Imaging Modalities for Assessing the Vascular Component of Diabetic Retinal Disease: Review and Consensus for an Updated Staging System.

Purpose: To review the evidence for imaging modalities in assessing the vascular component of diabetic retinal disease (DRD), to inform updates to the DRD staging system. Design: Standardized narrative review of the literature by an international expert workgroup, as part of the DRD Staging System Update Effort, a project of the Mary Tyler Moore Vision Initiative. Overall, there were 6 workgroups: Vascular Retina, Neural Retina, Systemic Health, Basic and Cellular Mechanisms, Visual Function, and Quality of Life. Participants: The Vascular Retina workgroup, including 16 participants from 4 countries. Methods: Literature review was conducted using standardized evidence grids for 5 modalities: standard color fundus photography (CFP), widefield color photography (WFCP), standard fluorescein angiography (FA), widefield FA (WFFA), and OCT angiography (OCTA). Summary levels of evidence were determined on a validated scale from I (highest) to V (lowest). Five virtual workshops were held for discussion and consensus. Main Outcome Measures: Level of evidence for each modality. Results: Levels of evidence for standard CFP, WFCP, standard FA, WFFA, and OCTA were I, II, I, I, and II respectively. Traditional vascular lesions on standard CFP should continue to be included in an updated staging system, but more studies are required before they can be used in posttreatment eyes. Widefield color photographs can be used for severity grading within the area covered by standard CFPs, although these gradings may not be directly interchangeable with each other. Evaluation of the peripheral retina on WFCP can be considered, but the method of grading needs to be clarified and validated. Standard FA and WFFA provide independent prognostic value, but the need for dye administration should be considered. OCT angiography has significant potential for inclusion in the DRD staging system, but various barriers need to be addressed first. Conclusions: This study provides evidence-based recommendations on the utility of various imaging modalities for assessment of the vascular component of DRD, which can inform future updates to the DRD staging system. Although new imaging modalities offer a wealth of information, there are still major gaps and unmet research needs that need to be addressed before this potential can be realized. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Effective treatment of optic neuropathies by intraocular delivery of MSC-sEVs through augmenting the G-CSF-macrophage pathway.

Optic neuropathies, characterized by injury of retinal ganglion cell (RGC) axons of the optic nerve, cause incurable blindness worldwide. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) represent a promising "cell-free" therapy for regenerative medicine; however, the therapeutic effect on neural restoration fluctuates, and the underlying mechanism is poorly understood. Here, we illustrated that intraocular administration of MSC-sEVs promoted both RGC survival and axon regeneration in an optic nerve crush mouse model. Mechanistically, MSC-sEVs primarily targeted retinal mural cells to release high levels of colony-stimulating factor 3 (G-CSF) that recruited a neural restorative population of Ly6Clow monocytes/monocyte-derived macrophages (Mo/MΦ). Intravitreal administration of G-CSF, a clinically proven agent for treating neutropenia, or donor Ly6Clow Mo/MΦ markedly improved neurological outcomes in vivo. Together, our data define a unique mechanism of MSC-sEV-induced G-CSF-to-Ly6Clow Mo/MΦ signaling in repairing optic nerve injury and highlight local delivery of MSC-sEVs, G-CSF, and Ly6Clow Mo/MΦ as therapeutic paradigms for the treatment of optic neuropathies.

Rapid Onsite Evaluation for Specimen Adequacy and Triage of Breast Masses in a Low-Resource Setting.

CONTEXT.­: Rapid onsite evaluation (ROSE) is critical in determining sample adequacy and triaging cytology samples. Although fine-needle aspiration biopsy (FNAB) is the primary method of initial tissue sampling in Tanzania, ROSE is not practiced. OBJECTIVE.­: To investigate the performance of ROSE in determining cellular adequacy and providing preliminary diagnoses in breast FNAB in a low-resource setting. DESIGN.­: Patients with breast masses were recruited prospectively from the FNAB clinic at Muhimbili National Hospital. Each FNAB was evaluated by ROSE for overall specimen adequacy, cellularity, and preliminary diagnosis. The preliminary interpretation was compared to the final cytologic diagnosis and histologic diagnosis, when available. RESULTS.­: Fifty FNAB cases were evaluated, and all were adequate for diagnosis on ROSE and final interpretation. Overall percentage of agreement (OPA) between preliminary and final cytologic diagnosis was 84%, positive percentage of agreement (PPA) was 33%, and negative percentage of agreement (NPA) was 100% (κ = 0.4, P < .001). Twenty-one cases had correlating surgical resections. OPA between preliminary cytologic and histologic diagnoses was 67%, PPA was 22%, and NPA was 100% (κ = 0.2, P = .09). OPA between final cytologic and histologic diagnoses was 95%, PPA was 89%, and NPA was 100% (κ = 0.9, P = <.001). CONCLUSIONS.­: False-positive rates of ROSE diagnoses for breast FNAB are low. While preliminary cytologic diagnoses had a high false-negative rate, final cytologic diagnoses had overall high concordance with histologic diagnoses. Therefore, the role of ROSE for preliminary diagnosis should be considered carefully in low-resource settings, and it may need to be paired with additional interventions to improve pathologic diagnosis.

Modified Thermodilution for Simultaneous Cardiac Output and Recirculation Assessment in Veno-venous Extracorporeal Membrane Oxygenation: A Prospective Diagnostic Accuracy Study.

BACKGROUND: Thermodilution is unreliable in veno-venous extracorporeal membrane oxygenation (VV-ECMO). Systemic oxygenation depends on recirculation fractions and ratios of extracorporeal membrane oxygenation (ECMO) flow to cardiac output. In a prospective in vitro simulation, this study assessed the diagnostic accuracy of a modified thermodilution technique for recirculation and cardiac output. The hypothesis was that this method provided clinically acceptable precision and accuracy for cardiac output and recirculation. METHODS: Two ECMO circuits ran in parallel: one representing a VV-ECMO and the second representing native heart, lung, and circulation. Both circuits shared the right atrium. Extra limbs for recirculation and pulmonary shunt were added. This study simulated ECMO flows from 1 to 2.5 l/min and cardiac outputs from 2.5 to 3.5 l/min with recirculation fractions (0 to 80%) and pulmonary shunts. Thermistors in both ECMO limbs and the pulmonary artery measured the temperature changes induced by cold bolus injections into the arterial ECMO limb. Recirculation fractions were calculated from the ratio of the areas under the temperature curve (AUCs) in the ECMO limbs and from partitioning of the bolus volume (flow based). With known partitioning of bolus volumes between ECMO and pulmonary artery, cardiac output was calculated. High-precision ultrasonic flow probes served as reference for Bland-Altman plots and linear mixed-effect models. RESULTS: Accuracy and precision for both the recirculation fraction based on AUC (bias, -5.4%; limits of agreement, -18.6 to 7.9%) and flow based (bias, -5.9%; limits of agreement, -18.8 to 7.0%) are clinically acceptable. Calculated cardiac output for all recirculation fractions was accurate but imprecise (RecirculationAUC: bias 0.56 l/min; limits of agreement, -2.27 to 3.4 l/min; and RecirculationFLOW: bias 0.48 l/min; limits of agreement, -2.22 to 3.19 l/min). Recirculation fraction increased bias and decreased precision. CONCLUSIONS: Adapted thermodilution for VV-ECMO allows simultaneous measurement of recirculation fraction and cardiac output and may help optimize patient management with severe respiratory failure.

Retention in an mHealth App Aiming to Promote the Use of HIV Pre-Exposure Prophylaxis Among Female Sex Workers in Dar es Salaam, Tanzania: Prospective Cohort Study.

Background: Increasing access to smartphones in sub-Saharan Africa offers an opportunity to leverage mobile health (mHealth) technology to improve access to health care in underserved populations. In the domain of HIV prevention, mHealth interventions can potentially contribute to solving the challenges of suboptimal adherence to pre-exposure prophylaxis (PrEP) and low retention in PrEP services among populations most vulnerable to HIV acquisition. However, there is a gap in the knowledge about the use of such interventions in sub-Saharan Africa. Objective: This study aims to evaluate the extent and predictors of retention in an mHealth app (Jichunge) that aims to promote adherence to PrEP and retention in PrEP care among female sex workers in Dar es Salaam, Tanzania. Methods: A prospective cohort of female sex workers residing in Dar es Salaam were recruited, using respondent-driven sampling. All participants were provided with the Jichunge app as they started PrEP. A questionnaire was used to collect data on sociodemographics and other structural factors, while app use data for the 60-day period following the first 150 days of being in the intervention arm were extracted from the app's back end. A multivariable log-binomial model was used to determine predictors of 6-month retention in the Jichunge app. Results: A total of 470 female sex workers were recruited. Nearly three-quarters of participants (206/284, 72.5%) who came to the 6-month follow-up interview no longer had the Jichunge app on their phones. The majority of these participants (193/206, 93.7%) no longer had access to the app because of issues related to their phones. Data extracted from the back end of the app showed that the use of the app declined over time, and only 13.4% (63/470) of the participants were retained (continued to use the app) after 6 months of intervention. At 6 months, women aged ≥35 years were >2 times more likely to use the app than women aged 18 to 24 years (adjusted risk ratio [aRR] 2.2, 95% CI 1.2-4.1; P=.01). Furthermore, retention in the app was higher among participants who demonstrated high PrEP awareness at baseline (aRR 1.8, 95% CI 1.1-3; P=.01) and among those who had experienced financial difficulties due to health care spending (aRR 1.9, 95% CI 1.2-3.2; P=.01). Conclusions: Most female sex workers (206/284, 72.5%) who were enrolled in PrEP care in Tanzania no longer used the Jichunge app after 6 months. Retention in the app at 6 months was predicted by older age, high PrEP awareness, and financial difficulties due to health care spending. Strategies for the long-term retention of participants in mHealth apps, such as systems for reinstallations of apps, should be considered during the design phase.

Nonhuman Primate Eyes Display Variable Growth and Aging Rates in Alignment With Human Eyes.

Purpose: To assess age-related biometric changes of the eye in nonhuman primates (NHPs), to and decipher the growth and aging rates and their comparability with humans. Methods: Ocular anatomic measurements were performed on 341 macaca fascicularis aged 0.5 to 23 years via multimodal approaches including IOLMaster 700. Linear or polynomial regression models were simulated to determine the best fitted age-related function. The metrics were compared with human equivalents in published reports. Results: Macaques exhibited a postnatal eye growth pattern similar to humans, characterized by continuous eye extension coordinated with dramatic reshaping of the lens but not the cornea. The age-related growth of lens thickness (LT), anterior chamber depth (ACD), and axis length (AL) exhibited nonlinear and bipolar patterns. The inflection points were 10 to 12 years old for LT and ACD and 13 to 15 years old for AL in macaques, which were comparable in chronological age at a ratio of ∼1: ratio with that in humans. In contrast, the speed of aging, including the increase in lens density and the decrease in retinal nerve fiber layer thickness, was comparable in relative age at a ratio of ∼1:3 according to the differences in lifespan between macaques and humans. Lens density was a robust indicator for the aging process. Conclusions: Macaque eyes recapitulated the age-related process of human eyes to varying extents with different growth and aging rates. Chronological age or relative age should be considered in different scenarios when macaques are included in preclinical studies.

A Genomic Analysis of Esophageal Squamous Cell Carcinoma in Eastern Africa.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) comprises 90% of all esophageal cancer cases globally and is the most common histology in low-resource settings. Eastern Africa has a disproportionately high incidence of ESCC. METHODS: We describe the genomic profiles of 61 ESCC cases from Tanzania and compare them to profiles from an existing cohort of ESCC cases from Malawi. We also provide a comparison to ESCC tumors in The Cancer Genome Atlas (TCGA). RESULTS: We observed substantial transcriptional overlap with other squamous histologies via comparison with TCGA PanCan dataset. DNA analysis revealed known mutational patterns, both genome-wide as well as in genes known to be commonly mutated in ESCC. TP53 mutations were the most common somatic mutation in tumors from both Tanzania and Malawi but were detected at lower frequencies than previously reported in ESCC cases from other settings. In a combined analysis, two unique transcriptional clusters were identified: a proliferative/epithelial cluster and an invasive/migrative/mesenchymal cluster. Mutational signature analysis of the Tanzanian cohort revealed common signatures associated with aging and cytidine deaminase activity (APOBEC) and an absence of signature 29, which was previously reported in the Malawi cohort. CONCLUSIONS: This study defines the molecular characteristics of ESCC in Tanzania, and enriches the Eastern African dataset, with findings of overall similarities but also some heterogeneity across two unique sites. IMPACT: Despite a high burden of ESCC in Eastern Africa, investigations into the genomics in this region are nascent. This represents the largest comprehensive genomic analysis ESCC from sub-Saharan Africa to date.

Behaviour and stability of thermodilution signals in a closed extracorporeal circuit: a bench study.

Thermodilution is the gold standard for cardiac output measurement in critically ill patients. Its application in extracorporeal therapy is limited, as a portion of the thermal indicator is drawn into the extracorporeal circuit. The behaviour of thermodilution signals in extracorporeal circuits is unknown. We investigated thermodilution curves within a closed-circuit and assessed the impact of injection volume, flow and distance on the behaviour of the thermodilution signals and catheter constants. We injected 3, 5, 7 and 10 ml of thermal indicator into a heated closed circuit. Thermistors at distances of 40, 60, 80, and 100 cm from the injection port recorded the thermodilution signals (at flow settings of 0.5, 1, 1.5, and 2 L/min). Area under the curve (AUC), rise time, exponential decay and catheter constants were analysed. Linear mixed-effects models were used to evaluate the impact of circuit flow, distance and injection volume. Catheter positioning did not influence AUC (78 injections). Catheter constants were independent of flow, injection volume or distance to the injection port. The distance to the injection port increased peak temperature and rise time and decreased exponential time constant significantly. The distance to the injection port did not influence catheter constants, but the properties of the thermodilution signal itself. This may influence measurements that depend on the exponential decay of the thermodilution signal such as right ventricular ejection fraction.

Effect of an mHealth intervention on retention in HIV pre-exposure prophylaxis services among female sex workers: Preliminary evidence of the use of the Jichunge app in Dar es Salaam, Tanzania.

Background: Mobile health (mHealth) applications have been reported to be effective in promoting access and adherence to health services. However, knowledge about their effect on retention in HIV preventive services among at-risk populations in sub-Saharan Africa is limited. Objective: We aimed to evaluate the effect of the Jichunge mHealth application on retention in HIV pre-exposure prophylaxis (PrEP) services among female sex workers in Dar es Salaam, Tanzania. Methods: We used respondent-driven sampling to recruit female sex workers eligible for PrEP and who owned a smartphone. All study participants were provided with a smartphone application (Jichunge app) aiming to promote PrEP use through medication reminders, easy access to PrEP information, online consultations with a doctor and/or peer educator, and online discussions between PrEP users. The effect of optimal use of the Jichunge app on retention in PrEP services at 1-month was modelled using log-binomial regression. Results: A total of 470 female sex workers with a median age of 26 (interquartile range: 22-30) years were recruited. Overall, 27.7% of female sex workers were retained in PrEP services at 1 month. Retention was twice as high among optimal users of the app than among sub-optimal users (adjusted risk ratios = 2.00, 95% confidence interval (CI): 1.41-2.83, p < 0.001). Conclusion: The optimal use of the Jichunge mHealth application was significantly associated with higher retention in PrEP services among female sex workers in Dar es Salaam.

HIV testing and associated factors among female sex workers in Tanzania: approaching the first 90% target?

Use of HIV testing services among FSW in sub-Saharan Africa (SSA) is below the desired UNAIDS target of 90%. We estimated the prevalence and factors associated with HIV testing among FSW in Dar es Salaam, Tanzania. A respondent-driven sampling method was used to recruit FSW aged 18. Modified Poisson regression models were used to determine factors associated with recent HIV testing. Of 958 surveyed FSW (median age 26 years), 85.4% (95% CI: 82.3, 88.1) reported to have ever been tested for HIV and 65.3% (95% CI: 61.2, 69.3) tested in the past 12 months. Condom use on the last day worked (prevalence ratio (PR) = 1.17; 95% CI: 0.99, 1.38), no or low self-perceived risk of HIV acquisition (PR = 1.16; 95% CI: 1.02, 1.32), having never felt stigmatized as a sex worker (PR = 1.18; 95% CI: 1.04, 1.33), and having been in contact with a peer educator (PR = 1.33; 95% CI: 1.18, 1.49) during the past year preceding the survey were associated with recent HIV testing. Interventions aiming to mitigate stigma due to sex work, improve health education to address risk perception as a barrier to HIV testing, and scaling up peer educator's engagement should be given priority.

Testing for Drug-Related Infectious Diseases and Determinants among People Who Use Drugs in a Low-Resource Setting: A Respondent-Driven Cross-Sectional Survey.

(1) Background: There is a dearth of data on the levels and determinants of testing for drug-related infectious diseases among people who use drugs (PWUD). We assessed the proportions and determinants of testing for drug-related infectious diseases to inform ongoing interventions for PWUD. (2) Methods: A cross-sectional study involving 599 PWUD was conducted in Dar es Salaam and Tanga between January and February 2019. Data were collected through a researcher-administered questionnaire using handheld tablets. Logistic regression models were used to identify independent testing determinants for drug-related infectious diseases. (3) Results: A majority (98.0%) of participants were males, with a mean age of 36.8 (SD = 7.8) years. 75.0%, 40.6%, 38.6%, and 8.2% reported having ever tested for HIV, tuberculosis (TB), sexually transmitted infections (STIs), and viral hepatitis, respectively. The likelihood of HIV testing was higher among those living with someone (AOR = 2.18, 95% CI: 1.09-4.68) compared with those who were homeless and perceived treatment was appropriate (AOR = 2.18, 95% CI: 1.05-4.46), but was lower among those who experienced mild to moderate (AOR = 0.44, 95% CI: 0.21-0.95) and severe internalized stigma (AOR = 0.44, 95% CI: 0.22-0.94) compared with those reporting no internalized stigma, and among those who experienced financial difficulties resulting from spending on health care services (AOR = 0.60, 95% CI: 0.40-0.89). Perception of treatment appropriateness (AOR = 2.29, 96% CI: 1.10-5.06) and severe enacted stigma (AOR = 1.90, 95% CI: 1.06-3.42) were associated with increased odds of TB testing. The odds of STIs testing increased among those who were married (AOR = 2.31, 95% CI: 1.45-3.72) compared with those who were single and those who had experienced mild (AOR = 2.39, 95% CI: 1.28-4.53) or severe (AOR = 6.20, 95% CI: 1.99-23.83) sexual violence, compared with those who had not experienced sexual violence. However, the odds decreased among those who had been remanded in the past month (AOR = 0.64, 95% CI: 0.43-0.95) compared with those who were not remanded and among those who had financial difficulties resulting from spending on health care services (AOR = 0.66, 95% CI: 0.47-0.94). The likelihood of testing for viral hepatitis testing increased among those who had heard about the comprehensive HIV intervention package (CHIP) (AOR = 2.59, 95% CI: 1.40-4.94); however, it decreased among those who had financial difficulties resulting from spending on health care services (AOR = 0.48, 95% CI: 0.24-0.92). (4) Conclusions: Except for HIV, PWUD had undergone limited testing for drug-related infectious diseases. The study findings highlight some factors influencing testing for the selected infectious diseases investigated, which should be targeted for tailored interventions to improve diagnosis and treatment.

Predictors of mHealth use in promoting adherence to pre-exposure prophylaxis among female sex workers: an evaluation of the Jichunge intervention in Dar es Salaam, Tanzania.

BACKGROUND: There is evidence that pre-exposure prophylaxis (PrEP) is effective in preventing HIV transmission, and PrEP is recommended by the World Health organization (WHO) for use by individuals at high risk of HIV infection. However, low adherence has been reported to hamper its effectiveness. Some evidence indicates that mHealth interventions may be a promising way of promoting PrEP adherence. Nevertheless, evaluations of mHealth interventions in Africa, the region most affected by HIV, are scarce. This study aimed at identifying the extent of and predictors for use of a smartphone based mHealth application among female sex workers in Dar es Salaam, Tanzania. METHODS: As part of a quasi-experimental study in Tanzania, 470 female sex workers who were eligible for PrEP and who owned a smartphone were recruited using respondent driven sampling. All participants were provided with an mHealth application called Jichunge, a smartphone-based app designed to promote adherence to PrEP by offering users information, advise and support during start-up and use of PrEP. We collected data through structured interviews at baseline and extracted user data from the app for a period of 30 days. Modified Poisson regression model with robust standard errors was used to identify predictors for the optimal use of the Jichunge app. RESULTS: Overall, the optimal use of the Jichunge app was 46.4%. Optimal use was significantly higher among women who were older (aPR = 1.3, 95% CI: 1.10-1.65, p = 0.004 for age 25-34 years, and aPR = 1.6, 95% CI: 1.19-2.07, p = 0.001 for age at least 35 years), who had secondary education or higher (aPR = 1.8, 95% CI: 1.08-2.94, p = 0.023), who had suboptimal social support (aPR = 1.2, 95% CI: 1.02-1.48, p = 0.030), who had high awareness of PrEP (aPR = 1.3, 95% CI: 1.08-1.55, p = 0.005), and who had experience using common mainstream social media applications (aPR = 1.4, 95% CI: 1.08-1.71, p = 0.009). CONCLUSION: Optimal use of the Jichunge app was substantially higher among women with higher age, higher education, higher PrEP awareness, less social support, and experience using common social media applications. Individual and interpersonal factors should be considered in planning mHealth interventions. Further studies to determine predictors of longer-term mHealth engagement are needed. TRIAL REGISTRATION: International Clinical Trials Registry Platform PACTR202003823226570 ; 04.03.2020.

An international report on bacterial communities in esophageal squamous cell carcinoma.

The incidence of esophageal squamous cell carcinoma (ESCC) is disproportionately high in the eastern corridor of Africa and parts of Asia. Emerging research has identified a potential association between poor oral health and ESCC. One possible link between poor oral health and ESCC involves the alteration of the microbiome. We performed an integrated analysis of four independent sequencing efforts of ESCC tumors from patients from high- and low-incidence regions of the world. Using whole genome sequencing (WGS) and RNA sequencing (RNAseq) of ESCC tumors from 61 patients in Tanzania, we identified a community of bacteria, including members of the genera Fusobacterium, Selenomonas, Prevotella, Streptococcus, Porphyromonas, Veillonella and Campylobacter, present at high abundance in ESCC tumors. We then characterized the microbiome of 238 ESCC tumor specimens collected in two additional independent sequencing efforts consisting of patients from other high-ESCC incidence regions (Tanzania, Malawi, Kenya, Iran, China). This analysis revealed similar ESCC-associated bacterial communities in these cancers. Because these genera are traditionally considered members of the oral microbiota, we next explored whether there was a relationship between the synchronous saliva and tumor microbiomes of ESCC patients in Tanzania. Comparative analyses revealed that paired saliva and tumor microbiomes were significantly similar with a specific enrichment of Fusobacterium and Prevotella in the tumor microbiome. Together, these data indicate that cancer-associated oral bacteria are associated with ESCC tumors at the time of diagnosis and support a model in which oral bacteria are present in high abundance in both saliva and tumors of some ESCC patients.

Risk Factors Associated With Early-Onset Esophageal Cancer in Tanzania.

PURPOSE: Eastern Africa is one of several regions affected by high incidence rates of esophageal squamous cell carcinoma (ESCC). A unique epidemiologic feature of ESCC in Eastern Africa is the high incidence in young people, with one-third of cases diagnosed at age < 45 years. This study aimed to investigate risk factors for early-onset ESCC in Tanzania through a secondary analysis of a matched case-control study. MATERIALS AND METHODS: From 2013 to 2015, ESCC cases were recruited at Muhimbili National Hospital and Ocean Road Cancer Institute in Dar es Salaam, Tanzania. Hospital controls were identified from patients with nonmalignant conditions and matched 1:1 for sex and age (± 10 years). Questionnaires were used to assess sociodemographic characteristics and environmental, dietary, and lifestyle risk exposures. Multivariate logistic regression models were used to estimate age-specific odds ratios of ESCC for exposures among participants age 30-44 and ≥ 45 years. RESULTS: A total of 471 cases and 471 controls were enrolled. Among cases, 100 (21%) were < 45 years. Multiple exposures were identified as risk factors for early-onset ESCC, several of which were unique to this age group, including infrequent teeth cleaning, secondhand tobacco smoke exposure, and pest infestation of grain and/or nuts. Lower socioeconomic status, family history of ESCC, tobacco smoking, home-brewed alcohol consumption, home storage of grain and/or nuts, and use of firewood for cooking were associated in the older but not the younger age group. Hot beverage intake was associated with increased ESCC risk in both age groups. CONCLUSION: Our results suggest that ESCC risk factors in Tanzania vary between age groups. With the data currently available, environmental and behavioral risk factors appear to play an important role in the high incidence of ESCC among young people.

Socio-cognitive factors influencing access to HIV prevention services among people who inject drugs in Dar es Salaam, Tanzania: An integrated bio-behavioural survey.

INTRODUCTION: People who inject drugs (PWID) in Sub-Saharan Africa have limited access to comprehensive HIV services. While it is important to inform programming, knowledge about factors influencing access to comprehensive HIV services is scarce. We assessed the proportions of PWID with access to HIV prevention services and associated socio-cognitive factors in Tanzania. METHODS: A cross-sectional survey was conducted among PWID between October and December 2017 in Dar es Salaam, Tanzania. Data on access to HIV prevention services, demographics and selected socio-cognitive factors were collected through structured face-to-face interviews. Weighted descriptive and forward selection multivariable logistics regression analyses were done to assess independent associations between HIV prevention services and predictors of interest. The results were two tailed and a p-value of less than 0.05 was considered statistically significant. RESULTS: The study included 611 PWID (males: 94.4%) with a median age of 34 years (Interquartile Range (IQR), 29-38). A large majority of participants reported to have access to condoms (87.8%), sterile needles/syringes (72.8%) and ever tested for HIV (66.0%). About half (52.0%) reported to have used condoms in the past one month and about a third (28.5%) accessed a peer educator. The odds of testing for HIV decreased among participants who perceived their HIV risk to be high (aOR = 0.29; 95%CI: 0.17-0.49) and those experienced sexual violence (aOR = 0.60; 95%CI 0.37-0.98). However, the odds of testing for HIV increased among participants with secondary level of education (aOR = 2.16; 95%CI: 1.06-5.55), and those who reported having correct comprehensive HIV knowledge (CCHK) (aOR = 1.63; 95%CI 1.12-2.41). The odds of access to condoms increased among females (aOR = 2.23; 95%CI: 1.04-5.02) but decreased among participants with secondary level of education (aOR = 0.41; 95%CI: 0.19-0.84), an income of >TZS 200,000 (aOR = 0.39; 95%CI: 0.23-0.66) and those who perceived their HIV risk to be high (aOR = 0.13; 95%CI: 0.03-0.36). The odds of access to peer educators was higher among participants with primary (aOR = 1.61; 95%CI: 1.01-2.26), and secondary (aOR = 2.71; 95%CI: 1.39-5.33) levels of education. The odds of access to sterile needle and syringe decreased among participants who perceived their HIV risk to be high (aOR = 0.11;95%CI 0.05-0.22), and low-medium (aOR = 0.25;95%CI 0.11-0.52) but increased among those with primary level of education (aOR = 1.72;95%CI 1.06-2.78). CONCLUSION: Access to condom, HIV testing, sterile needles and syringes were relatively high among PWID. However, condom use and access to peer educators was relatively low. HIV knowledge and risk perception, gender, education, and sexual violence influenced access to HIV prevention services. There is an urgent need to address the identified socio-cognitive factors and scale up all aspects of HIV prevention services to fast-track attainment of the 2025 UNAIDS goals and ending the HIV epidemic.

Treatment outcomes of esophageal cancer in Eastern Africa: protocol of a multi-center, prospective, observational, open cohort study.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is a major cause of cancer morbidity and mortality in Eastern Africa. The majority of patients with ESCC in Eastern Africa present with advanced disease at the time of diagnosis. Several palliative interventions for ESCC are currently in use within the region, including chemotherapy, radiation therapy with and without chemotherapy, and esophageal stenting with self-expandable metallic stents; however, the comparative effectiveness of these interventions in a low resource setting has yet to be examined. METHODS: This prospective, observational, multi-center, open cohort study aims to describe the therapeutic landscape of ESCC in Eastern Africa and investigate the outcomes of different treatment strategies within the region. The 4.5-year study will recruit at a total of six sites in Kenya, Malawi and Tanzania (Ocean Road Cancer Institute and Muhimbili National Hospital in Dar es Salaam, Tanzania; Kilimanjaro Christian Medical Center in Moshi, Tanzania; Tenwek Hospital in Bomet, Kenya; Moi Teaching and Referral Hospital in Eldoret, Kenya; and Kamuzu Central Hospital in Lilongwe, Malawi). Treatment outcomes that will be evaluated include overall survival, quality of life (QOL) and safety. All patients (≥18 years old) who present to participating sites with a histopathologically-confirmed or presumptive clinical diagnosis of ESCC based on endoscopy or barium swallow will be recruited to participate. Key clinical and treatment-related data including standardized QOL metrics will be collected at study enrollment, 1 month following treatment, 3 months following treatment, and thereafter at 3-month intervals until death. Vital status and QOL data will be collected through mobile phone outreach. DISCUSSION: This study will be the first study to prospectively compare ESCC treatment strategies in Eastern Africa, and the first to investigate QOL benefits associated with different treatments in sub-Saharan Africa. Findings from this study will help define optimal management strategies for ESCC in Eastern Africa and other resource-limited settings and will serve as a benchmark for future research. TRIAL REGISTRATION: This study was retrospectively registered with the ClinicalTrials.gov database on December 15, 2021,  NCT05177393 .

Aged Nrf2-Null Mice Develop All Major Types of Age-Related Cataracts.

Purpose: Age-related cataracts affect the majority of older adults and are a leading cause of blindness worldwide. Treatments that delay cataract onset or severity have the potential to delay cataract surgery, but require relevant animal models that recapitulate the major types of cataracts for their development. Unfortunately, few such models are available. Here, we report the lens phenotypes of aged mice lacking the critical antioxidant transcription factor Nfe2l2 (designated as Nrf2 -/-). Methods: Three independent cohorts of Nrf2 -/- and wild-type C57BL/6J mice were evaluated for cataracts using combinations of slit lamp imaging, photography of freshly dissected lenses, and histology. Mice were fed high glycemic diets, low glycemic diets, regular chow ad libitum, or regular chow with 30% caloric restriction. Results: Nrf2 -/- mice developed significant opacities between 11 and 15 months and developed advanced cortical, posterior subcapsular, anterior subcapsular, and nuclear cataracts. Cataracts occurred similarly in male mice fed high or low glycemic diets, and were also observed in 21-month male and female Nrf2 -/- mice fed ad libitum or 30% caloric restriction. Histological observation of 18-month cataractous lenses revealed significant disruption to fiber cell architecture and the retention of nuclei throughout the cortical region of the lens. However, fiber cell denucleation and initiation of lens differentiation was normal at birth, with the first abnormalities observed at 3 months. Conclusions: Nrf2 -/- mice offer a tool to understand how defective antioxidant signaling causes multiple forms of cataract and may be useful for screening drugs to prevent or delay cataractogenesis in susceptible adults.

Evolutionary pathways to SARS-CoV-2 resistance are opened and closed by epistasis acting on ACE2.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infects a broader range of mammalian species than previously predicted, binding a diversity of angiotensin converting enzyme 2 (ACE2) orthologs despite extensive sequence divergence. Within this sequence degeneracy, we identify a rare sequence combination capable of conferring SARS-CoV-2 resistance. We demonstrate that this sequence was likely unattainable during human evolution due to deleterious effects on ACE2 carboxypeptidase activity, which has vasodilatory and cardioprotective functions in vivo. Across the 25 ACE2 sites implicated in viral binding, we identify 6 amino acid substitutions unique to mouse-one of the only known mammalian species resistant to SARS-CoV-2. Substituting human variants at these positions is sufficient to confer binding of the SARS-CoV-2 S protein to mouse ACE2, facilitating cellular infection. Conversely, substituting mouse variants into either human or dog ACE2 abolishes viral binding, diminishing cellular infection. However, these same substitutions decrease human ACE2 activity by 50% and are predicted as pathogenic, consistent with the extreme rarity of human polymorphisms at these sites. This trade-off can be avoided, however, depending on genetic background; if substituted simultaneously, these same mutations have no deleterious effect on dog ACE2 nor that of the rodent ancestor estimated to exist 70 million years ago. This genetic contingency (epistasis) may have therefore opened the road to resistance for some species, while making humans susceptible to viruses that use these ACE2 surfaces for binding, as does SARS-CoV-2.

Development of a Mobile Health Application for HIV Prevention Among At-Risk Populations in Urban Settings in East Africa: A Participatory Design Approach.

BACKGROUND: There is limited evidence in Africa on the design and development of mobile health (mHealth) applications to guide best practices and ensure effectiveness. A pragmatic trial for HIV pre-exposure prophylaxis roll-out among key populations in Tanzania is needed. OBJECTIVE: We present the results of the development of a mobile app (Jichunge) intended to promote adherence to pre-exposure prophylaxis (PrEP) among men who have sex with men (MSM) and female sex workers (FSW) in Tanzania. METHODS: A participatory design approach was employed and guided by the information system research framework. MSM and FSW were the target populations. A total of 15 MSM and 15 FSW were engaged in the relevance and design cycles, while the piloting phase included 10 MSM and 20 FSW. RESULTS: The relevance cycle enabled the description of the existing problem, provided the compatible app features for the target population, and identified the need to develop an mHealth app that provides health services in a stigmatizing and discriminating environment. User involvement in the app's design and evaluation provided an opportunity to incorporate social, cultural, and community-specific features that ensured usability. In addition, the participants suggested valuable information to inform the app, text message services, medication registration, and chat platform designs. CONCLUSIONS: The participatory design approach in the development of mHealth apps is useful in identifying and validating population-specific functional features, improve usability, and ensuring future health impacts. Through this participatory process, the Jichunge app took end-user needs, perspectives, and experiences into account, eliciting enthusiasm regarding its potential role in supporting pre-exposure prophylaxis adherence for HIV and related behavioral change promotion. TRIAL REGISTRATION: International Clinical Trials Registry Platform PACTR202003823226570; https://trialsearch.who.int/Trial2.aspx?TrialID=PACTR202003823226570.

Myeloid cell modulation by a GLP-1 receptor agonist regulates retinal angiogenesis in ischemic retinopathy.

Ischemic retinopathies including diabetic retinopathy are major causes of blindness. Although neurons and Müller glia are recognized as important regulators of reparative and pathologic angiogenesis, the role of mononuclear phagocytes (MPs) - particularly microglia, the resident retinal immune cells - is unclear. Here, we found MP activation in human diabetic retinopathy, especially in neovessels from human neovascular membranes in proliferative retinopathy, including TNF-α expression. There was similar activation in the mouse oxygen-induced retinopathy (OIR) model of ischemia-induced neovascularization. Glucagon-like peptide-1 receptor (GLP-1R) agonists are in clinical use for glycemic control in diabetes and are also known to modulate microglia. Herein, we investigated the effect of a long-acting GLP-1R agonist, NLY01. Following intravitreal administration, NLY01 selectively localized to MPs in retina with OIR. NLY01 modulated MPs but not retinal endothelial cell viability, apoptosis, and tube formation in vitro. In OIR, NLY01 treatment inhibited MP infiltration and activation, including MP expression of cytokines in vivo. NLY01 significantly suppressed global induction of retinal inflammatory cytokines, promoted reparative angiogenesis, and suppressed pathologic retinal neovascularization. Collectively, these findings indicate the important role of mononuclear phagocytes in regulation of retinal vascularization in ischemia and suggest modulation of MPs as a potentially new treatment strategy for ischemic retinopathies.