Xpert Breast Cancer STRAT4 Assay using fine-needle aspiration biopsy samples in a resource-constrained setting: a prospective diagnostic accuracy study.

BACKGROUND: Use of fine-needle aspiration biopsy (FNAB) specimens on Xpert Breast Cancer STRAT4 Assay (STRAT4; Cepheid, Sunnyvale, CA, USA), a CE-marked in-vitro diagnostic medical device, could potentially increase access to breast cancer biomarker testing in resource-constrained settings. We aimed to assess the performance of a research use-only version of STRAT4 using FNAB specimens in Tanzania. METHODS: In this prospective diagnostic accuracy study, patients aged 18 years or older with palpable breast masses presenting to the FNAB Clinic at Muhimbili National Hospital (Dar es Salaam, Tanzania) were recruited consecutively. Patients who were pregnant, lactating, or had a previous diagnosis of breast cancer were excluded. STRAT4 testing was performed on off-label FNAB samples using four protocols: the 1 × protocol (using the standard lysate method) on FNAB smears (1 × FNAB), quick lysis and Maui protocols (both on FNAB smears), and the 1 × protocol on formalin-fixed paraffin-embedded (FFPE) cell block material (1 × cell block). For 1 × FNAB and 1 × cell block, tissue was processed using FFPE lysis reagent, incubated at 80°C with proteinase K, and followed by addition of 95% or higher ethanol. Quick lysis was processed using FFPE lysis reagent and 95% or higher ethanol, whereas Maui was processed using a proprietary research-use only lysis reagent. The primary outcomes were overall concordance, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) of STRAT4 as compared with immunohistochemistry or immunohistochemistry plus fluorescence in-situ hybridisation performed on cell blocks using clinically validated protocols in a Clinical Laboratory Improvement Amendments-accredited laboratory at the University of California, San Francisco (San Francisco, CA, USA). FINDINGS: Between Nov 29, 2017, and Dec 17, 2020, 208 patients were enrolled. Of 208 cases, 51 (25%) were excluded from analysis because of insufficient tissue in the cell block or absent cell blocks, leaving 157 participants (all female) for analysis. For oestrogen receptor, 1 × FNAB had the best performance, with an overall concordance of 95% (95% CI 90-100), sensitivity of 94% (85-100), specificity of 97% (90-100), and AUC of 0·96 (0·81-1·00). For progesterone receptor, 1 × cell block had the best overall performance (overall concordance 89% [95% CI 84-95], sensitivity 91% [82-99], and specificity 89% [81-97], with an AUC of 0·93 [0·89-0·99]) and 1 × FNAB performed the best among the smear protocols, with a concordance of 84% (95% CI 74-93), sensitivity of 63% (43-82), specificity of 97% (92-100), and AUC of 0·91 (0·72-0·97). For HER2, Maui had the highest agreement, with an overall concordance of 93% (95% CI 89-98), sensitivity of 96% (88-100), specificity of 92% (87-98), and AUC of 0·95 (0·98-1·00). For Ki67, Maui had the best performance of smear protocols, with a concordance of 73% (95% CI 64-82), sensitivity of 70% (58-81), specificity of 81% (66-96), and AUC of 0·80 (0·54-0·82). INTERPRETATION: Processing FNAB samples with STRAT4 is feasible in Tanzania, and performance for the oestrogen receptor is robust. Further optimisation of STRAT4 for FNAB has the potential to improve timely access to breast cancer diagnostics in resource-constrained settings. FUNDING: US National Institutes of Health; UCSF Global Cancer Program, Helen Diller Family Comprehensive Cancer Center; UCSF Department of Pathology; and Cepheid.

Goiter, iodine bioavailability and intrauterine growth restriction in Indigenous and Afro-descendant pregnant women from six non-metropolitan areas of Colombia (2019-2020).

INTRODUCTION: Iodine is an essential mineral for fetal growth and brain development. The aim of this research was to evaluate goiter, iodine deficiency and intrauterine growth restriction in pregnant women of minority ethnic groups in Colombia. METHODS: A cross-sectional study was performed in six non-metropolitan areas of Colombia. RESULTS: A total of 318 Indigenous and Afro-descendant pregnant women were invited to participate: 248 (83.2%) Indigenous and 50 (16.8%) Afro-descendants were studied. The mean age was 24 years (range 13-44 years). Of the women, 130 (43.5%) were from the department of Cauca, 72 (24.1%) were from Córdoba, 28 (9.4%) were from Guajira, 26 (8.8%) were from Sierra Nevada de Santa Marta, 22 (7.4%) were from Amazonas, 16 (5.4%) were from Meta and 4 (1.3%) were from the department of Cesar. A total of 244 (81.8%) were illiterate and 291 (97.7%) were of very low socioeconomic level. Goiter was observed in 69 (23.3%) pregnant women (38 (41.7%) from the department of Cauca, 10 (35.7%) from Guajira, 5 (31.2%) from Meta, 6 (27.2%) from Amazonas and 10 (13.8%) from Córdoba). Iodine deficiency (<100 µg/L) was observed in 42 (14.9%) pregnant women (16 (11.6%) mild (50-99 µg/L), 19 (13.8%) moderate (20-49 µg/L) and 7 (5.1%) severe (<20 µg/L)). Being literate was a protective factor for iodine deficiency (odds ratio (OR)=0.19, 95% confidence interval (CI) 0.04-0.84, p=0.016). Being illiterate and iodine deficient was only a risk factor for goiter (OR=6.72, 95%CI 3.9-9.5, p=0.038) in the department of Cauca. CONCLUSION: A high prevalence of goiter, iodine deficiency and intrauterine growth restriction was observed in minority ethnic groups of Colombia. The highest prevalence and risk was observed in the department of Cauca.

Suppression of inner blood-retinal barrier breakdown and pathogenic Müller glia activation in ischemia retinopathy by myeloid cell depletion.

Ischemic retinopathies including diabetic retinopathy are major causes of vision loss. Inner blood-retinal barrier (BRB) breakdown with retinal vascular hyperpermeability results in macular edema. Although dysfunction of the neurovascular unit including neurons, glia, and vascular cells is now understood to underlie this process, there is a need for fuller elucidation of the underlying events in BRB dysfunction in ischemic disease, including a systematic analysis of myeloid cells and exploration of cellular cross-talk. We used an approach for microglia depletion with the CSF-1R inhibitor PLX5622 (PLX) in the retinal ischemia-reperfusion (IR) model. Under non-IR conditions, PLX treatment successfully depleted microglia in the retina. PLX suppressed the microglial activation response following IR as well as infiltration of monocyte-derived macrophages. This occurred in association with reduction of retinal expression of chemokines including CCL2 and the inflammatory adhesion molecule ICAM-1. In addition, there was a marked suppression of retinal neuroinflammation with reduction in expression of IL-1b, IL-6, Ptgs2, TNF-a, and Angpt2, a protein that regulates BRB permeability. PLX treatment significantly suppressed inner BRB breakdown following IR, without an appreciable effect on neuronal dysfunction. A translatomic analysis of Müller glial-specific gene expression in vivo using the Ribotag approach demonstrated a strong suppression of Müller cell expression of multiple pro-inflammatory genes following PLX treatment. Co-culture studies of Müller cells and microglia demonstrated that activated microglia directly upregulates Müller cell-expression of these inflammatory genes, indicating Müller cells as a downstream effector of myeloid cells in retinal IR. Co-culture studies of these two cell types with endothelial cells demonstrated the ability of both activated microglia and Müller cells to compromise EC barrier function. Interestingly, quiescent Müller cells enhanced EC barrier function in this co-culture system. Together this demonstrates a pivotal role for myeloid cells in inner BRB breakdown in the setting of ischemia-associated disease and indicates that myeloid cells play a major role in iBRB dysregulation, through direct and indirect effects, while Müller glia participate in amplifying the neuroinflammatory effect of myeloid cells.

HIV pre-exposure prophylaxis use during periods of unprotected sex among female sex workers in Tanga city, Tanzania: a control arm analysis of the pragmatic quasi-experimental trial.

Background: Pre-exposure prophylaxis (PrEP) prevention-effective adherence is of critical importance but challenging particularly among key populations where periods of high HIV risk are frequent. We assessed the use of PrEP with reference to periods of unprotected sex among female sex workers in the city of Tanga. Methods: This was part of the pragmatic quasi-experimental trial for HIV PrEP rollout in Tanzania involving a control cohort of 313 female sex workers aged ≥18 years recruited by respondent-driven sampling and followed for 12 months. PrEP use and periods of condomless or unprotected sex were assessed at the 6th and 12th month of follow-up. Prevention-effective adherence was defined as PrEP use of ≥2 pills/week and ≥6 pills/week for anal and vaginal condomless sex. Multivariable modified Poisson regression was conducted to determine factors influencing PrEP use (≥2 pills/week). Results: Overall, 59.2 and 45.9% of participants had unprotected anal and vaginal sex with a client, respectively. The prevention-effective adherence for anal sex ranged from 8.0% (months 6) to 10.0% (months 12) while that of vaginal sex was from 10.1% (month 6) to 3.8% (month 12). Participants who lived with friends were 25.5 times more likely to use ≥2 PrEP doses per week than those who lived alone (aPR = 25.5; 95%CI: 2.55-255.42, p = 0.006). Compared to self-reporting poor health status, self-reporting good health status significantly increased the use of ≥2 PrEP doses per week (aPR = 17.4; 95%CI: 3.01-101.02, p = 0.001). Refusing condomless sex with a steady partner increased the likelihood of using ≥2 PrEP doses per week than accepting condomless sex with a steady partner (aPR = 11.2; 95%CI: 1.55-80.48, p = 0.017). The prevalence of using ≥2 PrEP doses per week was less among participants accepting condomless sex at high pay than those who refused (aPR = 0.1; 95%CI: 0.03-0.26, p = 0.000). Conclusion: Use of PrEP during periods of unprotected sex was rare among female sex workers. Living with friends, self-reporting good health status, and refusing condomless sex with steady partners were associated with increased use of ≥2 PrEP doses per week. However, accepting condomless sex for increased payment was associated with reduced use of ≥2 PrEP doses per week. This calls for an in-depth study to understand the perspectives and circumstances shaping poor adherence during periods of unprotected sex among female sex workers.

Rationale of Basic and Cellular Mechanisms Considered in Updating the Staging System for Diabetic Retinal Disease.

Purpose: Hyperglycemia is a major risk factor for early lesions of diabetic retinal disease (DRD). Updating the DRD staging system to incorporate relevant basic and cellular mechanisms pertinent to DRD is necessary to better address early disease, disease progression, the use of therapeutic interventions, and treatment effectiveness. Design: We sought to review preclinical and clinical evidence on basic and cellular mechanisms potentially pertinent to DRD that might eventually be relevant to update the DRD staging system. Participants: Not applicable. Methods: The Basic and Cellular Mechanisms Working Group (BCM-WG) of the Mary Tyler Moore Vision Initiative carefully and extensively reviewed available preclinical and clinical evidence through multiple iterations and classified these. Main Outcome Measures: Classification was made into evidence grids, level of supporting evidence, and anticipated future relevance to DRD. Results: A total of 40 identified targets based on pathophysiology and other parameters for DRD were grouped into concepts or evaluated as specific candidates. VEGFA, peroxisome proliferator-activated receptor-alpha related pathways, plasma kallikrein, and angiopoietin 2 had strong agreement as promising for use as biomarkers in diagnostic, monitoring, predictive, prognostic, and pharmacodynamic responses as well as for susceptibility/risk biomarkers that could underlie new assessments and eventually be considered within an updated DRD staging system or treatment, based on the evidence and need for research that would fit within a 2-year timeline. The BCM-WG found there was strong reason also to pursue the following important concepts regarding scientific research of DRD acknowledging their regulation by hyperglycemia: inflammatory/cytokines, oxidative signaling, vasoprotection, neuroprotection, mitophagy, and nutrients/microbiome. Conclusion: Promising targets that might eventually be considered within an updated DRD staging system or treatment were identified. Although the BCM-WG recognizes that at this stage little can be incorporated into a new DRD staging system, numerous potential targets and important concepts deserve continued support and research, as they may eventually serve as biomarkers and/or therapeutic targets with measurable benefits to patients with diabetes. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

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.

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.

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.

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.

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 .