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Background: Live oral rotavirus vaccines (LORVs) have significantly reduced rotavirus hospitalizations and deaths worldwide. However, LORVs are less effective in low- and middle-income countries (LMICs). Next-generation rotavirus vaccines (NGRVs) may be more effective but require administration by injection or a neonatal oral dose, adding operational complexity. Healthcare providers (HPs) were interviewed to assess rotavirus vaccine preferences and identify delivery issues as part of an NGRV value proposition. Objective: Determine HP vaccine preferences about delivering LORVs compared to injectable (iNGRV) and neonatal oral (oNGRV) NGRVs. Methods: 64 HPs from Ghana, Kenya, Malawi, Peru, and Senegal were interviewed following a mixed-method guide centered on three vaccine comparisons: LORV vs. iNGRV; LORV vs. oNGRV; oNGRV vs. iNGRV. HPs reviewed attributes for each vaccine in the comparisons, then indicated and explained their preference. Additional questions elicited views about co-administering iNGRV+LORV for greater public health impact, a possible iNGRV-DTP-containing combination vaccine, and delivering neonatal doses. Results: Almost all HPs preferred oral vaccine options over iNGRV, with many emphasizing an aversion to additional injections. Despite this strong preference, HPs described challenges delivering oral doses. Preferences for LORV vs. oNGRV were split, marked by disparate views on rotavirus disease epidemiology and the safety, need, and feasibility of delivering neonatal vaccines. Although overwhelmingly enthusiastic about an iNGRV-DTP-containing combination option, several HPs had concerns. HP views were divided on the feasibility of co-administering iNGRV+LORV, citing challenges around logistics and caregiver sensitization. Conclusion: Our findings provide valuable insights on delivering NGRVs in routine immunization. Despite opposition to injectables, openness to co-administering LORV+iNGRV to improve efficacy suggests future HP support of iNGRV if adequately informed of its advantages. Rationales for LORV vs. oNGRV underscore needs for training on rotavirus epidemiology and stronger service integration. Expressed challenges delivering existing LORVs merit further examination and indicate need for improved delivery. [ABSTRACT FROM AUTHOR]

Upon hearing the phrase Some cats meow, a listener might pragmatically infer that 'Some but not all cats meow'. This is known as a scalar implicature and it often arises when a speaker produces a weak linguistic expression instead of a stronger one. Several L2 studies claim that pragmatic inferences are generated by default and their comprehension presents no challenges to L2 learners. However, the evidence obtained from these studies largely stems from offline-based tasks that provide limited information about how scalar implicatures are processed. This study investigated scalar implicature processing among L2 speakers of English and the degree to which differences in L2 proficiency and Theory of Mind abilities would modulate pragmatic responding. The experiment used an online sentence verification paradigm that required participants to judge, among multiple control items, the veracity of under-informative sentences, such as Some cats are mammals, and to respond as quickly as possible. A true response to this item is indicative of a logical some and perhaps all reading and a false response to a pragmatic some but not all reading. Our results showed evidence that scalar inferences are not generated by default. The answer linked to the pragmatic reading some but not all took significantly longer to make relative to the answer that relies on the logical interpretation some and perhaps all. This processing slowdown was also significantly larger among participants with lower English proficiency. Further exploratory analyses of participants' Theory of Mind, as measured by the Social Skill subscale in the Autism Spectrum Quotient, revealed that socially inclined participants are more likely than the socially disinclined to derive a scalar inference. These results together provide new empirical insights into how L2 learners process scalar implicatures and thus implications for processing theories in experimental pragmatics and second language acquisition. [ABSTRACT FROM AUTHOR]

Background: Civil registration and vital statistics (CRVS) systems do not produce comprehensive data on maternal and child deaths in most low- and middle-income countries (LMICs), with most births and deaths which occur outside the formal health system going unreported. Community-based death reporting, investigation and review processes are being used in these settings to augment official registration of maternal and child deaths and to identify death-specific factors and associated barriers to maternal and childcare. This study aims to review how community-based maternal and child death reporting, investigation and review processes are carried out in LMICs. Methods: We conducted a scoping review of the literature published in English from January 2013 to November 2020, searching PubMed, EMBASE, PsycINFO, Joanna Briggs, The Cochrane Library, EBM reviews, Scopus, and Web of Science databases. We used descriptive analysis to outline the scope, design, and distribution of literature included in the study and to present the content extracted from each article. The scoping review is reported following the PRISMA reporting guideline for systematic reviews. Results: Of 3162 screened articles, 43 articles that described community-based maternal and child death review processes across ten countries in Africa and Asia were included. A variety of approaches were used to report and investigate deaths in the community, including identification of deaths by community health workers (CHWs) and other community informants, reproductive age mortality surveys, verbal autopsy, and social autopsy. Community notification of deaths by CHWs complements registration of maternal and child deaths missed by routinely collected sources of information, including the CRVS systems which mostly capture deaths occurring in health facilities. However, the accuracy and completeness of data reported by CHWs are sub-optimal. Conclusions: Community-based death reporting complements formal registration of maternal and child deaths in LMICs. While research shows that community-based maternal and child death reporting was feasible, the accuracy and completeness of data reported by CHWs are sub-optimal but amenable to targeted support and supervision. Studies to further improve the process of engaging communities in the review, as well as collection and investigation of deaths in LMICs, could empower communities to respond more effectively and have a greater impact on reducing maternal and child mortality. [ABSTRACT FROM AUTHOR]

High grade serous ovarian cancer (HGSC) is the most common and deadly type of ovarian cancer, largely due to difficulties in early diagnosis and rapid metastasis throughout the peritoneal cavity. Previous studies have shown that expression of Notch3 correlates with worse prognosis and increased tumorigenic cell behaviors in HGSC. We investigated the mechanistic role of Notch3 in a model of metastatic ovarian cancer using the murine ovarian surface epithelial cell line, ID8 IP2. Notch3 was activated in ID8 IP2 cells via expression of the Notch3 intracellular domain (Notch3IC). Notch3IC ID8 IP2 cells injected intraperitoneally caused accelerated ascites and reduced survival compared to control ID8 IP2, particularly in early stages of disease. We interrogated downstream targets of Notch3IC in ID8 IP2 cells by RNA sequencing and found significant induction of genes that encode adhesion and extracellular matrix proteins. Notch3IC ID8 IP2 showed increased expression of ITGA1 mRNA and cell-surface protein. Notch3IC-mediated increase of ITGA1 was also seen in two human ovarian cancer cells. Notch3IC ID8 IP2 cells showed increased adhesion to collagens I and IV in vitro. We propose that Notch3 activation in ovarian cancer cells causes increased adherence to collagen-rich peritoneal surfaces. Thus, the correlation between increased Notch3 signaling and poor prognosis may be influenced by increased metastasis of HGSC via increased adherence of disseminating cells to new metastatic sites in the peritoneum. [ABSTRACT FROM AUTHOR]

Half of under-5 deaths in South Africa occur at home, however the reasons remain poorly described and data on the care pathways during fatal childhood illness is limited. This study aimed to better describe care-seeking behavior in fatal childhood illness and to assess barriers to healthcare and modifiable factors that contribute to under-5 deaths in rural South Africa. We conducted a social autopsy study on all under-5 deaths in two rural South African health and demographic surveillance system sites. Descriptive analyses based on the Pathways to Survival Framework were used to characterise how caregivers move through the stages of seeking and providing care for children during their final illness and to identify modifiable factors that contributed to death. Of 53 deaths, 40% occurred outside health facilities. Rates of antenatal and perinatal preventative care-seeking were high: over 70% of mothers had tested for HIV, 93% received professional assistance during delivery and 79% of children were reportedly immunised appropriately for age. Of the 48 deaths tracked through the stages of the Pathways to Survival Framework, 10% died suddenly without any care, 23% received home care of whom 80% had signs of severe or possibly severe illness, and 85% sought or attempted to seek formal care outside the home. Although half of all children left the first facility alive, only 27% were referred for further care. Modifiable factors for preventing deaths during a child's final illness occur both inside and outside the home. The most important modifiable factors occurring inside the home relate to caregivers' recognition of illness and appreciation of urgency in response to the severity of the child's symptoms and signs. Outside the home, modifiable factors relate to inadequate referral and follow-up by health professionals. Further research should focus on identifying and overcoming barriers to referral. [ABSTRACT FROM AUTHOR]

Purpose: The sudden death of a child is a catastrophic event for both the family and the healthcare workers involved. Confidential enquiries provide a biomedical depiction of the processes and quality of care delivered and drive improvements in care. However, these rarely include an assessment of the patient/caregiver experience which is increasingly regarded as a key measure of quality of care. Methods: A parallel convergent mixed methods design was used to compare and contrast medically-assessed clinical quality of care with caregiver perceptions of quality and care in a cohort of sudden childhood deaths in emergency facilities in Cape Town, South Africa. Results: Amongst the 29 sudden childhood deaths, clinical quality of care was assessed as poor in 11 (38%) and the death was considered avoidable or potentially avoidable in 16 (55%). The main themes identified from the caregivers were their perception of the quality of care delivered (driven by perceived healthcare worker effort, empathy and promptness), the way the family was dealt with during the final resuscitation, and communications at the time of and after the death. Ten (35%) caregivers were predominantly negative about the care delivered, of whom four received fair clinical quality of care; 13 (49%) of caregivers had predominantly positive experiences, one of whom received poor clinical quality of care. Conclusions: Caregivers’ experiences of the healthcare service around their child’s death are influenced largely by the way healthcare workers communicate with them, as well as the perceived clinical effort. This is not always concordant with the clinically assessed quality of care. Simple interventions such as protocols and education of healthcare workers in dealing with families of a dying or deceased child could improve families’ experiences at a time when they are most vulnerable. [ABSTRACT FROM AUTHOR]

Objective: To characterise perceived household support for female education and the associations between educational support and HIV prevalence, HSV-2 prevalence and sexual risk behaviours. Methods: This cross-sectional study used baseline survey data from the Swa Koteka HPTN 068 trial undertaken in Mpumalanga, South Africa. The study included 2533 young women aged 13–20, in grades 8–11 at baseline. HIV and HSV-2 status were determined at baseline. Information about patterns of sexual behaviour and household support for education was collected during the baseline survey. Linear regression and binary logistic regression were used to determine associations between household support for education and both biological and behavioural outcomes. Results: High levels of educational support were reported across all measures. HIV prevalence was 3.2% and HSV-2 prevalence was 4.7%, both increasing significantly with age. Over a quarter (26.6%) of young women reported vaginal sex, with 60% reporting condom use at last sex. The median age of sexual debut was 16 years. Household educational support was not significantly associated with HIV or HSV-2; however, the odds of having had vaginal sex were significantly lower in those who reported greater homework supervision (OR 0.82, 95%CI: 0.72–0.94), those who engaged in regular discussion of school marks with a caregiver (OR 0.82, 95%CI: 0.71–0.95) and when caregivers had greater educational goals for the young woman (OR 0.82, 95%CI: 0.71–0.96). In contrast, greater caregiver disappointment at dropout was significantly associated with reported vaginal sex (OR 1.29, 95%CI: 1.14–1.46). Conclusion: Young women in rural South Africa report experiencing high levels of household educational support. This study suggests that greater household educational support is associated with lower odds of having vaginal sex and engaging in risky sexual behaviour, though not with HIV or HSV-2 prevalence. [ABSTRACT FROM AUTHOR]

This paper evaluates a novel high variability phonetic training paradigm that involves presenting spoken words in adverse conditions. The effectiveness, generalizability, and longevity of this high variability phonetic training in adverse conditions was evaluated using English phoneme contrasts in three experiments with Malaysian multilinguals. Adverse conditions were created by presenting spoken words against background multi-talker babble. In Experiment 1, the adverse condition level was set at a fixed level throughout the training and in Experiment 2 the adverse condition level was determined for each participant before training using an adaptive staircase procedure. To explore the effectiveness and sustainability of the training, phonemic discrimination ability was assessed before and immediately after training (Experiments 1 and 2) and 6 months after training (Experiment 3). Generalization of training was evaluated within and across phonemic contrasts using trained and untrained stimuli. Results revealed significant perceptual improvements after just three 20-minute training sessions and these improvements were maintained after 6 months. The training benefits also generalized from trained to untrained stimuli. Crucially, perceptual improvements were significantly larger when the adverse conditions were adapted before each training session than when it was set at a fixed level. As the training improvements observed here are markedly larger than those reported in the literature, this indicates that the individualized phonetic training regime in adaptive adverse conditions (HVPT-AAC) is highly effective at improving speech perception. [ABSTRACT FROM AUTHOR]

As an HIV prevention strategy, the scale-up of voluntary medical male circumcision (VMMC) is underway in 14 countries in Africa. For prevention impact, these countries must perform millions of circumcisions in adolescent and adult men before 2015. Although acceptability of VMMC in the region is well documented and service delivery efforts have proven successful, countries remain behind in meeting circumcision targets. A better understanding of men's VMMC-seeking behaviors and experiences is needed to improve communication and interventions to accelerate uptake. To this end, we conducted semi-structured interviews with 40 clients waiting for surgical circumcision at clinics in Zambia. Based on Stages of Change behavioral theory, men were asked to recount how they learned about adult circumcision, why they decided it was right for them, what they feared most, how they overcame their fears, and the steps they took to make it to the clinic that day. Thematic analysis across all cases allowed us to identify key behavior change triggers while within-case analysis elucidated variants of one predominant behavior change pattern. Major stages included: awareness and critical belief adjustment, norming pressures and personalization of advantages, a period of fear management and finally VMMC-seeking. Qualitative comparative analysis of ever-married and never-married men revealed important similarities and differences between the two groups. Unprompted, 17 of the men described one to four failed prior attempts to become circumcised. Experienced more frequently by older men, failed VMMC attempts were often due to service-side barriers. Findings highlight intervention opportunities to increase VMMC uptake. Reaching uncircumcised men via close male friends and female sex partners and tailoring messages to stage-specific concerns and needs would help accelerate men's movement through the behavior change process. Expanding service access is also needed to meet current demand. Improving clinic efficiencies and introducing time-saving procedures and advance scheduling options should be considered. [ABSTRACT FROM AUTHOR]

Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer. [ABSTRACT FROM AUTHOR]

Most endometrial cancers can be classified histologically as endometrioid, serous, or clear cell. Non-endometrioid endometrial cancers (NEECs; serous and clear cell) are the most clinically aggressive of the three major histotypes and are characterized by aneuploidy, a feature of chromosome instability. The genetic alterations that underlie chromosome instability in endometrial cancer are poorly understood. In the present study, we used Sanger sequencing to search for nucleotide variants in the coding exons and splice junctions of 21 candidate chromosome instability genes, including 19 genes implicated in sister chromatid cohesion, from 24 primary, microsatellite-stable NEECs. Somatic mutations were verified by sequencing matched normal DNAs. We subsequently resequenced mutated genes from 41 additional NEECs as well as 42 endometrioid ECs (EECs). We uncovered nonsynonymous somatic mutations in ESCO1, CHTF18, and MRE11A in, respectively, 3.7% (4 of 107), 1.9% (2 of 107), and 1.9% (2 of 107) of endometrial tumors. Overall, 7.7% (5 of 65) of NEECs and 2.4% (1 of 42) of EECs had somatically mutated one or more of the three genes. A subset of mutations are predicted to impact protein function. The co-occurrence of somatic mutations in ESCO1 and CHTF18 was statistically significant (P = 0.0011, two-tailed Fisher's exact test). This is the first report of somatic mutations within ESCO1 and CHTF18 in endometrial tumors and of MRE11A mutations in microsatellite-stable endometrial tumors. Our findings warrant future studies to determine whether these mutations are driver events that contribute to the pathogenesis of endometrial cancer. [ABSTRACT FROM AUTHOR]

ATAD5, the human ortholog of yeast Elg1, plays a role in PCNA deubiquitination. Since PCNA modification is important to regulate DNA damage bypass, ATAD5 may be important for suppression of genomic instability in mammals in vivo. To test this hypothesis, we generated heterozygous (Atad5+/m) mice that were haploinsuffficient for Atad5. Atad5+/m mice displayed high levels of genomic instability in vivo, and Atad5+/m mouse embryonic fibroblasts (MEFs) exhibited molecular defects in PCNA deubiquitination in response to DNA damage, as well as DNA damage hypersensitivity and high levels of genomic instability, apoptosis, and aneuploidy. Importantly, 90% of haploinsufficient Atad5 +/m mice developed tumors, including sarcomas, carcinomas, and adenocarcinomas, between 11 and 20 months of age. High levels of genomic alterations were evident in tumors that arose in the Atad5 +/m mice. Consistent with a role for Atad5 in suppressing tumorigenesis, we also identified somatic mutations of ATAD5 in 4.6% of sporadic human endometrial tumors, including two nonsense mutations that resulted in loss of proper ATAD5 function. Taken together, our findings indicate that loss-of-function mutations in mammalian Atad5 are sufficient to cause genomic instability and tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: The shortage of human resources for health, and in particular physicians, is one of the major barriers to achieve universal access to HIV care and treatment. In September 2005, a pilot program of nurse-centered antiretroviral treatment (ART) prescription was launched in three rural primary health centers in Rwanda. We retrospectively evaluated the feasibility and effectiveness of this task-shifting model using descriptive data. Methods and Findings: Medical records of 1,076 patients enrolled in HIV care and treatment services from September 2005 to March 2008 were reviewed to assess: (i) compliance with national guidelines for ART eligibility and prescription, and patient monitoring and (ii) key outcomes, such as retention, body weight, and CD4 cell count change at 6, 12, 18, and 24 mo after ART initiation. Of these, no ineligible patients were started on ART and only one patient received an inappropriate ART prescription. Of the 435 patients who initiated ART, the vast majority had adherence and side effects assessed at each clinic visit (89% and 84%, respectively). By March 2008, 390 (90%) patients were alive on ART, 29 (7%) had died, one (<1%) was lost to follow-up, and none had stopped treatment. Patient retention was about 92% by 12 mo and 91% by 24 mo. Depending on initial stage of disease, mean CD4 cell count increased between 97 and 128 cells/μl in the first 6 mo after treatment initiation and between 79 and 129 cells/μl from 6 to 24 mo of treatment. Mean weight increased significantly in the first 6 mo, between 1.8 and 4.3 kg, with no significant increases from 6 to 24 mo. Conclusions: Patient outcomes in our pilot program compared favorably with other ART cohorts in sub-Saharan Africa and with those from a recent evaluation of the national ART program in Rwanda. These findings suggest that nurses can effectively and safely prescribe ART when given adequate training, mentoring, and support. [ABSTRACT FROM AUTHOR]