bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing cardiovascular disease risk factor screening inequalities in India using Lot Quality Assurance Sampling
Authors: Nambiar Devaki , Bhaumik Soumyadeep , Pal Anita , Ved Rajani
Published: November 2020

Background

Cardiovascular diseases (CVDs) are the leading cause of mortality in India. India has rolled out Comprehensive Primary Health Care (CPHC) reforms including population based screening for hypertension and diabetes, facilitated by frontline health workers. Our study assessed blood pressure and blood sugar coverage achieved by frontline workers using Lot Quality Assurance Sampling (LQAS).

Methods

LQAS Supervision Areas were defined as catchments covered by frontline workers in primary health centres in two districts each of Uttar Pradesh and Delhi. In each Area, 19 households for each of four sampling universes (males, females, Above Poverty Line (APL) and Below Poverty Line (BPL)) were visited using probability proportional to size sampling. Following written informed consent procedures, a short questionnaire was administered to individuals aged 30 or older using tablets related to screening for diabetes and hypertension. Using the LQAS hand tally method, coverage across Supervision Areas was determined.

Results

A sample of 2052 individuals was surveyed, median ages ranging from 42 to 45 years. Caste affiliation, education levels, and occupation varied by location; the sample was largely married and Hindu. Awareness of and interaction with frontline health workers was reported in Uttar Pradesh and mixed in Delhi. Greater coverage of CVD risk factor screening (especially blood pressure) was seen among females, as compared to males. No clear pattern of inequality was seen by poverty status; some SAs did not have adequate BPL samples. Overall, blood pressure and blood sugar screening coverage by frontline health workers fell short of targeted coverage levels at the aggregate level, but in all sites, at least one area was crossing this threshold level.

Conclusion

CVD screening coverage levels at this early stage are low. More emphasis may be needed on reaching males. Sex and poverty related inequalities must be addressed by more closely studying the local context and models of service delivery where the threshold of screening is being met. LQAS is a pragmatic method for measuring program inequalities, in resource-constrained settings, although possibly not for spatially segregated population sub-groups.
A needs assessment for postgraduate training in selected public health disciplines: evidence from health services organisations in Lusaka, Zambia
Authors: Bulawayo Maio , Silumbwe Adam , Munakampe Margarate Nzala , Mukumbuta Nawa , Musabula Juliet , Chewe Mwimba , Mweemba Chris , Michelo Charles , Hangoma Peter
Published: November 2020

Background

As most low and middle-income countries seek to achieve universal health coverage targets, there is an ever-increasing need to train human resources with the required core skills and competencies. This study reports on a needs assessment conducted among health services organisations (HSOs) to understand postgraduate training needs and service gaps for selected public health disciplines – Health Policy and Systems, Health Economics, and Healthcare Management and Planning – at the University of Zambia.

Methods

The study adopted a cross-sectional design, comprising qualitative and quantitative components. Data were collected using semi-structured questionnaires administered to 32 representatives of purposively sampled public and private health service organisations based in Lusaka Zambia. The health services organisations included regulatory authorities, research institutions, government ministries, insurance firms and other cooperating partners.

Results

Overall (n = 22), more than 68% of the stakeholders reported that they had no employees that were formally trained in the three disciplines. More than 90% of the stakeholders opined that training in these disciplines would be beneficial in providing competencies to strengthen service provision. The horizontal skills mismatch for health economics, and health services management and planning were found to be 93 and 100%, respectively. Among the critical public health training needs were: policy development and analysis, economic evaluation, and strategic management.

Conclusions

This study confirms that introducing post-graduate training in the proposed public health disciplines will not only benefit Zambian health services organisations but also help strengthen the health systems in general. For other empirical contexts, the findings imply the need for the introduction of academic programmes which respond to ever-changing public health skills demanded. They should be matched with local priorities and service delivery.
Total cardiovascular or fatal events in people with type 2 diabetes and cardiovascular risk factors treated with dulaglutide in the REWIND trail: a post hoc analysis
Authors: Dagenais Gilles R. , Rydén Lars , Leiter Lawrence A. , Lakshmanan Mark , Dyal Leanne , Probstfield Jeffrey L. , Atisso Charles Messan , Shaw Jonathan E. , Conget Ignacio , Cushman William C. , Lopez-Jaramillo Patricio , Lanas Fernando , Munoz Ernesto German Cordona , Pirags Valdis , Pogosova Nana , Basile Jan , Sheu Wayne H. H. , Temelkova-Kurktschiev Theodora , Raubenheimer Peter J. , Keltai Matyas , Hall Stephanie , Pais Prem , Colhoun Helen M. , Riddle Matthew C. , Gerstein Hertzel C.
Published: November 2020

Background

The Researching cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) double blind randomized trial demonstrated that weekly subcutaneous dulaglutide 1.5 mg, a glucagon like peptide-1 receptor agonist, versus matched placebo reduced the first outcome of major adverse cardiovascular event (MACE), cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (594 versus 663 events) in 9901 persons with type 2 diabetes and either chronic cardiovascular disease or risk factors, and followed during 5.4 years. These findings were based on a time-to-first-event analysis and preclude relevant information on the burden of total major events occurring during the trial. This analysis reports on the total cardiovascular or fatal events in the REWIND participants

Methods

We compared the total incidence of MACE or non-cardiovascular deaths, and the total incidence of expanded MACE (MACE, unstable angina, heart failure or revascularization) or non-cardiovascular deaths between participants randomized to dulaglutide and those randomized to placebo. Incidences were expressed as number per 1000 person-years. Hazard ratios (HR) were calculated using the conditional time gap and proportional means models.

Results

Participants had a mean age of 66.2 years, 46.3% were women and 31% had previous cardiovascular disease. During the trial there were 1972 MACE or non-cardiovascular deaths and 3673 expanded MACE or non-cardiovascular deaths. The incidence of total MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 35.8 and 40.3 per 1000 person-years, respectively [absolute reduction = 4.5 per 1000 person-years; conditional time gap HR 0.90 (95% CI, 0.82–0.98) p = 0.020, and proportional means HR 0.89 (95% CI, 0.80–0.98) p = 0.022]. The incidence of total expanded MACE or non-cardiovascular deaths in the dulaglutide and placebo groups was 67.1 and 74.7 per 1000 person-years, respectively [absolute reduction = 7.6 per 1000 person-years; conditional time gap HR 0.93 (95% CI, 0.87–0.99) p = 0.023, and proportional means HR 0.90 (95% CI, 0.82–0.99) p = 0.028].

Conclusions

These findings suggest that weekly subcutaneous dulaglutide reduced total cardiovascular or fatal event burden in people with type 2 diabetes at moderate cardiovascular risk.

Clinical Trial Registration:https://www.clinicaltrials.gouv. Unique Identifier NCT01394952).
Intermittent screening and treatment with dihydroartemisinin-piperaquine for the prevention of malaria in pregnancy: implementation feasibility in a routine healthcare system setting in western Kenya
Authors: Hill Jenny , Ouma Peter , Oluoch Seth , Bruce Jane , Kariuki Simon , Desai Meghna , Webster Jayne
Published: November 2020

Background

Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended for preventing malaria in pregnancy in areas of moderate-to-high transmission in sub-Saharan Africa. However, due to increasing parasite resistance to SP, research on alternative strategies is a priority. The study assessed the implementation feasibility of intermittent screening and treatment (ISTp) in the second and third trimester at antenatal care (ANC) with malaria rapid diagnostic tests (RDTs) and treatment of positive cases with dihydroartemisinin-piperaquine (DP) compared to IPTp-SP in western Kenya.

Methods

A 10-month implementation study was conducted in 12 government health facilities in four sub-counties. Six health facilities were assigned to either ISTp-DP or IPTp-SP. Evaluation comprised of facility audits, ANC observations, and exit interviews. Intermediate and cumulative effectiveness analyses were performed on all processes involved in delivery of ISTp-DP including RDT proficiency and IPTp-SP ± directly observed therapy (DOT, standard of care). Logistic regression was used to identify predictors of receiving each intervention.

Results

A total of 388 and 389 women were recruited in the ISTp-DP and IPTp-SP arms, respectively. For ISTp-DP, 90% (289/320) of eligible women received an RDT. Of 11% (32/289) who tested positive, 71% received the correct dose of DP and 31% the first dose by DOT, and only 6% were counselled on subsequent doses. Women making a sick visit and being tested in a facility with a resident microscopist were more likely to receive ISTp-DP (AOR 1.78, 95% CI 1.31, 2.41; and AOR 3.75, 95% CI 1.31, 2.40, respectively). For IPTp-SP, only 57% received a dose of SP by DOT. Payment for a laboratory test was independently associated with receipt of SP by DOT (AOR 6.43, 95% CI 2.07, 19.98).

Conclusions

The findings indicate that the systems effectiveness of ANC clinics to deliver ISTp-DP under routine conditions was poor in comparison to IPTp-SP. Several challenges to integration of ISTp with ANC were identified that may need to be considered by countries that have introduced screening at first ANC visit and, potentially, for future adoption of ISTp with more sensitive RDTs. Understanding the effectiveness of ISTp-DP will require additional research on pregnant women’s adherence to ACT.
Digitalized mass distribution campaign of insecticide-treated nets (ITNs) in the particular context of Covid-19 pandemic in Benin: challenges and lessons learned
Authors: Aïkpon Rock , Affoukou Cyriaque , Hounpkatin Benjamin , Eclou Dieu-Donné , Cyaka Yves , Egwu Elijah , Agbessi Narcisse , Tokponnon Filémon , Salifou Sahidou , Salami Lamidhi , Hounto Aurore Ogouyemi
Published: November 2020

Background

In 2020, Benin has implemented a digitalized mass distribution campaign of insecticide-treated nets (ITNs) in the particular context of COVID-19 pandemic. This paper describes the implementation process as well as the challenges and lessons learned from this campaign.

Methods

A descriptive design was used for reporting the planning and implementation process of ITNs campaign. Moreover, the changes and adaptations related to COVID-19 pandemic are described.

Results

A total of 3,175,773 households were registered corresponding to a total of 14,423,998 persons (13.55% more from projection). Moreover, 94.16% (13,581,637 people) of enumerated population were protected. A total of 7,652,166 ITNs were distributed countrywide.

Conclusions

High political commitment, engagement and support add to the financial and technical supports from partners were the essential factors that make 2020 ITNs mass campaign success in Benin despite the particular context of COVID-19 pandemic. It is essential to maintain the prevention activities for malaria and this could substantially reduce the overall impact of the COVID-19 pandemic for the populations at malaria risk.
Molecular surveillance of anti-malarial resistance Pfdhfr and Pfdhps polymorphisms in African and Southeast Asia Plasmodium falciparum imported parasites to Wuhan, China
Authors: Jiang Tingting , Cheng Weijia , Yao Yi , Tan Huabing , Wu Kai , Li Jian
Published: November 2020

Background

Anti-malarial drug resistance is a severe challenge for eventual control and global elimination of malaria. Resistance to sulfadoxine-pyrimethamine (SP) increases as mutations accumulate in the Pfdhfr and Pfdhps genes. This study aimed to assess the polymorphisms and prevalence of mutation in these genes in the Plasmodium falciparum infecting migrant workers returning to Wuhan, China.

Methods

Blood samples were collected for 9 years (2011–2019). Parasite genomic DNA was extracted from blood spots on filter paper. The mutations were evaluated by nested PCR and sequencing. The single-nucleotide polymorphisms (SNPs) and haplotypes of the Pfdhfr and Pfdhps genes were analysed.

Results

Pfdhfr codon 108 showed a 94.7% mutation rate, while for Pfdhps, the rate for codon 437 was 79.0%. In total, five unique haplotypes at the Pfdhfr locus and 11 haplotypes at the Pfdhps locus were found while the Pfdhfr-Pfdhps combined loci revealed 28 unique haplotypes. A triple mutant (IRNI) of Pfdhfr was the most prevalent haplotype (84.4%). For Pfdhps, a single mutant (SGKAA) and a double mutant (SGEAA) were detected at frequencies of 37.8 and 22.3%, respectively. Among the combined haplotypes, a quadruple mutant (IRNI-SGKAA) was the most common, with a 30.0% frequency, followed by a quintuplet mutant (IRNI-SGEAA) with a frequency of 20.4%.

Conclusion

The high prevalence and saturation of Pfdhfr haplotypes and the medium prevalence of Pfdhps haplotypes demonstrated in the present data will provide support for predicting the status and progression of antifolate resistance in malaria-endemic regions and imported malaria in nonendemic areas. Additional interventions to evaluate and prevent SP resistance should be continuously considered.
Cultural respect in midwifery service provision for Aboriginal women: longitudinal follow-up reveals the enduring legacy of targeted program initiatives
Authors: Thackrah Rosalie D. , Wood Jennifer , Thompson Sandra C.
Published: November 2020

Background

Culturally competent maternity care provision to Aboriginal and Torres Strait Islander women was identified as a priority area by Australia’s National Maternity Services Plan in 2011. While midwifery programs responded by including core Indigenous content and community placements in curricula, little is known about whether knowledge learned, and insights gained in response to these initiatives have endured and been applied in clinical practice. This follow-up study explores the impact of a compulsory Indigenous unit and a remote clinical placement on two cohorts of non-Indigenous midwives who were participants in an earlier 2012–14 study.

Methods

Fourteen non-Indigenous participants who were either students or recent graduates in 2012–14 were located and re-interviewed in 2019–20. In-depth interviews based on a semi-structured interview guide were conducted by telephone or face-to face; recordings were transcribed and thematically analysed using standard qualitative procedures.

Results

Exposure to Indigenous content and settings during training had an enduring impact on participants’ midwifery practice; most felt better prepared to provide culturally safe care, build respectful relationships and advocate for improved services for Aboriginal women. Despite this positive legacy, they also expressed apprehension about causing offence and recognised their own knowledge deficits with regard to Aboriginal cultural practices. Organisational constraints, including restrictions on the number of family members accompanying a birthing mother were identified as barriers to optimal care; some positive organisational initiatives were also described.

Conclusions

This follow-up study provides encouraging evidence that well-designed and delivered Indigenous content and community placement opportunities in midwifery programs can have a lasting impact on service provision to Aboriginal women, contribute to a more informed, empathetic and culturally competent maternity workforce and help catalyse health service changes towards more culturally safe care.
Letter to the editor regarding “spatiotemporal association of low birth weight with Cs-137 deposition at the prefecture level in Japan after the Fukushima nuclear power plant accidents”
Authors: Soleman Sani Rachman , Fujitani Tomoko , Harada Kouji H.
Published: November 2020

In the previous report, association between increased low birth weight prevalence and radiocesium deposition after 2011 Fukushima nuclear disaster was found. However, the statistical analyses therein raised several questions. First, ecological variables are not justified enough to adjust potential confounding. Second, the spatiotemporal regression model does not consider temporal reduction in radiation dose rate. Third, dose-response plot between dose rates and odds ratios overestimates R2 and underestimates p value.
Association between the alanine aminotransferase/aspartate aminotransferase ratio and new-onset non-alcoholic fatty liver disease in a nonobese Chinese population: a population-based longitudinal study
Authors: Zou Yang , Zhong Ling , Hu Chong , Sheng Guotai
Published: November 2020

Background

The alanine aminotransferase (ALT)/aspartate aminotransferase (AST) ratio has been considered an alternative marker for hepatic steatosis. However, few studies have investigated the association of the ALT/AST ratio with non-alcoholic fatty liver disease (NAFLD) in nonobese people.

Methods

A total of 12,127 nonobese participants who were free of NAFLD participated in this study. The participants were divided into quintiles of the ALT/AST ratio. Multiple Cox regression models were used to explore the association of the ALT/AST ratio with new-onset NAFLD.

Results

During the five-year follow-up period, 2147 individuals (17.7%) developed new-onset NAFLD.

After adjusting for all non-collinear covariates, the multiple Cox regression analysis results showed that a higher ALT/AST ratio was independently associated with new-onset NAFLD in nonobese Chinese (adjusted hazard ratios [aHRs]: 2.10, 95% confidence intervals: 1.88, 2.36). The aHRs for NAFLD across increasing quintiles of the ALT/AST ratio were 1, 1.63 (1.30, 2.04), 2.07 (1.65, 2.60), 2.84 (2.33, 3.48) and 3.49 (2.78, 4.39) (P for trend< 0.001). The positive association was more significant among people with high blood pressure, high blood lipids and hyperglycaemia, as well as in men. Additionally, the regression spline showed that the saturation effect of the ALT/AST ratio on NAFLD risk was at 0.93 in this study population, which was 1.22 in males and 0.89 in females.

Conclusions

In nonobese Chinese individuals without NAFLD at baseline, the increase in the ALT/AST ratio is closely associated with the risk of new-onset NAFLD.
Impact of previous abdominal surgery on robotic-assisted rectal surgery in patients with locally advanced rectal adenocarcinoma: a propensity score matching study
Authors: Huang Ching-Wen , Su Wei-Chih , Chang Tsung-Kun , Ma Cheng-Jen , Yin Tzu-Chieh , Tsai Hsiang-Lin , Chen Po-Jung , Chen Yen-Cheng , Li Ching-Chun , Hsieh Yi-Chien , Wang Jaw-Yuan
Published: November 2020

Background

The application of minimally invasive surgery in patients with colorectal cancer (CRC) and a history of previous abdominal surgery (PAS) remains controversial. This retrospective study with propensity score matching (PSM) investigated the impact of PAS on robotic-assisted rectal surgery outcomes in patients with locally advanced rectal adenocarcinoma undergoing preoperative concurrent chemoradiotherapy (CCRT).

Methods

In total, 203 patients with locally advanced rectal adenocarcinoma who underwent preoperative CCRT and robotic-assisted rectal surgery between May 2013 and December 2019 were enrolled. Patients were categorized into PAS and non-PAS groups based on the PAS history. The PSM caliper matching method with 1-to-3 matches was used to match PAS patients with non-PAS.

Results

Of the 203 enrolled patients, 35 were PAS patients and 168 were non-PAS patients. After PSM, 32 PAS patients and 96 non-PAS patients were included for analysis. No significant between-group differences were noted in the perioperative outcomes, including median console time (165 min (PAS) vs. 175 min (non-PAS), P = 0.4542) and median operation time (275 min (PAS) vs. 290 min (non-PAS), P = 0.5943) after PSM. Postoperative recovery and overall complication rates were also similar (all P > 0.05). Moreover, the between-group differences in pathological or short-term oncological outcomes were also nonsignificant (all P > 0.05). No 30-day postoperative deaths were observed in either group.

Conclusion

The current results indicate that robotic-assisted surgery is safe and feasible for PAS patients with locally advanced rectal adenocarcinoma undergoing preoperative CCRT. However, future prospective randomized clinical trials are required to verify these findings.
Thyroid autoimmunity and IVF/ICSI outcomes in euthyroid women: a systematic review and meta-analysis
Authors: Venables Ashley , Wong Wilbert , Way Mandy , Homer Hayden Anthony
Published: November 2020

Background

Thyroid autoimmunity (TAI) – the presence of anti-thyroid peroxidase and/or anti-thyroglobulin antibodies – affects 8–14% of reproductively-aged women. It is hotly debated whether TAI adversely affects IVF/ICSI outcomes. This systematic review and meta-analysis evaluated the relationship between thyroid autoimmunity (TAI) and IVF/ICSI outcomes, both overall and amongst euthyroid women of known age using strict criteria for grouping pregnancy outcomes.

Methods

The review was registered with PROSPERO: CRD42019120947. Searches were undertaken in MEDLINE, EMBASE, Web of Science and Cochrane Database from Inception-March 2020. Primary outcomes were clinical pregnancy rate, clinical miscarriage rate, biochemical pregnancy loss, livebirth rate per-cycle and live birth rate per clinical pregnancy (CP).

Results

14 studies were included in the meta-analysis. Compared with women who tested negative for thyroid autoantibodies (TAI-), there was no significant difference in clinical pregnancy rate overall (OR 0.86; 95%CI [0.70, 1.05]; P = 0.14; 11 studies; I2 = 29.0%), or in euthyroid women (OR 0.88; 95%CI [0.69, 1.12]; P = 0.29; 10 studies; I2 = 32.0%). There was also no significant difference in clinical miscarriage rate overall (OR 1.04; 95%CI [0.52, 2.07]; P = 0.908; 8 studies; I2 = 53%), or in euthyroid women (OR 1.18; 95%CI [0.52, 2.64]; P = 0.69; 7 studies; I2 = 54%). There was no significant difference in biochemical pregnancy loss (OR 1.14; 95%CI [0.48, 2.72]; P = 0.769; 4 studies; I2 = 0.0%), live birth rate per cycle (OR 0.84; 95%CI [0.67, 1.06]; P = 0.145; I2 = 1.7%), live birth rate per clinical pregnancy (OR 0.67; 95%CI [0.28, 1.60]; P = 0.369; I2 = 69.2%), both overall and in euthyroid women as all studies included consisted of euthyroid women only. There was also no significant difference in number of embryos transferred, number of oocytes retrieved, mean maternal age or TSH levels overall or in euthyroid women.

Conclusion

The findings of the present study suggest that thyroid autoimmunity has no effect on pregnancy outcomes in euthyroid women alone, or in euthyroid women and women with subclinical hypothyroidism.
Agnostic evaluation of ipilimumab and nivolumab association: a metanalysis
Authors: Marchetti Paolo , Botticelli Andrea , Ascierto Antonio Paolo , Curigliano Giuseppe , Giannarelli Diana
Published: November 2020

Background

Ipilimumab and Nivolumab, targeting the molecules CTLA-4, PD-1, respectively,have shown efficacy against several types of cancer. Despite these results, only a small percentage of patients maintains a long-lasting effect. Even Ipilimumab, in combination with nivolumab, has demonstrated a significant clinical benefit in multiple tumor types. However, no trial has been designed with the primary endpoint to compare the efficacy of nivolumab plus ipilimumab combined, compared to nivolumab alone. Hence, the added value of ipilimumab in the combination has not clearly been established yet. The aim of this study was to demonstrate the superiority of the combination strategy compared to the single agent therapy.

Materials and methods

We performed a meta-analysis of Phase I-II-III Clinical Trials, published from 2010 up to 2020, in which the combination of ipilimumab plus nivolumab was compared to nivolumab alone. We extracted ORR, OS and PFS HR on the basis of treatment from the subgroup analysis of each trial.

Results

A total of 7 trials were included in the present meta-analysis. Overall, 1313 patients were treated with the nivolumab plus ipilimumab combination compared to 1110 patients treated with nivolumabalone. All trials reported the Objective response rate(ORR), no heterogeneity was found among studies and the pooled Odds Ratio was highly in favor of the nivolumab plus ipilimumab combination with respect to nivolumab alone (1.683; 95% CI: 1.407–2.012; P < 0.0001). Three studies were considered for Progression free survival (PFS) analysis, and the pooled Hazard Ratio favored the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.807; 95% CI: 0.719–0.907; P < 0.0001). The Overall survival(OS) endpoint was considered only in 2 trials, and the pooled HR favored, also in this case, the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.87; 95% CI: 0.763–0.997; P = 0.045).

Conclusions

The combination of ipilimumab plus nivolumab seems to be superior to nivolumab alone in cancer patients, regardless of histology.
Early cases of SARS-CoV-2 infection in Uganda: epidemiology and lessons learned from risk-based testing approaches – March-April 2020
Authors: Migisha Richard , Kwesiga Benon , Mirembe Bernadette Basuta , Amanya Geofrey , Kabwama Steven N. , Kadobera Daniel , Bulage Lilian , Nsereko Godfrey , Wadunde Ignatius , Tindyebwa Tonny , Lubwama Bernard , Kagirita Atek A. , Kayiwa John T. , Lutwama Julius J. , Boore Amy L. , Harris Julie R. , Bosa Henry Kyobe , Ario Alex Riolexus
Published: November 2020

Background

On March 13, 2020, Uganda instituted COVID-19 symptom screening at its international airport, isolation and SARS-CoV-2 testing for symptomatic persons, and mandatory 14-day quarantine and testing of persons traveling through or from high-risk countries. On March 21, 2020, Uganda reported its first SARS-CoV-2 infection in a symptomatic traveler from Dubai. By April 12, 2020, 54 cases and 1257 contacts were identified. We describe the epidemiological, clinical, and transmission characteristics of these cases.

Methods

A confirmed case was laboratory-confirmed SARS-CoV-2 infection during March 21–April 12, 2020 in a resident of or traveler to Uganda. We reviewed case-person files and interviewed case-persons at isolation centers. We identified infected contacts from contact tracing records.

Results

Mean case-person age was 35 (±16) years; 34 (63%) were male. Forty-five (83%) had recently traveled internationally (‘imported cases’), five (9.3%) were known contacts of travelers, and four (7.4%) were community cases. Of the 45 imported cases, only one (2.2%) was symptomatic at entry. Among all case-persons, 29 (54%) were symptomatic at testing and five (9.3%) were pre-symptomatic. Among the 34 (63%) case-persons who were ever symptomatic, all had mild disease: 16 (47%) had fever, 13 (38%) reported headache, and 10 (29%) reported cough. Fifteen (28%) case-persons had underlying conditions, including three persons with HIV. An average of 31 contacts (range, 4–130) were identified per case-person. Five (10%) case-persons, all symptomatic, infected one contact each.

Conclusion

The first 54 case-persons with SARS-CoV-2 infection in Uganda primarily comprised incoming air travelers with asymptomatic or mild disease. Disease would likely not have been detected in these persons without the targeted testing interventions implemented in Uganda. Transmission was low among symptomatic persons and nonexistent from asymptomatic persons. Routine, systematic screening of travelers and at-risk persons, and thorough contact tracing will be needed for Uganda to maintain epidemic control.
Patients with pretreatment leukoencephalopathy and older patients have more cognitive decline after whole brain radiotherapy
Authors: Chan Matthew , Ferguson David , Ni Mhurchu Elaine , Yuan Ren , Gondara Lovedeep , McKenzie Michael , Olson Robert , Thiessen Brian , Lalani Nafisha , Ma Roy , Nichol Alan
Published: November 2020

Purpose

To investigate predictors of cognitive decline after whole brain radiotherapy (WBRT) for brain metastases.

Methods

A secondary analysis of a phase 2 clinical trial was conducted in patients who received stereotactic radiosurgery for 1–10 brain metastases and WBRT (NCT01046123). The Montreal Cognitive Assessment (MoCA) was performed at baseline and every 3 months after WBRT. Baseline T2-weighted fluid attenuation inversion recovery magnetic resonance imaging was independently assessed by two neuroradiologists for the presence of white matter hyperintensities (WMH) using the Fazekas visual rating scale. WMH were also manually segmented for volumetric analysis. Univariable and multivariable logistic regression were used to test the association between baseline variables and MoCA score decline.

Results

Forty-six patients survived ≥ 3 months after treatment. Age (OR 1.12 (1.04–1.21), p < 0.01), baseline WMH volume (OR 1.20, 95% CI 1.06–1.52, p = 0.02) and baseline Fazekas score ≥ 3/6 (OR 6.4, 95% CI 1.7–24.7, p < 0.01) were predictive of MoCA score decline. In multivariable analysis, age was the only significant predictor of MoCA decline. However, all three patients with pre-treatment leukoencephalopathy (Fazekas score = 6/6) had notable adverse outcomes due to cognitive impairment: one required full-time home nursing support and two were institutionalized.

Conclusion

A greater decline in cognition after WBRT was observed in older patients and patients with a higher baseline WMH burden. Although this study is small and hypothesis-generating, we propose that radiation oncologists should exercise caution in prescribing WBRT if leukoencephalopathy is present on pre-treatment imaging.

Trial Registration: clinicaltrials.gov identifier NCT01046123. First posted January 11, 2010. https://clinicaltrials.gov/ct2/show/NCT01046123
Transplantation of a heart donated after circulatory death via thoraco-abdominal normothermic regional perfusion and results from the first Spanish case
Authors: Pérez Redondo Marina , Alcántara Carmona Sara , Villar García Susana , Forteza Gil Alberto , Villanueva Fernández Héctor , Hernández-Pérez Francisco José , Campo-Cañaveral de la Cruz José Luis , Velasco Calvo Rocío , Segovia-Cubero Javier , Alonso Menárguez Beatriz , del Río Gallegos Francisco , Coll Elisabeth , Domínguez-Gil González Beatriz , Rubio Muñoz Juan José
Published: November 2020

Background

Controlled donation after circulatory death (cDCD) has emerged as one of the main strategies for increasing the organ donor pool. Because of the ischemic injury that follows the withdrawal of life-sustaining therapies, hearts from cDCD donors have not been considered for transplantation until recently. The ex-situ perfusion of hearts directly procured from cDCD donors has been used to allow the continuous perfusion of the organ and the assessment of myocardial viability prior to transplantation. Based on our experience with abdominal normothermic regional perfusion in cDCD, we designed a protocol to recover and validate hearts from cDCD donors using thoraco-abdominal normothermic regional perfusion without the utilization of an ex-situ device.

Case presentation

We describe the first case of a cDCD heart transplant performed with this approach in Spain. The donor was a 43-year-old asthmatic female diagnosed with severe hypoxic encephalopathy. She was considered a potential cDCD donor and a suitable candidate for multiorgan procurement including the heart via thoraco-abdominal normothermic regional perfusion. The heart recipient was a 60-year-old male diagnosed with amyloid cardiomyopathy. Cold ischemia time was 55 min. The surgery was uneventful.

Conclusions

This case report, the first of its kind in Spain, supports the feasibility of evaluating and successfully transplanting cDCD hearts without the need for ex-situ perfusion based on the use of thoraco-abdominal normothermic regional perfusion opening the way for multiorgan donation in cDCD.
Extracellular vesicular Wnt7b mediates HPV E6-induced cervical cancer angiogenesis by activating the β-catenin signaling pathway
Authors: Qiu Jun-Jun , Sun Shu-Gen , Tang Xiao-Yan , Lin Ying-Ying , Hua Ke-Qin
Published: November 2020

Background

The E6 oncoproteins of human papillomavirus (HPV) 16/18 are the critical drivers of cervical cancer (CC) progression. Extracellular vesicles (EVs) are emerging as critical mediators of cancer-tumor microenvironment (TME) communication. However, whether EVs contribute to HPV 16/18 E6-mediated impacts on CC progression remains unclear.

Methods

A series of in vitro and in vivo assays were performed to elucidate the roles and mechanism of EV-Wnt7b in HPV E6-induced CC angiogenesis. The prognostic value of serum EV-Wnt7b was determined and a predictive nomogram model was established.

Results

HPV 16/18 E6 upregulated Wnt7b mRNA expression in four HPV 16/18-positive CC cell lines and their EVs. In vitro and in vivo experiments demonstrated that EV-Wnt7b mRNA was transferred to and modulated human umbilical vein endothelial cells (HUVECs) toward more proliferative and proangiogenic behaviors by impacting β-catenin signaling. Clinically, serum EV-Wnt7b levels were elevated in CC patients and significantly correlated with an aggressive phenotype. Serum EV-Wnt7b was determined to be an independent prognostic factor for CC overall survival (OS) and recurrence-free survival (RFS). Notably, we successfully established a novel predictive nomogram model using serum EV-Wnt7b, which showed good prediction of 1- and 3-year OS and RFS.

Conclusions

Our results illustrate a potential crosstalk between HPV 16/18-positive CC cells and HUVECs via EVs in the TME and highlight the potential of circulating EV-Wnt7b as a novel predictive biomarker for CC prognosis.
Prediction of hypotension events with physiologic vital sign signatures in the intensive care unit
Authors: Yoon Joo Heung , Jeanselme Vincent , Dubrawski Artur , Hravnak Marilyn , Pinsky Michael R. , Clermont Gilles
Published: November 2020

Background

Even brief hypotension is associated with increased morbidity and mortality. We developed a machine learning model to predict the initial hypotension event among intensive care unit (ICU) patients and designed an alert system for bedside implementation.

Materials and methods

From the Medical Information Mart for Intensive Care III (MIMIC-3) dataset, minute-by-minute vital signs were extracted. A hypotension event was defined as at least five measurements within a 10-min period of systolic blood pressure ≤ 90 mmHg and mean arterial pressure ≤ 60 mmHg. Using time series data from 30-min overlapping time windows, a random forest (RF) classifier was used to predict risk of hypotension every minute. Chronologically, the first half of extracted data was used to train the model, and the second half was used to validate the trained model. The model’s performance was measured with area under the receiver operating characteristic curve (AUROC) and area under the precision recall curve (AUPRC). Hypotension alerts were generated using risk score time series, a stacked RF model. A lockout time were applied for real-life implementation.

Results

We identified 1307 subjects (1580 ICU stays) as the hypotension group and 1619 subjects (2279 ICU stays) as the non-hypotension group. The RF model showed AUROC of 0.93 and 0.88 at 15 and 60 min, respectively, before hypotension, and AUPRC of 0.77 at 60 min before. Risk score trajectories revealed 80% and > 60% of hypotension predicted at 15 and 60 min before the hypotension, respectively. The stacked model with 15-min lockout produced on average 0.79 alerts/subject/hour (sensitivity 92.4%).

Conclusion

Clinically significant hypotension events in the ICU can be predicted at least 1 h before the initial hypotension episode. With a highly sensitive and reliable practical alert system, a vast majority of future hypotension could be captured, suggesting potential real-life utility.
Use of postmenopausal hormone therapies and risk of histology- and hormone receptor-defined breast cancer: results from a 15-year prospective analysis of NIH-AARP cohort
Authors: Wang Shao-Ming , Pfeiffer Ruth M. , Gierach Gretchen L. , Falk Roni T.
Published: November 2020

Background

Menopausal hormone therapy (MHT) increases breast cancer (BC) risk, but cohort studies largely consider use only at enrollment. Evidence is limited on how changes in MHT use alter the magnitude of risk, and whether risk varies between invasive and in situ cancer, by histology or by hormone receptor status.

Methods

We investigated the roles of estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT) on BC risk overall, by histology and estrogen receptor (ER) and progesterone receptor (PR) status, and on incidence of in situ disease, in the NIH-AARP cohort. Participants included 118,760 postmenopausal women (50–71 years), of whom 63.5% (n = 75,398) provided MHT use information at baseline in 1996 and in a follow-up survey in 2004, subsequent to the dissemination in 2002 of the Women’s Health Initiative trial safety concerns regarding EPT. ET analyses included 50,476 women with hysterectomy (31,439 with follow-up data); EPT analyses included 68,284 women with intact uteri (43,959 with follow-up data). Adjusted hazard ratios (HRs) were estimated using Cox proportional hazards models using age as the time metric with follow-up through 2011.

Results

Eight thousand three hundred thirty-three incident BC cases were accrued, 2479 in women with follow-up data. BC risk was not elevated in current ET users at baseline (HR = 1.05, 95% confidence interval [CI] CI = 0.95–1.16) but was higher in women continuing use through 2004 (HR = 1.35, 95% CI = 1.04–1.75). Ever EPT use at baseline was associated with elevated BC risk overall (HR = 1.54 (1.44–1.64), with a doubling in risk for women with 10 or more years of use, for in situ disease, and across subtypes defined by histology and ER/PR status (all p < 0.004). Risk persisted in women who continued EPT through 2004 (HR = 1.80, 95% CI = 1.39–2.32). In contrast, no association was seen in women who discontinued EPT before 2004 (HR = 1.14, 95% CI = 0.99–1.30).

Conclusions

ET use was not associated with BC risk in this cohort, although excess risk was suggested in women who continued use through 2004. EPT use was linked to elevated in situ and invasive BC risk, and elevated risk across invasive BC histologic and hormone receptor-defined subtypes, with the highest risk for women who continued use through the 2004 follow-up survey.
Combined the SMAC mimetic and BCL2 inhibitor sensitizes neoadjuvant chemotherapy by targeting necrosome complexes in tyrosine aminoacyl-tRNA synthase-positive breast cancer
Authors: Lee Kyung-Min , Lee Hyebin , Han Dohyun , Moon Woo Kyung , Kim Kwangsoo , Oh Hyeon Jeong , Choi Jinwoo , Hwang Eun Hye , Kang Seong Eun , Im Seock-Ah , Lee Kyung-Hun , Ryu Han Suk
Published: November 2020

Background

Chemotherapy is the standard treatment for breast cancer; however, the response to chemotherapy is disappointingly low. Here, we investigated the alternative therapeutic efficacy of novel combination treatment with necroptosis-inducing small molecules to overcome chemotherapeutic resistance in tyrosine aminoacyl-tRNA synthetase (YARS)-positive breast cancer.

Methods

Pre-chemotherapeutic needle biopsy of 143 invasive ductal carcinomas undergoing the same chemotherapeutic regimen was subjected to proteomic analysis. Four different machine learning algorithms were employed to determine signature protein combinations. Immunoreactive markers were selected using three common candidate proteins from the machine-learning algorithms and verified by immunohistochemistry using 123 cases of independent needle biopsy FFPE samples. The regulation of chemotherapeutic response and necroptotic cell death was assessed using lentiviral YARS overexpression and depletion 3D spheroid formation assay, viability assays, LDH release assay, flow cytometry analysis, and transmission electron microscopy. The ROS-induced metabolic dysregulation and phosphorylation of necrosome complex by YARS were assessed using oxygen consumption rate analysis, flow cytometry analysis, and 3D cell viability assay. The therapeutic roles of SMAC mimetics (LCL161) and a pan-BCL2 inhibitor (ABT-263) were determined by 3D cell viability assay and flow cytometry analysis. Additional biologic process and protein-protein interaction pathway analysis were performed using Gene Ontology annotation and Cytoscape databases.

Results

YARS was selected as a potential biomarker by proteomics-based machine-learning algorithms and was exclusively associated with good response to chemotherapy by subsequent immunohistochemical validation. In 3D spheroid models of breast cancer cell lines, YARS overexpression significantly improved chemotherapy response via phosphorylation of the necrosome complex. YARS-induced necroptosis sequentially mediated mitochondrial dysfunction through the overproduction of ROS in breast cancer cell lines. Combination treatment with necroptosis-inducing small molecules, including a SMAC mimetic (LCL161) and a pan-BCL2 inhibitor (ABT-263), showed therapeutic efficacy in YARS-overexpressing breast cancer cells.

Conclusions

Our results indicate that, before chemotherapy, an initial screening of YARS protein expression should be performed, and YARS-positive breast cancer patients might consider the combined treatment with LCL161 and ABT-263; this could be a novel stepwise clinical approach to apply new targeted therapy in breast cancer patients in the future.
DNA polymerase epsilon is required for heterochromatin maintenance in Arabidopsis
Authors: Bourguet Pierre , López-González Leticia , Gómez-Zambrano Ángeles , Pélissier Thierry , Hesketh Amy , Potok Magdalena E. , Pouch-Pélissier Marie-Noëlle , Perez Magali , Da Ines Olivier , Latrasse David , White Charles I. , Jacobsen Steven E. , Benhamed Moussa , Mathieu Olivier
Published: November 2020

Background

Chromatin organizes DNA and regulates its transcriptional activity through epigenetic modifications. Heterochromatic regions of the genome are generally transcriptionally silent, while euchromatin is more prone to transcription. During DNA replication, both genetic information and chromatin modifications must be faithfully passed on to daughter strands. There is evidence that DNA polymerases play a role in transcriptional silencing, but the extent of their contribution and how it relates to heterochromatin maintenance is unclear.

Results

We isolate a strong hypomorphicArabidopsis thalianamutant of the POL2A catalytic subunit of DNA polymerase epsilon and show that POL2A is required to stabilize heterochromatin silencing genome-wide, likely by preventing replicative stress. We reveal that POL2A inhibits DNA methylation and histone H3 lysine 9 methylation. Hence, the release of heterochromatin silencing in POL2A-deficient mutants paradoxically occurs in a chromatin context of increased levels of these two repressive epigenetic marks. At the nuclear level, the POL2A defect is associated with fragmentation of heterochromatin.

Conclusion

These results indicate that POL2A is critical to heterochromatin structure and function, and that unhindered replisome progression is required for the faithful propagation of DNA methylation throughout the cell cycle.
Genetic feature engineering enables characterisation of shared risk factors in immune-mediated diseases
Authors: Burren Oliver S. , Reales Guillermo , Wong Limy , Bowes John , Lee James C. , Barton Anne , Lyons Paul A. , Smith Kenneth G. C. , Thomson Wendy , Kirk Paul D. W. , Wallace Chris
Published: November 2020

Background

Genome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging.

Methods

Exploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension “basis” that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging.

Results

We identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations.

Conclusions

Requiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities.