Overuse and Misuse of Antibiotics and the Clinical Consequence in Necrotizing Pancreatitis: An Observational Multicenter Study.

OBJECTIVE: The use and impact of antibiotics and the impact of causative pathogens on clinical outcomes in a large real-world cohort covering the entire clinical spectrum of necrotizing pancreatitis remain unknown. SUMMARY BACKGROUND DATA: International guidelines recommend broad-spectrum antibiotics in patients with suspected infected necrotizing pancreatitis. This recommendation is not based on high-level evidence and clinical effects are unknown. MATERIALS AND METHODS: This study is a post-hoc analysis of a nationwide prospective cohort of 401 patients with necrotizing pancreatitis in 15 Dutch centers (2010-2019). Across the patient population from the time of admission to 6 months postadmission, multivariable regression analyses were used to analyze (1) microbiological cultures and (2) antibiotic use. RESULTS: Antibiotics were started in 321/401 patients (80%) administered at a median of 5 days (P25-P75: 1-13) after admission. The median duration of antibiotics was 27 days (P25-P75: 15-48). In 221/321 patients (69%) infection was not proven by cultures at the time of initiation of antibiotics. Empirical antibiotics for infected necrosis provided insufficient coverage in 64/128 patients (50%) with a pancreatic culture. Prolonged antibiotic therapy was associated with Enterococcus infection (OR 1.08 [95% CI 1.03-1.16], P =0.01). Enterococcus infection was associated with new/persistent organ failure (OR 3.08 [95% CI 1.35-7.29], P <0.01) and mortality (OR 5.78 [95% CI 1.46-38.73], P =0.03). Yeast was found in 30/147 cultures (20%). DISCUSSION: In this nationwide study of patients with necrotizing pancreatitis, the vast majority received antibiotics, typically administered early in the disease course and without a proven infection. Empirical antibiotics were inappropriate based on pancreatic cultures in half the patients. Future clinical research and practice must consider antibiotic selective pressure due to prolonged therapy and coverage of Enterococcus and yeast. Improved guidelines on antimicrobial diagnostics and therapy could reduce inappropriate antibiotic use and improve clinical outcomes.

Bioguided isolation of potential antitumor agents from the aerial parts of cultivated cardoon (Cynara cardunculus var. altilis).

Hepatocellular carcinoma (HCC) is one of the leading causes of mortality worldwide; therefore, searching for an effective treatment for this illness is of great importance. In the present work, in vitro cytotoxic activity of the ethanol extract of the aerial parts of Cynara cardunculus L. against human liver carcinoma cells (Hep G2) was tested. Additionally, the antitumor activity of the extract was confirmed using chemically induced rat liver carcinogenesis with diethylnitrosamine (DEN). Moreover, bioguided fractionation and column chromatographic separation of the active compounds were carried out. The extract of C. cardunculus showed a promising cytotoxic activity according to the protocols of the National Cancer Institute. Bioguided chromatographic separation of the ethanol extract of C. cardunculus led to the isolation of seven secondary metabolites including two sesquiterpene lactones as the principal active components of the methylene chloride soluble fraction, grosheimin (IC50 = 7.49 µg/mL) and cynaropicrin (IC50 = 13.9 µg/mL). The compounds were characterized by different spectroscopic techniques such as EI-MS, IR and NMR. Additionally, in silico analysis of the two active compounds revealed their ability to bind with caspase-3 via hydrogen bonds interactions to initiate apoptosis of cancer cells. The results shed the light on the significance of C. cardunculus as a potential source of antitumor agents.

Protective effects of perindopril against indomethacin-induced gastric mucosal damage through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling pathways.

Indomethacin is a widely used nonsteroidal anti-inflammatory drug; however, its clinical utility is accompanied by serious adverse reactions including peptic ulcers. The current study aims to investigate the protective potential of perindopril against indomethacin-induced gastric injury in rats. Perindopril (4 mg/kg) was administered orally for 7 days and indomethacin (60 mg/kg, single oral dose) was administered on the 7th day, 1 h after perindopril administration. Pantoprazole was used as a standard agent. Ulcer index (UI), preventive index ratio (PI), histopathological examination, oxidative stress, and inflammatory biomarkers were investigated. Perindopril significantly decreased UI while increased PI and counteracted histopathological aberrations induced by indomethacin. It alleviated indomethacin-induced oxidative stress by lowering NO while increasing GSH content and superoxide dismutase activity. Perindopril significantly downregulated TNF-α and asymmetric dimethylarginine (ADMA), while significantly upregulated COX-2, PGE-2, dimethylarginine dimethylaminohydrolase-1 (DDAH-1), ANG-(1-7), and ACE-2 expression. Together, these findings suggest the gastroprotective effects of perindopril through modulation of DDAH-1/ADMA and ACE-2/ANG-(1-7) signaling.HIGHLIGHTSPerindopril attenuated gastric histopathological damage.It increased GSH content and SOD activity while decreased NO content.It modulated gastric ADMA and DDAH-1 activity.It reduced TNF-α, while increased COX-2 and PGE-2 expression.It upregulated ACE-2 activity and ANG-(1-7) protein expression.

Operational experiences associated with the implementation of near point-of-care early infant diagnosis of HIV in Myanmar: a qualitative study.

BACKGROUND: Timely diagnosis and early initiation of life-saving antiretroviral therapy are critical factors in preventing mortality among HIV-infected infants. However, resource-limited settings experience numerous challenges associated with centralised laboratory-based testing, including low rates of testing, complex sample referral pathways and unacceptably long turnaround times for results. Point-of-care (POC) HIV testing for HIV-exposed infants can enable same-day communication of results and early treatment initiation for HIV-infected infants. However, complex operational issues and service integration can limit utility and must be well understood prior to implementation. We explored and documented the challenges and enabling factors in implementing the POC Xpert® HIV-1 Qual test (Cepheid, Sunnyvale, CA, USA) for early infant diagnosis (EID) as part of routine services in four public hospitals in Myanmar. METHODS: This sub-study was part of a randomised controlled stepped-wedge trial (Australian and New Zealand Clinical Trials Registry, number 12616000734460) designed to investigate the impact of POC testing for EID in Myanmar and Papua New Guinea. Infants recruited during the intervention phase underwent POC testing at the participating hospitals as part of routine care. Semi-structured interviews with 23 caregivers, 12 healthcare providers and 10 key informants were used to explore experiences of POC-EID testing. The research team and hospital staff documented and discussed implementation challenges throughout the study. RESULTS: Overall, caregivers and healthcare workers were satisfied with the short turnaround time of the POC test. Occasional delays in POC testing were mostly attributable to late receipt of samples by laboratory technicians and communication constraints among healthcare staff. Hospital staff valued technical assistance from the research group and the National Health Laboratory. Despite staff shortages and infrastructure challenges such as unreliable electricity supply and cramped space, healthcare workers and caregivers found the implementation of the POC test to be feasible at pilot sites. CONCLUSIONS: As plans for national scale-up evolve, there needs to be a continual focus on staff training, communication pathways and infrastructure. Other models of care, such as allowing non-laboratory-trained personnel to perform POC testing, and cost effectiveness should also be evaluated.

Field Performance and Diagnostic Accuracy of a Low-Cost Instrument-Free Point-of-Care CD4 Test (Visitect CD4) Performed by Different Health Worker Cadres among Pregnant Women.

Measuring CD4 counts remains an important component of HIV care. The Visitect CD4 is the first instrument-free low-cost point-of-care CD4 test with results interpreted visually after 40 min, providing a result of ≥350 CD4 cells/mm3 The field performance and diagnostic accuracy of the test was assessed among HIV-infected pregnant women in South Africa. A nurse performed testing at the point-of-care using both venous and finger-prick blood, and a counselor and laboratory staff tested venous blood in the clinic laboratory (four Visitect CD4 tests/participant). Performance was compared to the mean CD4 count from duplicate flow cytometry tests on venous blood (FACSCalibur Trucount). In 2017, 156 patients were enrolled, providing a total of 624 Visitect CD4 tests (468 venous and 156 finger-prick samples). Of 624 tests, 28 (4.5%) were inconclusive. Generalized linear mixed modeling showed better performance of the test on venous blood (sensitivity = 81.7%; 95% confidence interval [CI] = 72.3 to 91.1]; specificity = 82.6%, 95% CI = 77.1 to 88.1) than on finger-prick specimens (sensitivity = 60.7%; 95% CI = 45.0 to 76.3; specificity = 89.5%, 95% CI = 83.2 to 95.8; P = 0.001). No difference in performance was detected by cadre of health worker (P = 0.113) or between point-of-care versus laboratory-based testing (P = 0.108). Adequate performance of Visitect CD4 with different operators and at the point of care, with no need of electricity or instrument, shows the potential utility of this device, especially for facilitating decentralization of CD4 testing services in rural areas.

Type-Specific Human Papillomavirus Prevalence, Incident Cases, Persistence, and Associated Pregnancy Outcomes Among HIV-Infected Women in Kenya.

BACKGROUND: Persistent infection with high-risk types of human papillomavirus (HPV) is the preeminent factor driving the development of cervical cancer. There are large gaps in knowledge about both the role of pregnancy in the natural history of HPV infection and the impact of HPV on pregnancy outcomes. METHODS: This single-site prospective cohort substudy, nested within an international multisite randomized controlled trial, assessed prevalence, incident cases, and persistence of type-specific HPV infection, and the association between persistence of high-risk HPV infection with pregnancy outcomes among HIV-infected pregnant women in Kenya, including HIV transmission to infants. Type-specific HPV was assessed using a line probe assay in pregnancy and again at 3 months after delivery. HIV status of children was determined using polymerase chain reaction at 6 weeks. RESULTS: In total, 84.1% (206/245) of women had a high-risk HPV infection at enrollment. Three quarters (157/206) of these infections persisted postpartum. Persistence of HPV16 and/or HPV18 types was observed in more than half (53.4%; 39/73) of women with this infection at enrollment. Almost two-thirds had an incident high-risk HPV infection postpartum, which was not present in pregnancy (62.5%), most commonly HPV52 (19.0%). After adjustments, no association was detected between persistent high-risk HPV and preterm birth. All mothers of the 7 cases of infant HIV infection had persistent high-risk HPV infection (P = 0.044). CONCLUSIONS: High levels of high-risk HPV infection and type-specific persistence were documented, heightening the urgency of mass role out of HPV vaccination. The association between HPV persistence and HIV transmission is a novel finding, warranting further study.

Outcome predictors of autologous hematopoietic stem cell transplantation in children with relapsed and refractory Hodgkin lymphoma: Single-center experience in a lower-middle-income country.

BACKGROUND: Children and adolescents with HL have excellent long-term survival exceeding 95% after combined modality treatment. However, about 20% will either relapse or have PRF. Salvage HDCT followed by AHSCT is considered to be the preferential treatment. OBJECTIVE: To describe the outcome (OS and EFS) and prognostic factors in pediatric patients with relapsed or refractory HL (r/rHL) who underwent AHSCT. METHODS: We retrospectively included 43 pediatric patients with r/rHL who underwent AHSCT from July 1, 2007, till December 31, 2016, at the Children's Cancer Hospital of Egypt. MAC regimen given was CMV. RESULTS: Of the whole cohort, 88.4% of patients achieved CR, while 11.6% had a positive PET scan prior to transplantation. The 3-year OS and EFS were 85% and 70.6%, respectively. The 3-year OS for patients > 10 years was 94% versus 65.5% for patients 10 years of age or younger (P = 0.046). There is strong tendency toward better 3-year OS for patients with negative PET scan as compared to those with positive PET scan before AHSCT, 89.4% vs 60%, respectively (P = 0.059). This tendency is also applicable when looking at the 3-year EFS for the two groups, 78.3% vs 40%, respectively (P = 0.069). CONCLUSION: Poor predictors of OS were younger age and positive PET scan before AHSCT. The latter, along with single modality treatment before AHSCT, were poor predictors of EFS.

Qualitative assessment of South African healthcare worker perspectives on an instrument-free rapid CD4 test.

BACKGROUND: Accurate measurement of CD4 cell counts remains an important tenet of clinical care for people living with HIV. We assessed an instrument-free point-of-care CD4 test (VISITECT® CD4) based on a lateral flow principle, which gives visual results after 40 min. The test involves five steps and categorises CD4 counts as above or below 350 cells/µL. As one component of a performance evaluation of the test, this qualitative study explored the views of healthcare workers in a large women and children's hospital on the acceptability and feasibility of the test. METHODS: Perspectives on the VISITECT® CD4 test were elicited through in-depth interviews with eight healthcare workers involved in the performance evaluation at an antenatal care facility in Johannesburg, South Africa. Audio recordings were transcribed in full and analysed thematically. RESULTS: Healthcare providers recognised the on-going relevance of CD4 testing. All eight perceived the VISITECT® CD4 test to be predominantly user-friendly, although some felt that the need for precision and optimal concentration in performing test procedures made it more challenging to use. The greatest strength of the test was perceived to be its quick turn-around of results. There were mixed views on the semi-quantitative nature of the test results and how best to integrate this test into existing health services. Participants believed that patients in this setting would likely accept the test, given their general familiarity with other point-of-care tests. CONCLUSIONS: Overall, the VISITECT® CD4 test was acceptable to healthcare workers and those interviewed were supportive of scale-up and implementation in other antenatal care settings. Both health workers and patients will need to be oriented to the semi-quantitative nature of the test and how to interpret the results of tests.

Prevention of postpartum haemorrhage by community-based auxiliary midwives in hard-to-reach areas of Myanmar: a qualitative inquiry into acceptability and feasibility of task shifting.

BACKGROUND: In Myanmar, postpartum haemorrhage is the leading cause of maternal mortality and contributes to around 30% of all maternal deaths. The World Health Organization recommends training and supporting auxiliary midwives to administer oral misoprostol for prevention of postpartum haemorrhage in resource-limited settings. However, use of misoprostol by auxiliary midwives has not formally been approved in Myanmar. Our study aimed to explore community and provider perspectives on the roles of auxiliary midwives and community-level provision of oral misoprostol by auxiliary midwives. METHODS: A qualitative inquiry was conducted in Ngape Township, Myanmar. A total of 15 focus group discussions with midwives, auxiliary midwives, community members and mothers with children under the age of three were conducted. Ten key informant interviews were performed with national, district and township level health planners and implementers of maternal and child health services. All audio recordings were transcribed verbatim in Myanmar language. Transcripts of focus group discussions were fully translated into English before coding, while key informants' data were coded in Myanmar language. Thematic analysis was done using ATLAS.ti software. RESULTS: Home births are common and auxiliary midwives were perceived as an essential care provider during childbirth in hard-to-reach areas. Main reasons provided were that auxiliary midwives are more accessible than midwives, live in the hard-to-reach areas, and are integrated in the community and well connected with midwives. Auxiliary midwives generally reported that their training involved instruction on active management of the third stage of labour, including use of misoprostol, but not all auxiliary midwives reported using misoprostol in practice. Supportive reasons for task-shifting administration of oral misoprostol to auxiliary midwives included discussions around the good relationship and trust between auxiliary midwives and midwives, whereby midwives felt confident distributing misoprostol to auxiliary midwives. However, the lack of clear government-level written permission to distribute the drug was perceived as a barrier to task shifting. CONCLUSION: This study highlights the acceptability of misoprostol use by auxiliary midwives to prevent postpartum haemorrhage, and findings suggest that it should be considered as a promising intervention for task shifting in Myanmar.

DNA Methylation Signatures in Vaginal Fluid Samples for Detection of Cervical and Endometrial Cancer.

OBJECTIVE: A noninvasive tool that allows individuals to be monitored who are at risk of developing a malignancy is an unmet need. Such a test would need to consist of a molecular signature that allows for gradual judgment to assess the efficacy of preventive strategies. Here we performed a proof-of-principle study to test whether a DNA methylation (DNAme) signature in fluid collected from the vagina is able to identify women with cervical or endometrial cancer. MATERIALS AND METHODS: DNA from vaginal fluid samples from 111 women (30, 8, 73 with endometrial cancer, cervical cancer, and benign gynecological conditions, respectively) were analyzed for DNAme using the Illumina 450k DNA methylation bead array assay, which allows the assessment of DNAme at more than 480.000 CpG sites. We developed a cervical and an endometrial cancer DNAme signature by comparing normal and cancerous cervical and endometrial samples from the publicly available The Cancer Genome Atlas data and developed deviation scores to assess the potential of discriminating cancer from a control sample using a vaginal fluid DNAme signature. RESULTS: More than 60% of variations in DNAme in our vaginal fluid cannot be explained by those clinical or technical factors that we were aware of. Both the cervical and the endometrial cancer DNAme signature resulted in receiver operating characteristic area under the curve between 0.75 and 0.83 to discriminate controls and the cancers for which the signature has been designed for. CONCLUSIONS: Whole DNAme signatures based on array technologies in body fluids are able to discriminate cancer cases from controls.

Effect of intermittent fasting on lipid biokinetics in obese and overweight patients with type 2 diabetes mellitus: prospective observational study.

BACKGROUND: Intermittent fasting (IF) is a commonly used dietary practice that alternates between periods of unrestricted dietary consumption and abstinence from caloric intake. IF reduces caloric intake along with metabolic switch from utilization of glucose to fatty acids and ketones and resulting in reduction in adiposity and subsequently insulin resistance. Thus, it has been hypothesized that IF regimens can improve body composition in obese and overweight individuals. AIM: To assess the effect of IF on lipid biokinetics in obese and overweight patients with type 2 diabetes (T2D). PATIENTS AND METHODS: Thirty overweight or obese T2D patients were recruited from the diabetes outpatient clinics at the Specialized Medical Hospital, Mansoura University. Patients were subjected to time restricted fasting for 16 h (from dawn to sunset) during Ramadan. Anthropometric data were measured for participants before and 3 weeks after Ramadan fasting. Fasting plasma glucose (FPG), HbA1c, lipid profile, leptin, beta hydroxybutyrate (ßHB) and high sensitive CRP levels were measured 1 week before and 3 weeks after Ramadan fasting. RESULTS: 30 diabetic patients were recruited with a mean age of 54.3 ± 7.2 years. 24 (80%) were females. Obesity was diagnosed in 27 cases (90%). The median diabetes duration was 10 years. The study showed a statistically significant decrease in post-fasting body weight (BW), Body mass index (BMI), waist circumference (WC) & hip circumference (HC). There was a statistically significant decrease of post-fasting low density lipoprotein (LDL-C), Total cholesterol (TC), and leptin. The study also showed a statistically significant increase of post-fasting high density lipoprotein (HDL-C) and ßHB. No significant change was found in post-fasting levels of HbA1c, FPG, triglycerides (TG) or high sensitive CRP. Post-fasting leptin was positively correlated with post-fasting BW, BMI, WC, and HC. Post-fasting ßHB was positively correlated with post-fasting TG, HbA1c, and LDL-C. Leptin levels change (pre vs post fasting) was positively correlated with the change in LDL-C levels. CONCLUSION: IF reduced leptin and increased ß-hydroxybutyrate levels. IF is an effective tool for losing weight and visceral fat and improving lipid profile in obese and overweight patients with T2D.

Multicomponent interventions to improve routine childhood vaccine uptake in low and middle-income countries: a scoping review protocol.

INTRODUCTION: Vaccine coverage remains inequitable globally. Many systematic reviews have looked at the effectiveness of strategies to improve vaccine uptake; however, these reviews frequently lack data from low and middle-income countries (LMICs), where evidence of cost-effective strategies is most valuable. This is partly because reviews often exclude non-randomised, observational or unpublished evaluations that are common in LMICs. Many reviews also exclude multicomponent interventions due to challenges isolating the effect of each component. A comprehensive mapping of multicomponent interventions implemented in LMICs would increase the visibility of studies excluded from systematic reviews and improve comparability of future evaluations by providing guidance for researchers on evaluation frameworks. This scoping review aims to identify, compare and summarise the properties and evaluation methods of multicomponent interventions to improve uptake of routine childhood vaccines in LMICs, and to assess the strengths and limitations of evaluation frameworks applied. METHODS AND ANALYSIS: This review will be conducted using the Joanna Briggs Institute methodology for scoping reviews and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses Extension for Scoping Reviews guidelines. We will search the following databases: MEDLINE, Embase, PubMed, Cochrane, Eldis and Global Health (CAB Direct), Global Index Medicus, 3ie Portal, Google Scholar, COnnecting REpositories, and reference lists. One author will screen titles and abstracts and extract data from included articles using a pretested data extraction template. Uncertainties will be resolved through discussion with another author. Only studies published in English will be included for full review. We will assess the practicability, applicability, sensitivity and specificity of the evaluation frameworks used and present results using descriptive statistics, summary tables and charts. ETHICS AND DISSEMINATION: Ethics approval is not required. The review will be submitted as part of a doctoral thesis, presented at conferences and published in peer-reviewed journals. STUDY REGISTRATION: https://osf.io/7r84g.

Liraglutide limits the immunogenic cell death-mediated ROS propagation and PI3K/AKT inactivation after doxorubicin-induced gonadotoxicity in rats: Involvement of the canonical Hedgehog trajectory.

Chemotherapy-accompanied reproductive dysfunction has lately begun to draw the attention of the scientific community owing to the irreversible impact on the patient's quality of life. Here we tended to investigate the potential role of liraglutide (LRG) in modulating the canonical Hedgehog (Hh) signaling in doxorubicin (DXR)-induced gonadotoxicity in rats. Female virgin Wistar rats were divided into 4 groups; control, DXR-treated (25 mg/kg, single i.p. injection), LRG-treated (150 µg/Kg/day, s.c) and itraconazole (ITC; 150 mg/kg/day, p.o)-pretreated group, as the Hh pathway inhibitor. Treatment with LRG potentiated the PI3K/AKT/p-GSK3ß cascade and relieved the oxidative burden-induced by the DXR-driven immunogenic cell death (ICD). LRG also upregulated the expression of the Desert hedgehog ligand (DHh) and the patched-1 (PTCH1) receptor and augmented the protein level of Indian hedgehog (IHh) ligand, Gli1 and cyclin-D1 (CD1). Besides, hypertranscription of IHh, DHh, Ptch1, Smo, Gli1/2 and CD1 genes along with a transcriptional recession of Gli3 gene were reported in LRG-treated group. ITC pre-administration partially abrogated this positive effect of LRG, proving the implication of the examined pathway. Microscopically, LRG ameliorated the follicular atresia noticed in the DXR group; effect that was, at least partially, declined by ITC pre-treatment. These findings end to a conclusion that LRG treatment might hinder the DXR-associated reproductive toxicity, resultant from ROS generated by the cells undergoing ICD, and trigger follicular growth and repair by the PI3K/AKT- dependent switching-on of the canonical Hh pathway.

Evaluation of an Online Training Program on COVID-19 for Health Workers in Papua New Guinea.

BACKGROUND: Health worker training is an important component of a holistic outbreak response, and travel restrictions resulting from the COVID-19 pandemic have highlighted the potential of virtual training. Evaluation of training activities is essential for understanding the effectiveness of a training program on knowledge and clinical practice. We conducted an evaluation of the online COVID-19 Healthcare E-Learning Platform (CoHELP) in Papua New Guinea (PNG) to assess its effectiveness, measure engagement and completion rates, and determine barriers and enablers to implementation, in order to inform policy and practice for future training in resource-limited settings. METHODS: The evaluation team conducted a mixed methods evaluation consisting of pre- and post-knowledge quizzes; quantification of engagement with the online platform; post-training surveys; qualitative interviews with training participants, non-participants, and key informants; and audits of six health facilities. RESULTS: A total of 364 participants from PNG signed up to participate in the CoHELP online training platform, with 41% (147/360) completing at least one module. Of the 24 participants who completed the post-training survey, 92% (22/24) would recommend the program to others and 79% (19/24) had used the knowledge or skills gained through CoHELP in their clinical practice. Qualitative interviews found that a lack of time and infrastructural challenges were common barriers to accessing online training, and participants appreciated the flexibility of online, self-paced learning. CONCLUSIONS: Initially high registration numbers did not translate to ongoing engagement with the CoHELP online platform, particularly for completion of evaluation activities. Overall, the CoHELP program received positive feedback from participants involved in the evaluation, highlighting the potential for further online training courses in PNG.

The effect of the Xpert HIV-1 Qual test on early infant diagnosis of HIV in Myanmar and Papua New Guinea: a pragmatic, cluster-randomised, stepped-wedge, open-label trial.

BACKGROUND: Despite proven benefits for child health, coverage of early infant diagnosis of HIV remains suboptimal in many settings. We aimed to assess the effect of a point-of-care early infant diagnosis test on time-to-results communication for infants vertically exposed to HIV. METHODS: This pragmatic, cluster-randomised, stepped-wedge, open-label trial assessed the effect of the Xpert HIV-1 Qual early infant diagnosis test (Cepheid) on time-to-results communication, compared with standard care laboratory-based testing of dried blood spots using PCR. Hospitals were the unit of randomisation for one-way crossover from control to intervention phase. Each site had between 1 month and 10 months of control phase before transitioning to the intervention, with a total of 33 hospital-months in the control phase and 45 hospital-months in the intervention phase. We enrolled infants vertically exposed to HIV at six public hospitals: four in Myanmar and two in Papua New Guinea. Infants had to have mothers with confirmed HIV infection, be younger than 28 days, and required HIV testing to be eligible for enrolment. Health-care facilities providing prevention of vertical transmission services were eligible for participation. The primary outcome was communication of early infant diagnosis results to the infant's caregiver by 3 months of age, assessed by intention to treat. This completed trial was registered with the Australian and New Zealand Clinical Trials Registry, 12616000734460. FINDINGS: In Myanmar, recruitment took place between Oct 1, 2016, and June 30, 2018; in Papua New Guinea, recruitment was between Dec 1, 2016, and Aug 31, 2018. A total of 393 caregiver-infant pairs were enrolled in the study across both countries. Independent of study time, the Xpert test reduced time to early infant diagnosis results communication by 60%, compared with the standard of care (adjusted time ratio 0·40, 95% CI 0·29-0·53, p<0·0001). In the control phase, two (2%) of 102 study participants received an early infant diagnosis test result by 3 months of age compared with 214 (74%) of 291 in the intervention phase. No safety and adverse events were reported related to the diagnostic testing intervention. INTERPRETATION: This study reinforces the importance of scaling up point-of-care early infant diagnosis testing in resource-constrained and low HIV-prevalence settings, typical of the UNICEF East Asia and Pacific region. FUNDING: National Health and Medical Research Council of Australia.

Endometrial Cancer Individualized Scoring System (ECISS): A machine learning-based prediction model of endometrial cancer prognosis.

OBJECTIVE: To establish a prognostic model for endometrial cancer (EC) that individualizes a risk and management plan per patient and disease characteristics. METHODS: A multicenter retrospective study conducted in nine European gynecologic cancer centers. Women with confirmed EC between January 2008 to December 2015 were included. Demographics, disease characteristics, management, and follow-up information were collected. Cancer-specific survival (CSS) and disease-free survival (DFS) at 3 and 5 years comprise the primary outcomes of the study. Machine learning algorithms were applied to patient and disease characteristics. Model I: pretreatment model. Calculated probability was added to management variables (model II: treatment model), and the second calculated probability was added to perioperative and postoperative variables (model III). RESULTS: Of 1150 women, 1144 were eligible for 3-year survival analysis and 860 for 5-year survival analysis. Model I, II, and III accuracies of prediction of 5-year CSS were 84.88%/85.47% (in train and test sets), 85.47%/84.88%, and 87.35%/86.05%, respectively. Model I predicted 3-year CSS at an accuracy of 91.34%/87.02%. Accuracies of models I, II, and III in predicting 5-year DFS were 74.63%/76.72%, 77.03%/76.72%, and 80.61%/77.78%, respectively. CONCLUSION: The Endometrial Cancer Individualized Scoring System (ECISS) is a novel machine learning tool assessing patient-specific survival probability with high accuracy.

Role of ADMA/DDAH-1 and iNOS/eNOS signaling in the gastroprotective effect of tadalafil against indomethacin-induced gastric injury.

Non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastric ulcers represent a significant clinical concern and adversely affect the quality of life. Inducible nitric oxide synthase/endothelial nitric oxide synthase (iNOS/eNOS) and asymmetric dimethylarginine/ dimethylarginine dimethylaminohydrolase-1 (ADMA/DDAH-1) signaling are key players in gastric ulcer pathogenesis. This work was planned to explore the role of iNOS/eNOS and ADMA/DDAH-1 signaling in rats with indomethacin-induced gastric ulcer, as potential pathways for the gastro-protective effect of tadalafil. Split into 5 separate groups, rats were assigned to control, tadalafil (10 mg/kg, p.o), indomethacin (single oral dose of 60 mg/kg), indomethacin + pantoprazole (40 mg/kg, p.o), and indomethacin + tadalafil (10 mg/kg, p.o). The results indicated that pretreatment with tadalafil significantly reduced ulcer index (UI), increased preventive index (PI), and counteracted indomethacin-induced histopathological aberrations. Tadalafil significantly reduced the gastric content of NO while it significantly elevated that of GSH and enhanced SOD activity. It significantly reduced the gastric expression of TNF-α and ADMA while it significantly elevated that of COX-2, PGE-2, and DDAH-1. Western blot analysis revealed that pretreatment with tadalafil significantly reduced iNOS protein expression while it significantly elevated that of eNOS. Collectively, these data suggest that tadalafil exerts potential protective effect against indomethacin-induced ulcer through suppression of inflammation, attenuation of oxidative stress, and boosting of antioxidants. Moreover, tadalafil protective effects are mediated via upregulation of PGE-2 with modulating the signaling pathways of ADMA/DDAH-1, and iNOS/eNOS. As a result, the current evidence corroborates the use of tadalafil in controlling gastric ulcers and preventing NSAID gastric side effects.

Integrating HPV vaccination programs with enhanced cervical cancer screening and treatment, a systematic review.

A WHO global strategy launched in November 2020 sets out an ambitious pathway towards the worldwide elimination of cervical cancer as a public health problem within the next 100 years. Achieving this goal will require investment in innovative approaches. This review aims to describe integrated approaches that combine human papillomavirus (HPV) vaccination and cervical cancer screening in low- and middle-income countries (LMIC), and their efficacy in increasing uptake of services. A systematic review was conducted analyzing relevant papers from Embase, Medline, CINAHL and CAB Global Health databases, as well as grey literature. Narrative synthesis was performed on the included studies. Meta-analysis was not appropriate due to the heterogeneity and nature of included studies. From 5,278 titles screened, 11 uncontrolled intervention studies from four countries (from Africa and east Asia) were included, all from the past 12 years. Four distinct typologies of integration emerged that either increased awareness of HPV and/or cervical cancer screening, and/or coupled the delivery of HPV vaccination and cervical cancer screening programs. The synthesis of findings suggests that existing HPV vaccination programs can be a useful pathway for educating mothers and other female caregivers about cervical cancer screening; through in person conversations with care providers (preferred) or take-home communications products. Integrated service delivery through outreach and mobile clinics may overcome geographic and economic barriers to access for both HPV vaccination and cervical cancer screening, however these require significant program and system resources. One study promoted HPV vaccination as part of integrated service delivery, but there were no other examples found that examined use of cervical cancer screening platforms to promote or educate on HPV vaccination. This review has demonstrated gaps in published literature on attempts to integrate HPV vaccination and cervical cancer screening. The most promising practices to date seem to relate to integrated health communications for cervical cancer prevention. Future research should further explore the opportunities for integrated health communications to support the efforts towards the new global cervical cancer elimination agenda, and costs and feasibility of integrated service delivery for underserved populations.

Middle-East OBGYN Graduate Education (MOGGE) Foundation practice guidelines: prevention of group B Streptococcus infection in pregnancy and in newborn. Practice guideline no. 02-O-20.

Rectovaginal colonization with group B streptococcus (GBS) is commonly encountered in pregnancy. GBS is the most common cause of early onset neonatal sepsis, which is associated with 12% case-fatality rate. Although screening protocols and prophylactic treatment are readily available worldwide, practice in low-resource countries is challenged by lack of awareness and limited implementation of these protocols. In addition, antibiotic susceptibility pattern may vary globally owing to different regulations of antibiotic prescription or prevalence of certain bacterial serotypes. This guideline appraises current evidence on screening and management of GBS colonization in pregnancy particularly in low-resource settings.

Synthesis, Cytotoxicity and Docking Simulation of Novel Annulated Dihydroisoquinoline Heterocycles.

OBJECTIVE: Coupling of ethyl 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-1-yl)acetate 2 with diazotized anilines in ethanol in the presence of sodium acetate yielded 2-(2-arylhydrazono)-2-(6,7- dimethoxy-3,4-dihydroisoquinolin-1-yl)acetate (4a-f). METHODS: Treatment of 2 with α-bromoketones 6a-f in dry benzene at reflux gave the corresponding isoquinolinium bromides 7a-f. Refluxing of each of the salts 7a-f in dry benzene and in the presence of triethylamine yielded 2-arylpyrrolo-[2,1-a]isoquinoline structures 8a-f, that converted to ethyl (E)-8,9- dimethoxy-3-(phenyldiazen-yl)-2-(aryl)-5,6-dihydropyrrolo[2,1-a]isoquinoline-1-carboxylate (9a-f) upon treatment with diazotized anilines 3 in ethanol in the presence of sodium acetate. RESULTS AND CONCLUSION: Cytotoxic assay was performed for in vitro antitumor screening against caucasian breast adenocarcinoma (MCF7), hepatocellular carcinoma (HepG2) and colorectal carcinoma (HCT-116) cell lines. The results were compared with the standard anticancer drug (doxorubicin). Molecular docking using MOE 2014.09 software was carried out for the most potent compound 4d, which showed the highest binding affinity towards the four tested proteins and thus initiated apoptosis of cancer cells.