WHO Global Database, and the search engine-Google Scholar for articles listed until July 2021 and presented a narrative synthesis of findings from 39 articles. The epidemiology, causative factors, incidence parameters, pharmacological treatment, and recommendations for low- and middle-income countries are enlisted. This study concludes that a majority of the globally reported COVID-19 associated mucormycosis cases stemmed from India. Individuals receiving systemic corticosteroids or who have a history of diabetes mellitus are more prone to contracting the disease. Public health authorities in LMIC are recommended to strengthen antifungal therapies for COVID-19 associated mucormycosis and to strategize reduction in diabetes mellitus prevalence.

Initiation of Liver Transplant in Nepal: A Milestone.

Background: The incidence of chronic liver disease is increasing in the Nepalese population. Liver transplantation (LT) is the best option for patients with end-stage liver disease (ESLD). Nepal's first liver transplant was performed in 2016 in an international collaborative effort at Shahid Dharmabhakta National Transplant Centre (SDNTC), Bhaktapur, Nepal. We aim to report details of the first five patients who had undergone liver transplantation in SDNTC before the beginning of the COVID-19 outbreak in the history of transplantation in Nepal. Method: A descriptive analysis of the clinical data of five adult recipients of liver transplantation at SDNTC was done. We described the patient's demographics, length of stay, and survival of all the first five patients who had undergone four living donor liver transplantations and one brain-dead donor liver transplantation in SDNTC before the beginning of the COVID-19 outbreak. Results: Recipients were between 36 and 63 years old. The recipients of the four live donor liver transplants (LDLT) and one brain-dead donor liver transplant (DDLT) had alcoholic liver disease and cryptogenic liver disease, leading to end-stage liver disease. The model for end-stage liver disease (MELD) scores ranged from 23 to 34. Out of five, four recipients and four donors are doing well and relishing the prospect of a normal life, while the recipient of a brain-dead donor liver transplant passed away due to postoperative primary graft failure. Conclusion: Despite the small number of liver transplants that have been done, the success of these has created confidence in a sustainable liver transplantation program in Nepal.

Patient Perspectives on the Use of Frailty, Cognitive Function, and Age in Kidney Transplant Evaluation.

BACKGROUND: The allocation of scarce deceased donor kidneys is a complex process. Transplant providers are increasingly relying on constructs such as frailty and cognitive function to guide kidney transplant (KT) candidate selection. Patient views of the ethical issues surrounding the use of such constructs are unclear. We sought to assess KT candidates' attitudes and beliefs about the use of frailty and cognitive function to guide waitlist selection. METHODS: KT candidates were randomly recruited from an ongoing single-center cohort study of frailty and cognitive function. Semi-structured interviews were conducted, and thematic analysis was performed. Inductively derived themes were mapped onto bioethics principles. RESULTS: Twenty interviews were conducted (65% contact rate, 100% participation rate) (60% male; 70% White). With respect to the use of frailty and cognitive function in waitlisting decisions, four themes emerged in which participants: (1) valued maximizing a scarce resource (utility); (2) prioritized equal access to all patients (equity); (3) appreciated a proportional approach to the use of equity and utility (precautionary utility); and (4) sought to weigh utility- and equity-based concerns regarding social support. While some participants believed frailty and cognitive function were useful constructs to maximize utility, others believed their use would jeopardize equity. Patients were uncomfortable with using single factors such as frailty or cognitive impairment to deny someone access to transplantation; participants instead encouraged using the constructs to identify opportunities for intervention to improve frailty and cognitive function prior to KT. CONCLUSIONS: KT candidates' values mirrored the current allocation strategy, seeking to balance equity and utility in a just manner, albeit with conflicting viewpoints on the appropriate use of frailty and cognitive impairment in waitlisting decisions.

Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment of ENO1-Deleted Cancers.

Cancers harboring homozygous deletion of the glycolytic enzyme enolase 1 (ENO1) are selectively vulnerable to inhibition of the paralogous isoform, enolase 2 (ENO2). A previous work described the sustained tumor regression activities of a substrate-competitive phosphonate inhibitor of ENO2, 1-hydroxy-2-oxopiperidin-3-yl phosphonate (HEX) (5), and its bis-pivaloyoxymethyl prodrug, POMHEX (6), in an ENO1-deleted intracranial orthotopic xenograft model of glioblastoma [Nature Metabolism 2020, 2, 1423-1426]. Due to poor pharmacokinetics of bis-ester prodrugs, this study was undertaken to identify potential non-esterase prodrugs for further development. Whereas phosphonoamidate esters were efficiently bioactivated in ENO1-deleted glioma cells, McGuigan prodrugs were not. Other strategies, including cycloSal and lipid prodrugs of 5, exhibited low micromolar IC50 values in ENO1-deleted glioma cells and improved stability in human serum over 6. The activity of select prodrugs was also probed using the NCI-60 cell line screen, supporting its use to examine the relationship between prodrugs and cell line-dependent bioactivation.

Usefulness of Electoral Models for COVID-19 Vaccine Distribution.

Purpose of Review: In response to the COVID-19 pandemic, there has been a remarkably accelerated development of vaccines worldwide. However, an effective distribution system is crucial for vaccination at a national level. Ecuador was one of the first Latin American countries to be most severely affected by the pandemic. It has been struggling to expand its vaccination drive and requires a strategy that provides an achievable vaccination rate and maintains its primary care services. This study aims to provide an efficient vaccination model to achieve herd immunity by utilizing the country's existing infrastructure (the centralized electoral system) for mass vaccination. Recent Findings: The national electoral data from 2017 and 2021 were used to create estimates for the proposed vaccination model. Two model variations, total personnel, needed, and the number of days needed to vaccinate 50%, 75%, and 100% of the population were considered. The numbers of vaccines needed, and vaccination sites were estimated based on the current number of registered voters and polling stations. The results from the proposed model show that 17,892,353 people can be vaccinated, at 40,093 polling stations, by 90,209 personnel if one vaccinator was available per polling station. Summary: Based on this model, even a conservative estimate shows that 12.56 days are needed to achieve herd immunity, and 16.74 days are needed to vaccinate the entire population of Ecuador. Additionally, we propose that this vaccination model can be used as a blueprint for any country to address similar catastrophes in the future. Supplementary Information: The online version contains supplementary material available at 10.1007/s40475-022-00251-y.

Health system adaptations and considerations to facilitate optimal oral pre-exposure prophylaxis scale-up in sub-Saharan Africa.

Following WHO's 2015 recommendation, countries in sub-Saharan Africa have progressively scaled up oral pre-exposure prophylaxis (PrEP) as part of combination HIV prevention. PrEP has potential to significantly reduce new HIV infections in sub-Saharan Africa if it is widely available, accessible, and effectively used. Initial scale-up efforts have generated progress, drawing lessons from existing HIV interventions, such as antiretroviral therapy and biomedical prevention. However, beset by unprepared health systems, scale-up has been slow, resulting in suboptimal coverage among priority groups at higher risk of HIV acqusition. Using the WHO health system building blocks framework, this Review synthesises literature on essential considerations for PrEP scale-up in sub-Saharan Africa, highlighting the importance of health system adaptability and responsiveness.

HIV PrEP is more than ART-lite: Longitudinal study of real-world PrEP services data identifies missing measures meaningful to HIV prevention programming.

INTRODUCTION: Evidence indicates HIV oral pre-exposure prophylaxis (PrEP) is highly efficacious and effective. Substantial early discontinuation rates are reported by many programs, which may be misconstrued as program failure. However, PrEP use may be non-continuous and still effective, since HIV risk fluctuates. Real-world PrEP use phenomena, like restarting and cyclical use, and the temporal characteristics of these use patterns are not well described. The objective of our study was to characterize and identify predictors of use patterns observed in large PrEP scale-up programs in Africa. METHODS: We analysed demographic and clinical data routinely collected during client visits between 2017 and 2019 in three Jhpiego-supported programs in Kenya, Lesotho and Tanzania. We characterized duration on/off PrEP and, using ordinal regression, modelled the likelihood of spending additional time off and identified factors associated with increasing cycle number. The Andersen-Gill model was used to identify predictors of time to PrEP discontinuation. To analyse factors associated with a client's first return following initiation, we used a two-step Heckman probit. RESULTS: Among 47,532 clients initiating PrEP, approximately half returned for follow-up. With each increase in cycle number, time off PrEP between use cycles decreased. The Heckman first-step model showed an increased probability of returning versus not by older age groups and among key and vulnerable population groups versus the general population; in the second-step model older age groups and key and vulnerable populations were less likely in Kenya, but more likely in Lesotho, to return on-time (refill) versus delayed (restarting). CONCLUSIONS: PrEP users frequently cycle on and off PrEP. Early discontinuation and delays in obtaining additional prescriptions were common, with broad predictive variability noted. Time off PrEP decreased with cycle number in all countries, suggesting normalization of use with experience. More nuanced measures of use are needed than exist for HIV treatment if effective use of PrEP is to be meaningfully measured. Providers should be equipped with measures and counselling messages that recognize non-continuous and cyclical use patterns so that clients are supported to align fluctuating risk and use, and can readily restart PrEP after stopping, in effect empowering them further to make their own prevention choices.

The Influence of Coronavirus Disease-2019 (COVID-19) On Parkinson's Disease: An Updated Systematic Review.

BACKGROUND: COVID-19 has affected global communities with multiple neurological complications in addition to other critical medical issues. COVID-19 binds to the host's angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed in the neurons and glial cells, acting as an entry port to the central nervous system (CNS). ACE2 receptors are abundantly expressed on dopamine neurons, which may worsen the prognosis of motor symptoms in Parkinson's disease (PD). SARS-CoV-2 may lead to an indirect response via immune-mediated cytokine storms and propagate through the CNS leading to damage. In this systematic review, we aim to provide thorough analyses of associations between COVID-19 and neurological outcomes for patients with PD. METHODS: Using PRISMA statement 2020, a systematic review was conducted to isolate confirmed COVID-19 patients and analyze the PD-associated neurological outcomes using the following databases: PubMed, Science Direct, Google Scholar, and Cochrane databases. The following keywords were used "COVID19, SARS-CoV-2, Parkinson's disease, Pandemic, Mortality." A modified Delphi process was employed. RESULTS: Of the 355 studies located during the initial round of screening, 16 were included in the final synthesis. Of PD patients who tested positive for SARS-CoV-2, worsening motor symptoms and other viral-associated symptoms were reported. These symptoms included bradykinesia, tremors, gait disturbances, delirium and dementia, and severe spasms of arms and legs. Encephalopathy was presented in 2 of the included studies. Increased mortality rates were identified for hospitalized patients due to COVID-19 and PD as compared to other patient groups. CONCLUSION: Patients with PD may experience substantial worsening of symptoms due to COVID 19. Given the novelty of neurological-viral associations, clinical studies in the future ought to explore the disease severity and neurological outcomes in COVID-19 positive patients with PD as compared to non-PD patients, in addition to understanding the role of ACE2 in increased vulnerability to contracting the infection and as a treatment modality.

Bioreducible Phosphonoamidate Pro-drug Inhibitor of Enolase: Proof of Concept Study.

Glycolysis inhibition remains aspirational in cancer therapy. We recently described a promising phosphonate inhibitor of enolase for cancers harboring homozygous deletions of ENO1. Here, we describe the application of a nitroheterocycle phosphonoamidate pro-drug pair to capitalize on tumor hypoxia. This bioreducible prodrug exhibits greater-than 2-fold potency under hypoxic conditions compared to normoxia and exhibits robust stability in biological fluids. Our work provides strong in vitro proof-of-concept for using bioreduction as a pro-drug delivery strategy in the context of enolase inhibition.