Allele-Specific Chromosome Removal after Cas9 Cleavage in Human Embryos.

Correction of disease-causing mutations in human embryos holds the potential to reduce the burden of inherited genetic disorders and improve fertility treatments for couples with disease-causing mutations in lieu of embryo selection. Here, we evaluate repair outcomes of a Cas9-induced double-strand break (DSB) introduced on the paternal chromosome at the EYS locus, which carries a frameshift mutation causing blindness. We show that the most common repair outcome is microhomology-mediated end joining, which occurs during the first cell cycle in the zygote, leading to embryos with non-mosaic restoration of the reading frame. Notably, about half of the breaks remain unrepaired, resulting in an undetectable paternal allele and, after mitosis, loss of one or both chromosomal arms. Correspondingly, Cas9 off-target cleavage results in chromosomal losses and hemizygous indels because of cleavage of both alleles. These results demonstrate the ability to manipulate chromosome content and reveal significant challenges for mutation correction in human embryos.

Hyperactive Rac stimulates cannibalism of living target cells and enhances CAR-M-mediated cancer cell killing.

The 21kD GTPase Rac is an evolutionarily ancient regulator of cell shape and behavior. Rac2 is predominantly expressed in hematopoietic cells where it is essential for survival and motility. The hyperactivating mutation Rac2E62K also causes human immunodeficiency, although the mechanism remains unexplained. Here, we report that in Drosophila, hyperactivating Rac stimulates ovarian cells to cannibalize neighboring cells, destroying the tissue. We then show that hyperactive Rac2E62K stimulates human HL60-derived macrophage-like cells to engulf and kill living T cell leukemia cells. Primary mouse Rac2+/E62K bone-marrow-derived macrophages also cannibalize primary Rac2+/E62K T cells due to a combination of macrophage hyperactivity and T cell hypersensitivity to engulfment. Additionally, Rac2+/E62K macrophages non-autonomously stimulate wild-type macrophages to engulf T cells. Rac2E62K also enhances engulfment of target cancer cells by chimeric antigen receptor-expressing macrophages (CAR-M) in a CAR-dependent manner. We propose that Rac-mediated cell cannibalism may contribute to Rac2+/E62K human immunodeficiency and enhance CAR-M cancer immunotherapy.

Subnational Projections of Lymphatic Filariasis Elimination Targets in Ethiopia to Support National Level Policy.

BACKGROUND: Lymphatic filariasis (LF) is a debilitating, poverty-promoting, neglected tropical disease (NTD) targeted for worldwide elimination as a public health problem (EPHP) by 2030. Evaluating progress towards this target for national programmes is challenging, due to differences in disease transmission and interventions at the subnational level. Mathematical models can help address these challenges by capturing spatial heterogeneities and evaluating progress towards LF elimination and how different interventions could be leveraged to achieve elimination by 2030. METHODS: Here we used a novel approach to combine historical geo-spatial disease prevalence maps of LF in Ethiopia with 3 contemporary disease transmission models to project trends in infection under different intervention scenarios at subnational level. RESULTS: Our findings show that local context, particularly the coverage of interventions, is an important determinant for the success of control and elimination programmes. Furthermore, although current strategies seem sufficient to achieve LF elimination by 2030, some areas may benefit from the implementation of alternative strategies, such as using enhanced coverage or increased frequency, to accelerate progress towards the 2030 targets. CONCLUSIONS: The combination of geospatial disease prevalence maps of LF with transmission models and intervention histories enables the projection of trends in infection at the subnational level under different control scenarios in Ethiopia. This approach, which adapts transmission models to local settings, may be useful to inform the design of optimal interventions at the subnational level in other LF endemic regions.

An Ensemble Framework for Projecting the Impact of Lymphatic Filariasis Interventions Across Sub-Saharan Africa at a Fine Spatial Scale.

BACKGROUND: Lymphatic filariasis (LF) is a neglected tropical disease targeted for elimination as a public health problem by 2030. Although mass treatments have led to huge reductions in LF prevalence, some countries or regions may find it difficult to achieve elimination by 2030 owing to various factors, including local differences in transmission. Subnational projections of intervention impact are a useful tool in understanding these dynamics, but correctly characterizing their uncertainty is challenging. METHODS: We developed a computationally feasible framework for providing subnational projections for LF across 44 sub-Saharan African countries using ensemble models, guided by historical control data, to allow assessment of the role of subnational heterogeneities in global goal achievement. Projected scenarios include ongoing annual treatment from 2018 to 2030, enhanced coverage, and biannual treatment. RESULTS: Our projections suggest that progress is likely to continue well. However, highly endemic locations currently deploying strategies with the lower World Health Organization recommended coverage (65%) and frequency (annual) are expected to have slow decreases in prevalence. Increasing intervention frequency or coverage can accelerate progress by up to 5 or 6 years, respectively. CONCLUSIONS: While projections based on baseline data have limitations, our methodological advancements provide assessments of potential bottlenecks for the global goals for LF arising from subnational heterogeneities. In particular, areas with high baseline prevalence may face challenges in achieving the 2030 goals, extending the "tail" of interventions. Enhancing intervention frequency and/or coverage will accelerate progress. Our approach facilitates preimplementation assessments of the impact of local interventions and is applicable to other regions and neglected tropical diseases.

Family presence during resuscitation: Perceptions and confidence of intensive care nurses in an Australian metropolitan hospital.

BACKGROUND: While literature supporting family presence during resuscitation (FPDR) was first published over three decades ago, the practice remains controversial. Benefits have been confirmed, and barriers to practice identified through international research. The extent that FPDR is practised in Australian intensive care units (ICUs) is currently unknown. OBJECTIVES: To examine ICU nurses' previous exposure and experiences with FPDR To establish their perceptions of the risks and benefits of the practice, as well as their confidence participating. METHODS: A descriptive, cross-sectional study design, using validated FPDR risk-benefits and confidence scales, was distributed electronically to registered nurses working within a single adult ICU in Australia. RESULTS: Fifty-six percent (n = 45) of respondents had never witnessed FPDR. Respondents were divided on whether families had the right to be present or should be given the option. ICU nurses perceived benefits for families but not for the patients involved or for the nurses participating. Nurses indicated they felt conflicted between the needs of the family, preserving the quality of the care delivered to a deteriorating patient, and protecting the safety of all stakeholders. Support for FPDR was often dependent on the availability of resources such as a family-support person. CONCLUSION: This research establishes that ICU nurses lacked exposure to FPDR but were confident in their ability to perform, be observed, and support families during a resuscitation event. Therefore, confidence is likely not a factor in a decision to reject the practice. Further education is indicated as there remained a reluctance to adopt FPDR practice, despite many of the barriers reported having already been largely disproven by the available literature. Institutions have a role in policy development, ensuring adequate resources, and education.

Risk factors associated with higher mortality in patients with cardiac implantable electronic device infection.

INTRODUCTION: Cardiac Implantable Electronic Devices (CIEDs) are widely used for the management of advanced heart failure and ventricular arrhythmias. CIED-Infection (CIED-I) has very high mortality, especially in the subsets of patients with limited health-care access and delayed presentation. The purpose of this study is to identify the risk-predictors mortality in subjects with CIED-I. METHODS: We performed a retrospective cohort study of a regional database in patients presenting with CIED infections to tertiary care medical centers across Western New York, USA from 2012 to 2020. The clinical outcomes included recurrent device infection (any admission for CIED-I after the first hospitalization for device infection), septic complications (pulmonary embolism, respiratory failure, septic shock, decompensated HF, acute kidney injury) and mortality outcomes (death during hospitalization, within 30 days from CIED-I, and within 1 year from CIED-I). We studied associations between categorical variables and hard outcomes using χ2 tests and used one-way analysis of variance to measure between-groups differences. RESULTS: We identified 296 patients with CIED-I, among which 218 (74%) were male, 237 (80%) were white and the mean age at the time of infection was 69.2 ± 13.7 years. One-third of the patients were referred from the regional facilities. Staphylococcus aureus was responsible for most infections, followed by Enterococcus fecalis. On multivariate analysis, the covariates associated with significantly increased mortality risk included referral from regional facility (OR: 2.0;1.0-4.0), hypertension (Odds ratio, OR: 3.2;1.3-8.8), right ventricular dysfunction (OR: 2.6;1.2-5.1), end-stage renal disease (OR: 2.6;1.1-6.2), immunosuppression (OR: 11.4;2.5-53.3), and septic shock as a complication of CIED-I (OR: 3.9;1.3-10.8). CONCLUSION: Hypertension, right ventricular dysfunction, immunosuppression, and end-stage renal disease are associated with higher mortality after CIED-I. Disproportionately higher mortality was also noted in subjects referred from the regional facilities. This underscores the importance of early clinical risk-assessment, and the need for a robust referral infrastructure to improve patient outcomes.

Contact Area and Deformation of Escherichia coli Cells Adhered on a Cationic Surface.

When bacteria adhere to surfaces, the chemical and mechanical character of the cell-substrate interface guides cell function and the development of microcolonies and biofilms. Alternately on bactericidal surfaces, intimate contact is critical to biofilm prevention. The direct study of the buried cell-substrate interfaces at the heart of these behaviors is hindered by the small bacterial cell size and inaccessibility of the contact region. Here, we present a total internal reflectance fluorescence depletion approach to measure the size of the cell-substrate contact region and quantify the gap separation and curvature near the contact zone, providing an assessment of the shapes of the near-surface undersides of adhered bacterial cells. Resolution of the gap height is about 10%, down to a few nanometers at contact. Using 1 and 2 µm silica spheres as calibration standards we report that, for flagella-free Escherichia coli (E. coli) adhering on a cationic poly-l-lysine layer, the cell-surface contact and apparent cell deformation vary with adsorbed cell configuration. Most cells adhere by their ends, achieving small contact areas of 0.15 µm2, corresponding to about 1-2% of the cell's surface. The altered Gaussian curvatures of end-adhered cells suggest the flattening of the envelope within the small contact region. When cells adhere by their sides, the contact area is larger, in the range 0.3-1.1 µm2 and comprising up to ∼12% of the cell's total surface. A region of sharper curvature, greater than that of the cells' original spherocylindrical shape, borders the flat contact region in cases of side-on or end-on cell adhesion, suggesting envelope stress. From the measured curvatures, precise stress distributions over the cell surface could be calculated in future studies that incorporate knowledge of envelope moduli. Overall the small contact areas of end-adhered cells may be a limiting factor for antimicrobial surfaces that kill on contact rather than releasing bactericide.

Prioritizing interventions for preventing COVID-19 outbreaks in military basic training.

Like other congregate living settings, military basic training has been subject to outbreaks of COVID-19. We sought to identify improved strategies for preventing outbreaks in this setting using an agent-based model of a hypothetical cohort of trainees on a U.S. Army post. Our analysis revealed unique aspects of basic training that require customized approaches to outbreak prevention, which draws attention to the possibility that customized approaches may be necessary in other settings, too. In particular, we showed that introductions by trainers and support staff may be a major vulnerability, given that those individuals remain at risk of community exposure throughout the training period. We also found that increased testing of trainees upon arrival could actually increase the risk of outbreaks, given the potential for false-positive test results to lead to susceptible individuals becoming infected in group isolation and seeding outbreaks in training units upon release. Until an effective transmission-blocking vaccine is adopted at high coverage by individuals involved with basic training, need will persist for non-pharmaceutical interventions to prevent outbreaks in military basic training. Ongoing uncertainties about virus variants and breakthrough infections necessitate continued vigilance in this setting, even as vaccination coverage increases.

Women's perspectives on disrespect and abuse during facility-based childbirth in Ethiopia: a qualitative study.

BACKGROUND: Disrespect and abuse violates women's basic human rights and autonomy and can traumatize women who are already in a vulnerable position during childbirth and deter them from utilizing skilled care for future childbirth. This study explored women's perspectives on the acceptability of disrespect and abuse during facility-based childbirth in Ethiopia. METHODS: A qualitative descriptive design using five focus group discussions and fifteen in-depth, semi-structured, interviews was conducted with women between October 2019 to January 2020 in north Showa zone of Oromia region, central Ethiopia. Using purposive sampling, women who had given birth at public health facilities of North Showa zone during the twelve months preceding data collection were recruited, regardless of birth outcome. Inductive thematic analysis using Open Code software was used to explore the perspectives of participants. RESULTS: While women reject disrespectful and abusive acts during childbirth generally, they may consider some disrespectful acts as acceptable and or necessary under certain circumstances. Four emerging themes were identified. (1) Disrespect and abuse is not acceptable, (2) Disrespectful and abusive actions are acceptable only if intended to save lives, (3) Disrespectful and abusive actions are an accepted part of everyday practice to prevent complications and adverse outcomes, (4) Disrespectful and abusive actions are necessary to discipline disobedient women. CONCLUSION: Women's perceptions of disrespectful and abusive acts of care providers is deeply rooted within the context of violence in Ethiopia and the societal hierarchies that have systematically disempowered women. Given the pervasiveness of disrespect and abusive actions during childbirth, policymakers, clinical managers and care providers must take these essential contextual and societal norms into account and devise comprehensive clinical interventions that addresses the root causes.

Polyphosphate is an extracellular signal that can facilitate bacterial survival in eukaryotic cells.

Polyphosphate is a linear chain of phosphate residues and is present in organisms ranging from bacteria to humans. Pathogens such as Mycobacterium tuberculosis accumulate polyphosphate, and reduced expression of the polyphosphate kinase that synthesizes polyphosphate decreases their survival. How polyphosphate potentiates pathogenicity is poorly understood. Escherichia coli K-12 do not accumulate detectable levels of extracellular polyphosphate and have poor survival after phagocytosis by Dictyostelium discoideum or human macrophages. In contrast, Mycobacterium smegmatis and Mycobacterium tuberculosis accumulate detectable levels of extracellular polyphosphate, and have relatively better survival after phagocytosis by D. discoideum or macrophages. Adding extracellular polyphosphate increased E. coli survival after phagocytosis by D. discoideum and macrophages. Reducing expression of polyphosphate kinase 1 in M. smegmatis reduced extracellular polyphosphate and reduced survival in D. discoideum and macrophages, and this was reversed by the addition of extracellular polyphosphate. Conversely, treatment of D. discoideum and macrophages with recombinant yeast exopolyphosphatase reduced the survival of phagocytosed M. smegmatis or M. tuberculosisD. discoideum cells lacking the putative polyphosphate receptor GrlD had reduced sensitivity to polyphosphate and, compared to wild-type cells, showed increased killing of phagocytosed E. coli and M. smegmatis Polyphosphate inhibited phagosome acidification and lysosome activity in D. discoideum and macrophages and reduced early endosomal markers in macrophages. Together, these results suggest that bacterial polyphosphate potentiates pathogenicity by acting as an extracellular signal that inhibits phagosome maturation.

Depletion attractions drive bacterial capture on both non-fouling and adhesive surfaces, enhancing cell orientation.

Depletion attractions, occurring between surfaces immersed in a polymer solution, drive bacteria adhesion to a variety of surfaces. The latter include the surfaces of non-fouling coatings such as hydrated polyethylene glycol (PEG) layers but also, as demonstrated in this work, surfaces that are bacteria-adhesive, such as that of glass. Employing a flagella free E. coli strain, we demonstrate that cell adhesion on glass is enhanced by dissolved polyethylene oxide (PEO), exhibiting a faster rate and greater numbers of captured cells compared with the slower capture of the same cells on glass from a buffer solution. After removal of depletant, any cell retention appears to be governed by the substrate, with cells immediately released from non-fouling PEG surfaces but retained on glass. A distinguishing feature of cells captured by depletion on PEG surfaces is their orientation parallel to the surface and very strong alignment with flow. This suggests that, in the moments of capture, cells are able to rotate as they adhere. By contrast on glass, captured cells are substantially more upright and less aligned by flow. On glass the free polymer exerts forces that slightly tip cells towards the surface. Free polymer also holds cells still on adhesive and non-fouling surfaces alike but, upon removal of free PEO, cells retained on glass tend to be held by one end and exhibit a Brownian type rotational rocking.

Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.

Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.

Predicting lymphatic filariasis elimination in data-limited settings: A reconstructive computational framework for combining data generation and model discovery.

Although there is increasing importance placed on the use of mathematical models for the effective design and management of long-term parasite elimination, it is becoming clear that transmission models are most useful when they reflect the processes pertaining to local infection dynamics as opposed to generalized dynamics. Such localized models must also be developed even when the data required for characterizing local transmission processes are limited or incomplete, as is often the case for neglected tropical diseases, including the disease system studied in this work, viz. lymphatic filariasis (LF). Here, we draw on progress made in the field of computational knowledge discovery to present a reconstructive simulation framework that addresses these challenges by facilitating the discovery of both data and models concurrently in areas where we have insufficient observational data. Using available data from eight sites from Nigeria and elsewhere, we demonstrate that our data-model discovery system is able to estimate local transmission models and missing pre-control infection information using generalized knowledge of filarial transmission dynamics, monitoring survey data, and details of historical interventions. Forecasts of the impacts of interventions carried out in each site made by the models estimated using the reconstructed baseline data matched temporal infection observations and provided useful information regarding when transmission interruption is likely to have occurred. Assessments of elimination and resurgence probabilities based on the models also suggest a protective effect of vector control against the reemergence of LF transmission after stopping drug treatments. The reconstructive computational framework for model and data discovery developed here highlights how coupling models with available data can generate new knowledge about complex, data-limited systems, and support the effective management of disease programs in the face of critical data gaps.

Identification and Preliminary Structure-Activity Relationship Studies of 1,5-Dihydrobenzo[e][1,4]oxazepin-2(3H)-ones That Induce Differentiation of Acute Myeloid Leukemia Cells In Vitro.

Acute myeloid leukemia (AML) is the most aggressive type of blood cancer, and there is a continued need for new treatments that are well tolerated and improve long-term survival rates in patients. Induction of differentiation has emerged as a promising alternative to conventional cytotoxic chemotherapy, but known agents lack efficacy in genetically distinct patient populations. Previously, we established a phenotypic screen to identify small molecules that could stimulate differentiation in a range of AML cell lines. Utilising this strategy, a 1,5-dihydrobenzo[e][1,4]oxazepin-2(3H)-one hit compound was identified. Herein, we report the hit validation in vitro, structure-activity relationship (SAR) studies and the pharmacokinetic profiles for selected compounds.

Elimination or Resurgence: Modelling Lymphatic Filariasis After Reaching the 1% Microfilaremia Prevalence Threshold.

The low prevalence levels associated with lymphatic filariasis elimination pose a challenge for effective disease surveillance. As more countries achieve the World Health Organization criteria for halting mass treatment and move on to surveillance, there is increasing reliance on the utility of transmission assessment surveys (TAS) to measure success. However, the long-term disease outcomes after passing TAS are largely untested. Using 3 well-established mathematical models, we show that low-level prevalence can be maintained for a long period after halting mass treatment and that true elimination (0% prevalence) is usually slow to achieve. The risk of resurgence after achieving current targets is low and is hard to predict using just current prevalence. Although resurgence is often quick (<5 years), it can still occur outside of the currently recommended postintervention surveillance period of 4-6 years. Our results highlight the need for ongoing and enhanced postintervention monitoring, beyond the scope of TAS, to ensure sustained success.

Food Bank-Based Diabetes Prevention Intervention to Address Food Security, Dietary Intake, and Physical Activity in a Food-Insecure Cohort at High Risk for Diabetes.

PURPOSE AND OBJECTIVES: Although food insecurity is associated with poor dietary intake and risk of chronic disease, few studies have demonstrated the effectiveness of diabetes prevention interventions delivered through food banks. Food banks serve vulnerable communities. The purpose of this pilot project was to assess the effectiveness of a food bank-delivered intervention aimed at improving food security and reducing risk factors for type 2 diabetes among at-risk clients. INTERVENTION APPROACH: We screened adult English- and Spanish-speaking food bank clients for type 2 diabetes risk at 12 community food distribution sites in Alameda County, California. Screening and enrollment for a pilot intervention took place from November 2017 to March 2018. Intervention components were delivered from November 2017 through March 2019. The intervention included monthly diabetes-appropriate food packages, text-based health education, and referrals to health care. EVALUATION METHODS: Food bank staff members administered surveys to participants at baseline, 6 months (midpoint), and 12 months (postintervention); participants self-reported all responses. Primary outcomes assessed were food security status, dietary intake, health-related behaviors, and body mass index (BMI). Information on demographic characteristics, food pantry access, health care use, and symptoms of depression was also collected. RESULTS: We screened 462 food bank clients for eligibility. Of the 299 who were eligible, 244 enrolled; 90.6% were female, 80.1% were Hispanic, and 49.1% had an annual household income less than $20,000. At baseline, 68.8% of participants had low or very low food security. At midpoint, participants had significant improvements in food security status, dietary intake, physical activity, health status, and depression scores. Mean BMI did not change. IMPLICATIONS FOR PUBLIC HEALTH: This intervention demonstrated that food banks can effectively screen clients at high risk for diabetes and improve household food security and other risk factors for diabetes. Food banks may be an important and strategic partner for health care systems or community-based organizations working to prevent diabetes in food-insecure populations.

A Dose-Response Analysis of Crystalloid Administration during Esophageal Resection.

OBJECTIVES: The purpose of this retrospective study was to investigate the role of intraoperative crystalloid administration on postoperative hospital length of stay (phLOS) and on the incidence of previously reported adverse events in 100 consecutive patients who underwent esophageal resection. METHODS: The role of previously reported patient demographics, clinical characteristics, and intraoperative crystalloid administration on the duration of phLOS underwent statistical screening criteria for multivariable analysis, including the use of an instrumental variable to measure the role of unmeasured confounders on phLOS. Tests to assess the likelihood of causality also were performed. RESULTS: When the volumes of intraoperative crystalloids were expressed as dose-response relationships to outcomes, progressive decreases in phLOS, variances in phLOS, and the incidences of unplanned surgical intensive care unit admission, postoperative pneumonia, respiratory failure requiring orotracheal intubation, nonsinus cardiac dysrhythmias, and anastomotic leak were observed. Intraoperative transfusion of packed red blood cells greatly increased the duration of phLOS, which was not associated with estimated blood loss, length of surgical operation, or unplanned surgical intensive care unit admission. Instrumental variable analysis revealed no significant influence on phLOS. Causality tests supported the role of intraoperative crystalloid administration in reducing the duration and variance of phLOS. CONCLUSIONS: A dose-response relationship was clinically observed between intraoperative crystalloid administration and the duration and variance of phLOS and with commonly reported postoperative adverse events. Intraoperative transfusion of packed red blood cells greatly increased phLOS that was not associated with the severity of the surgical operation. Instrumental variables and tests for causality further supported the role of intraoperative crystalloid administration in reducing the duration and variance of phLOS.

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models.

Background: With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling. Methods: We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%. Results: Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance). Conclusions: Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

Death effects of reveromycin A in normal and disease-associated cells of the joint.

Earlier work in our laboratory demonstrated that naturally occurring reveromycin A (Rev A) causes apoptosis in osteoclasts without accompanying necrosis. Rev A death effects in both normal and diseased joint cells were investigated in this study. A dose of 10 µM Rev A did not cause apoptosis nor necrosis in monolayer chondrocytes, even at pH 6.8, a pH mimicking that of an inflamed joint. In contrast, at the acidic pH Rev A did induce significant apoptosis (fourfold increase at 48 h of treatment, P < 0.005) in normal synoviocytes without accompanying necrosis. Western blot of the normal synoviocyte proteins revealed that cytochrome c levels were not significantly changed over the time course of treatment nor did caspase 8 activity increase; therefore, Rev A appears to exert this apoptotic effect through a mechanism independent of the classical intrinsic and extrinsic pathways. Fibroblast-like synoviocytes isolated from rheumatoid arthritis patients (RAFLS) as well as normal human fibroblast-like synoviocytes (NHFLS), cells known to play key roles in arthritic joint pathology, were also subjected to Rev A treatment at both physiologic and acidic pH's. Neither apoptosis nor necrosis was induced in either RAFLS or NHFLS. Parallel mitomycin C treatment of NHFLS induced both apoptosis and necrosis. Comparative structure-activity analyses of Rev A and mitomycin C revealed that Rev A is less likely to cross the cell membrane at near neutral pH. Collectively the data reveal that a physiological dose of Rev A under acidic conditions induces normal synoviocytes to undergo apoptosis while pathologic fibroblast-like synoviocytes are resistant to apoptosis and necrosis.

Comprehensive Diabetes Self-Management Support From Food Banks: A Randomized Controlled Trial.

OBJECTIVES: To determine whether food bank provision of self-management support and diabetes-appropriate food improves glycemic control among clients with diabetes. METHODS: We screened 5329 adults for diabetes at food pantries (n = 27) affiliated with food banks in Oakland, California; Detroit, Michigan; and Houston, Texas, between October 2015 and September 2016. We individually randomized 568 participants with hemoglobin A1c (HbA1c) 7.5% or greater to waitlist control or 6-month intervention including food, diabetes education, health care referral, and glucose monitoring. The primary outcome was HbA1c at 6 months. RESULTS: Food security (relative risk [RR] = 0.85; 95% confidence interval [CI] = 0.73, 0.98), food stability (RR = 0.77; 95% CI = 0.64, 0.93), and fruit and vegetable intake (risk difference [RD] = 0.34; 95% CI = 0.34, 0.34) significantly improved among intervention participants. There were no differences in self-management (depressive symptoms, diabetes distress, self-care, hypoglycemia, self-efficacy) or HbA1c (RD = 0.24; 95% CI = -0.09, 0.58). CONCLUSIONS: Food banks are ideally situated to provide diabetes-appropriate food to food-insecure households. Effective strategies for food banks to support improvements in diabetes clinical outcomes require additional study. Public Health Implications. Moving chronic disease support from clinics into communities expands reach into vulnerable populations. However, it is unclear how community interventions should be integrated with clinical care to improve disease outcomes. TRIAL REGISTRATION NUMBER: NCT02569060.