The HACE1 E3 ligase mediates RAC1-dependent control of mTOR signaling complexes.

HACE1 is a HECT family E3 ubiquitin-protein ligase with broad but incompletely understood tumor suppressor activity. Here, we report a previously unrecognized link between HACE1 and signaling complexes containing mammalian target of rapamycin (mTOR). HACE1 blocks mTORC1 and mTORC2 activities by reducing mTOR stability in an E3 ligase-dependent manner. Mechanistically, HACE1 binds to and ubiquitylates Ras-related C3 botulinum toxin substrate 1 (RAC1) when RAC1 is associated with mTOR complexes, including at focal adhesions, leading to proteasomal degradation of RAC1. This in turn decreases the stability of mTOR to reduce mTORC1 and mTORC2 activity. HACE1 deficient cells show enhanced mTORC1/2 activity, which is reversed by chemical or genetic RAC1 inactivation but not in cells expressing the HACE1-insensitive mutant, RAC1K147R . In vivo, Rac1 deletion reverses enhanced mTOR expression in KRasG12D -driven lung tumors of Hace1-/- mice. HACE1 co-localizes with mTOR and RAC1, resulting in RAC1-dependent loss of mTOR protein stability. Together, our data demonstrate that HACE1 destabilizes mTOR by targeting RAC1 within mTOR-associated complexes, revealing a unique ubiquitin-dependent process to control the activity of mTOR signaling complexes.

Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.

BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19). METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry. RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration. CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).

Safety assessment of Enterococcus lactis strains complemented with comparative genomics analysis reveals probiotic and safety characteristics of the entire species.

BACKGROUND: The gut microbiota is considered a rich source for potential novel probiotics. Enterococcus genus is a normal component of a healthy gut microbiota, suggesting its vital role. Nosocomial infections caused mainly by E. facalis and E. faecium have been attributed to the plasticity of the Enterococcus genomes. In this study, we assessed the probiotic and safety characteristics of two E. lactis strains isolated from the human gut microbiota using in-vitro and in silico approaches. Additionally, the safety of the E. lactis species was evaluated using comparative genomics analysis. RESULTS: The two E. lactis strains 10NA and 50NA showed resistance to bile salts and acid tolerance with antibacterial activity against Escherichia coli, Salmonella typhi, and Clostridioides difficile. For safety assays, the two strains did not display any type of hemolysis on blood agar, and the survival of Caco-2 cells was not significantly different (P-value > 0.05) compared to the control using cell free supernatants at 100% (v/v), 50% (v/v), 10% (v/v), and 5% (v/v) concentrations. Regarding antibiotic susceptibility, both strains were sensitive to vancomycin, tetracycline, and chloramphenicol. Comprehensive whole-genome analysis revealed no concerning associations between virulence or antibiotic resistance genes and any of the identified mobile genetic elements. Comparative genome analysis with closely related E. faecium species genomes revealed the distinctive genomic safety of the E. lactis species. CONCLUSIONS: Our two E. lactis strains showed promising probiotic properties in-vitro. Their genomes were devoid of any transferable antibiotic resistance genes. In silico comparative analysis confirmed the safety of the E. lactis species. These results suggest that E. lactis species could be a potential source for safer Enterococcus probiotic supplements.

A digital score of tumour-associated stroma infiltrating lymphocytes predicts survival in head and neck squamous cell carcinoma.

The infiltration of T-lymphocytes in the stroma and tumour is an indication of an effective immune response against the tumour, resulting in better survival. In this study, our aim was to explore the prognostic significance of tumour-associated stroma infiltrating lymphocytes (TASILs) in head and neck squamous cell carcinoma (HNSCC) through an AI-based automated method. A deep learning-based automated method was employed to segment tumour, tumour-associated stroma, and lymphocytes in digitally scanned whole slide images of HNSCC tissue slides. The spatial patterns of lymphocytes and tumour-associated stroma were digitally quantified to compute the tumour-associated stroma infiltrating lymphocytes score (TASIL-score). Finally, the prognostic significance of the TASIL-score for disease-specific and disease-free survival was investigated using the Cox proportional hazard analysis. Three different cohorts of haematoxylin and eosin (H&E)-stained tissue slides of HNSCC cases (n = 537 in total) were studied, including publicly available TCGA head and neck cancer cases. The TASIL-score carries prognostic significance (p = 0.002) for disease-specific survival of HNSCC patients. The TASIL-score also shows a better separation between low- and high-risk patients compared with the manual tumour-infiltrating lymphocytes (TILs) scoring by pathologists for both disease-specific and disease-free survival. A positive correlation of TASIL-score with molecular estimates of CD8+ T cells was also found, which is in line with existing findings. To the best of our knowledge, this is the first study to automate the quantification of TASILs from routine H&E slides of head and neck cancer. Our TASIL-score-based findings are aligned with the clinical knowledge, with the added advantages of objectivity, reproducibility, and strong prognostic value. Although we validated our method on three different cohorts (n = 537 cases in total), a comprehensive evaluation on large multicentric cohorts is required before the proposed digital score can be adopted in clinical practice. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Incremental mortality associated with nontuberculous mycobacterial lung disease among US Medicare beneficiaries with chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in patients with nontuberculous mycobacterial lung disease (NTMLD). Both conditions are associated with increased morbidity and mortality, but data are lacking on the additional burden associated with NTMLD among patients with COPD. Thus, the goal of this study was to assess the incremental mortality risk associated with NTMLD among older adults with COPD. METHODS: A retrospective cohort study was conducted using the US Medicare claims database (2010-2017). Patients with preexisting COPD and NTMLD (cases) were matched 1:3 by age and sex with patients with COPD without NTMLD (control patients). Patients were followed up until death or data cutoff (December 31, 2017). Incremental risk of mortality was evaluated by comparing the proportions of death, annualized mortality rate, and mortality hazard rate between cases and control patients using both univariate and multivariate analyses adjusting for age, sex, comorbidities, and COPD severity. RESULTS: A total of 4,926 cases were matched with 14,778 control patients. In univariate analyses, a higher proportion of cases (vs. control patients) died (41.5% vs. 26.7%; P < 0.0001), unadjusted annual mortality rates were higher among cases (158.5 vs. 86.0 deaths/1000 person-years; P < 0.0001), and time to death was shorter for cases. This increased mortality risk was also reflected in subsequent multivariate analyses. Patients with COPD and NTMLD were more likely to die (odds ratio [95% CI], 1.39 [1.27-1.51]), had higher mortality rates (rate ratio [95% CI], 1.36 [1.28-1.45]), and had higher hazard of death (hazard ratio [95% CI], 1.37 [1.28-1.46]) than control patients. CONCLUSIONS: The substantial incremental mortality burden associated with NTMLD in patients with COPD highlights the importance of developing interventions targeting this high-risk group and may indicate an unmet need for timely and appropriate management of NTMLD.

Cognitive functioning in women with breast cancer: psychometric properties of the Arabic version of the Functional Assessment of Cancer Therapy-Cognitive Function Tool.

BACKGROUND: The Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) evaluates perceived cognitive functioning and their impact on quality of life. This study was designed to evaluate the factors associated with cognitive functioning in a sample of women with breast cancer (BC) in Lebanon. We also sought to explore the psychometric properties of the FACT-Cog Arabic version. METHODS: A cross-sectional study was carried out between March and August 2020 among women with BC. Socio-demographic and clinical characteristics were collected. In addition, patients were asked to complete the FACT-Cog Arabic version as well as the European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire 30, the Patient Health Questionnaire (PHQ-9), and the Generalized Anxiety Disorder (GAD-7). The internal consistency of the FACT-Cog tool was evaluated using Cronbach's alpha. Content, convergent, and known group validity of the FACT-Cog Arabic version were also evaluated. All statistical analyses were performed using SPSS version 23.0. RESULTS: A sample of 134 women with BC was collected. Internal consistencies of the FACT-cog total scale and its subscales were high (Cronbach's α between 0.83 and 0.95). The convergent validity of the FACT-Cog Arabic version was supported by the positive correlation with the EORTC-cognitive functioning subscale. Moreover, negative correlations were found between FACT-Cog scale and fatigue, pain, anxiety, as well as depression. Known-group validity was supported by the statistically significant mean differences of the FACT-Cog total scale between patients in early (I &II) and late (III & IV) BC stages. Unmarried BC patients as well as those having higher depressive symptoms and a lower quality of life were found to be at higher risk of cognitive impairment. CONCLUSION: The FACT-Cog Lebanese Arabic version is a valid and reliable tool for assessing perceived cognitive functioning in BC women. Higher level of depression and impaired quality of life were associated with a decline in cognitive functioning.

In Vitro and In Vivo Antibiofilm Activity of Red Onion Scales: An Agro-Food Waste.

Red onion wastes (ROW) are valuable sources of bioactive metabolites with promising antimicrobial effects. Methicillin-resistant Staphylococcus aureus (MRSA) infections are a growing risk in hospitals and communities. This study aims to investigate the in vitro and in vivo antibiofilm activities of the acidified ethanolic extract of red onion scales (RO-T) and its fractions against an MRSA vaginal colonization model. The RO-T extract, as well as its anthocyanin-rich fraction (RO-P) and flavonoid-rich fraction (RO-S), recorded a promising antibacterial activity against highly virulent strains of bacteria (MRSA, Acinetobacter baumannii, Escherichia coli and Pseudomonas aeruginosa). RO-S showed the highest antibacterial activity (MBC of 0.33 ± 0.11 mg/mL) against MRSA USA300 and significantly eradicated its biofilm formation with an IC50 of 0.003. Using a rat model, in vivo assessment on all samples, which were formulated as a hydrogel, revealed a significant reduction of MRSA bacterial load recovered from an infected vagina compared to that of the negative control group (NCG). RO-T extract and vancomycin groups recorded the highest antibacterial activity with a bacterial load 2.998 and 3.358 logs lower than the NCG, respectively. The histopathological investigation confirmed our findings. RO-T and RO-S were standardized for their quercetin content. Finally, ROW offers a new potent antibiofilm agent mostly due to its high quercetin content.

Hypertriglyceridemia in Critically Ill Patients With SARS-CoV-2 Infection.

BACKGROUND: Patients with SARS-CoV-2 infection could develop severe disease requiring critical care admission. Case reports indicated high incidence of hypertriglyceridemia (HTG) in critically ill patients infected with SARS-CoV-2, which might be related to the drugs. OBJECTIVE: We sought to determine the risk factors associated with HTG in this population and to investigate the relationship between HTG and lipase. METHODS: A retrospective observational study was conducted at our hospital between March 1 and June 30, 2020. Patients were included if they were ≥18 years old, admitted to the intensive care unit (ICU), tested positive for SARS-CoV-2, and had triglycerides (TG) checked during their hospital stay. RESULTS: Of the 111 critically ill patients, 103 patients were included. Males comprised 88.3% of the sample. The median TG at baseline was 197.4 (IQR: 139.8-283) mg/dL. The lipase median level at baseline was 23.00 (IQR: 0.00-69.50) IU/L. The results of the mixed-effects logistic regression analysis indicated that patient-level variables, favipiravir use, blood glucose level, and propofol use were significantly associated with HTG. There was no relationship between lipase and TG levels over time. Furthermore, TG concentrations over time showed a similar trend to inflammatory markers. CONCLUSION AND RELEVANCE: The incidence of clinically significant HTG was high and was associated with propofol and favipiravir use. HTG might reflect the high inflammatory state in these patients. Clinicians should look at the full picture before changing therapies based only on HTG. Our findings need to be replicated in a larger prospective study.

Incidence and predictors of acute kidney injury among women with severe pre-eclampsia at Mbarara Regional Referral Hospital.

BACKGROUND: The presence of acute kidney injury (AKI) in pre-eclampsia complicates treatment including; increasing length of hospital stay and a need to access services like dialysis which are largely expensive in resource-limited settings. We aimed to determine incidence and predictors of acute kidney injury among women with severe pre-eclampsia at Mbarara Regional Referral Hospital in southwestern Uganda. METHODS: We carried out a hospital-based prospective cohort study from 16 November  2018 to 18 April 2019, among pregnant women with severe pre-eclampsia followed up in the hospital. We enrolled 70 mothers with severe pre-eclampsia and eclampsia; we excluded patients with a history of chronic kidney disease, chronic hypertension, and gestational hypertension. Data on socio-demographics, laboratory parameters, health system, obstetric and medical factors were collected. Baseline serum creatinine, complete blood count, and CD4 T-cell count were all done at admission (0-hour). A second serum creatinine was done at 48-hours to determine the presence of AKI and AKI was defined as a relative change of serum creatinine value at least 1.5 times the baseline (i.e., at admission) within 48 h. The proportion of women diagnosed with acute kidney injury among the total number of women with severe pre-eclampsia was reported as incidence proportion. Univariate and multivariate logistic regression was used to establish the association between acute kidney injury and severe pre-eclampsia. RESULTS: Incidence of acute kidney injury was high (42.86%) among women with severe pre-eclampsia. Antenatal care attendance was protective with an odds ratio of 0.14 (0.03, 0.73), p-value 0.020 at bivariate analysis but had no statistical significance at multivariate analysis. Eclampsia was an independent risk factor for acute kidney injury. (aOR 5.89 (1.51, 38.88), p-value 0.014. CONCLUSION: The incidence of acute kidney injury in patients with severe pre-eclampsia is high. Eclampsia is an independent risk factor of acute kidney injury. The findings of this study highlight the urgent need for more research and better perinatal care for these women.

Impact of initiation of amikacin liposome inhalation suspension on hospitalizations and other healthcare resource utilization measures: a retrospective cohort study in real-world settings.

BACKGROUND: Mycobacterium avium complex lung disease (MAC-LD) is an infection that is increasing in frequency, associated with substantial disease burden, and often refractory to treatment. Amikacin liposome inhalation suspension (ALIS) is the first therapy approved for refractory MAC-LD. In the CONVERT study of adult patients with refractory MAC-LD, adding ALIS to a multidrug background regimen showed evidence of MAC infection elimination in sputum by month 6, which was maintained in most patients through the end of treatment (≤ 12 months post-conversion). This study assessed changes in healthcare resource utilization (HCRU) among patients initiating ALIS in real-world settings. METHODS: This retrospective cohort study of the All-Payer Claims Database (October 2018-April 2020) included patients aged ≥ 18 years with ≥ 1 pharmacy claim for ALIS and ≥ 12 months of continuous health plan enrollment pre- and post-ALIS initiation. Respiratory disease-related (and all-cause) HCRU (hospitalizations, length of stay [LOS], emergency department [ED] visits, and outpatient office visits) were compared 12 months pre- and post-ALIS initiation. Outcomes were reported at 6-month intervals; 0-6 months pre-ALIS initiation was the reference period for statistical comparisons. RESULTS: A total of 331 patients received ALIS, with HCRU highest in the 6 months pre-ALIS initiation. Compared with 26.9% during the reference period, respiratory-related hospitalizations decreased to 19.3% (P < 0.01) and 15.4% (P < 0.0001) during 0-6 and 7-12 months post-ALIS initiation, respectively. Mean number of respiratory disease-related hospitalizations per patient/6-month period decreased from 1.0 (reference period) to 0.6 (P < 0.0005) at both timepoints post-ALIS initiation. A similar pattern was observed for all-cause hospitalizations and hospitalizations per patient/6-month period (both P < 0.005). Reductions in all-cause and respiratory disease-related LOS post-ALIS initiation were significant (both P < 0.05). ED visits were few and unchanged during the study. Significant reductions per patient/6-month period in all-cause and respiratory-related outpatient office visits were observed post-ALIS initiation (all P < 0.01). CONCLUSIONS: In this first real-world study of ALIS, respiratory disease-related (and all-cause) hospitalizations and outpatient visits were reduced in the 12 months following ALIS initiation. The results of this study provide HCRU-related information to better understand the impact of initiating ALIS treatment. TRIAL REGISTRATION: Not appliable.

Unveiling Antimicrobial and Antioxidant Compositional Differences between Dukkah and Za'atar via SPME-GCMS and HPLC-DAD.

Interest in plant-based diets has been on the rise in recent years owing to the potential health benefits of their individual components and the notion that plant-based diets might reduce the incidence of several diseases. Egyptian dukkah and Syrian za'atar are two of the most historic and famous Middle Eastern herbal blends used for their anti-inflammatory, hypolipidemic, and antidiabetic effects. Headspace SPME-GCMS and HPLC-DAD were adopted for characterizing the aroma profile and phenolic compounds of both herbal blends, respectively. Further, vapor-phase minimum inhibitory concentration was employed for assessing each blend's antibacterial potential, while their antioxidant potential was estimated via in vitro antioxidant assays. SPME headspace analysis indicated the abundance of ethers and monoterpene hydrocarbons, while HPLC revealed the presence of several phenolics including rosmarinic acid, ferulic acid, and rutin. Biological investigations affirmed that vapor-phase of the tested blends exhibited antibacterial activities against Gram-positive and Gram-negative pathogens, while the antioxidant potential of the blends was investigated and expressed as Trolox (125.15 ± 5.92 to 337.26 ± 13.84 µM T eq/mg) and EDTA (18.08 ± 1.62 to 51.69 41 ± 5.33 µM EDTA eq/mg) equivalent. The presented study offers the first insight into the chemical profile and biological activities of both dukkah and za'atar.

Deregulation of long noncoding RNAs ANCR, TINCR, HOTTIP and SPRY4-IT1 in plasma of systemic sclerosis patients: SPRY4-IT1 as a novel biomarker of scleroderma and its subtypes.

Systemic sclerosis or systemic scleroderma (SSc) is an inflammatory autoimmune disease whose pathogenesis remains ambiguous; however, epigenetics, including long noncoding RNAs (lncRNAs) is an emerging paradigm. To date, the expression, role and clinical significance of most lncRNAs in SSc remain unelucidated. Herein, we investigated the plasma expression profiles of lncRNAs; ANCR, TINCR, HOTTIP, and SPRY4-IT1, which were linked to skin biology, in SSc patients and its subtypes, their potential as diagnostic tools and their correlations with autoantibodies and disease manifestations. Sixty-three SSc patients and thirty-five healthy volunteers were recruited. Autoantibody profile (anti-Scl-70, anti-centromere, anti-RNA polymeraseIII, anti-ribonucleoprotein, antinuclear, and anti-phospholipid antibodies) was determined. lncRNAs analysis was conducted using RT-qPCR. Plasma TINCR, HOTTIP, and SPRY4-IT1 upregulation and ANCR downregulation were observed in SSc patients compared with controls. SPRY4-IT1 was superior in SSc diagnosis in ROC analysis and predicted its risk in multivariate logistic analysis. Plasma SPRT4-IT1 was higher in diffuse than limited SSc. SPRY4-IT1 and HOTTIP were positively correlated with modified Rodnan skin score while ANCR showed a negative correlation only in limited SSc. ANCR and TINCR were positively correlated with disease duration and ESR, respectively. ANCR and SPRY4-IT1 were positively correlated with pulmonary hypertension. HOTTIP was positively correlated with antinuclear antibody. SPRY4-IT1 was positively correlated with HOTTIP in the whole group, and with TINCR only in diffuse SSc. We introduce plasma SPRY4-IT1, HOTTIP, ANCR and TINCR as novel candidate biomarkers for SSc, with SPRY4-IT1 could predict SSc diagnosis and discriminate its subtypes. Our findings widen the epigenetic landscape of SSc and provide surrogates for future predictive studies.

Spectrum and prevalence of BRCA1/2 germline mutations in Pakistani breast cancer patients: results from a large comprehensive study.

BACKGROUND: Pathogenic germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers worldwide. To refine the spectrum of BRCA1/2 mutations and to accurately estimate the prevalence of mutation in the Pakistani population, we studied 539 breast cancer patients selected for family history and age of diagnosis. METHODS: Comprehensive screening for BRCA1/2 germline mutations was performed using state-of-the-art technologies. RESULTS: A total of 133 deleterious mutations were identified in 539 families (24.7%), comprising 110 in BRCA1 and 23 in BRCA2. The prevalence of BRCA1/2 small-range mutations and large genomic rearrangements was 55.4% (36/65) for families with breast and ovarian cancer, 27.4% (67/244) for families with two or more cases of breast cancer, 18.5% (5/27) for families with male breast cancer, and 12.3% (25/203) for families with a single case of early-onset breast cancer. Nine mutations were specific to the Pakistani population. Eighteen mutations in BRCA1 and three in BRCA2 were recurrent and accounted for 68.2% (75/110) and 34.8% (8/23) of all identified mutations in BRCA1 and BRCA2, respectively. Most of these mutations were exclusive to a specific ethnic group and may result from founder effects. CONCLUSIONS: Our findings show that BRCA1/2 mutations account for one in four cases of hereditary breast/ovarian cancer, one in five cases of male breast cancer, and one in eight cases of early-onset breast cancer in Pakistan. Our study suggests genetic testing of an extended panel of 21 recurrent BRCA1/2 mutations for appropriately selected patients and their families in Pakistan.

Cardiovascular disease risk factors in Pakistani population with newly diagnosed Type 2 diabetes mellitus: A cross-sectional study of selected family practitioner clinics in four provinces of Pakistan (CardiP Study).

OBJECTIVE: To explore cardiovascular risk factors in people with newly-diagnosed type 2 diabetes mellitus. METHODS: The cross-sectional, prospective, multicentre, study was conducted from June 2014 till July 2015 at family practice clinics in 27 cities across Pakistan, and comprised individuals aged 30-50 years diagnosed with type 2 diabetes mellitus within the preceding six months. Laboratory investigations were conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, and Aga Khan University Hospital, Karachi. The 10-year absolute risk of fatal or non-fatal coronary heart disease and stroke was calculated using the United Kingdom Prospective Diabetes Study Risk Engine version 2.0. Data were analysed using SPSS 19. RESULTS: Out of 888 subjects, 362(40.8%) were women and 526(59.2%) were men. The overall mean presenting age was 42.4}5.8 years. After stratification by age, those ≥40 years were significantly associated with higher glycated haemoglobin (p=0.02) and those ≤39 years were associated with higher levels of very low density lipoprotein (p=0.001) and triglyceride (p=0.006). The mean risk estimate for CHD was 9.7% (95% Confidence Interval (CI) 9.0- 10.1)), for fatal CHD 4.4% (95% CI 4.0-4.6), for stroke 1.5% (95% CI 1.2-1.7), and for fatal stroke 0.25% (95% CI 0.24- 0.26). CONCLUSIONS: There is a need for screening cardiovascular risk factors even in younger age groups of newlydiagnosed diabetes.

Training reproductive health professionals in a post-conflict environment: exploring medical, nursing, and midwifery education in Mogadishu, Somalia.

Following two decades of civil war, Somalia recently entered the post-conflict rebuilding phase that has resulted in the rapid proliferation of higher education institutions. Given the high maternal mortality ratio, the federal government has identified the reproductive health education of health service professionals as a priority. Yet little is known about the coverage of contraception, abortion, pregnancy, childbirth, and sexual and gender-based violence (SGBV) in medicine, nursing, or midwifery. In 2016, we conducted a multi-methods study to understand the reproductive health education and training landscape and identify avenues by which development of the next generation of health service professionals could be improved. Our study comprised two components: interviews with 20 key informants and 7 focus group discussions (FGDs) with 48 physicians, nurses, midwives, and medical students. Using the transcripts, memos, and field notes, we employed a multi-phased approach to analyse our data for content and themes. Our findings show that reproductive health education for medical and nursing students is inconsistent and significant content gaps, particularly in abortion and SGBV, exist. Students have few clinical training opportunities and the overarching challenges plaguing higher education in Somalia also impact health professions programmes in Mogadishu. There is currently a window of opportunity to develop creative strategies to improve the breadth and depth of evidence-based education and training, and multi-stakeholder engagement and the promotion of South-South exchanges appear warranted.

Health-related quality of life among patients treated with lurasidone: results from a switch trial in patients with schizophrenia.

BACKGROUND: Patients with schizophrenia frequently switch between antipsychotics, underscoring the need to achieve and maintain important treatment outcomes such as health-related quality of life (HRQoL) following the switch. This analysis evaluated HRQoL changes among patients with schizophrenia switched from their current antipsychotic to lurasidone. METHODS: Stable but symptomatic outpatients with schizophrenia were switched from their current antipsychotic to lurasidone in a six-week, open-label trial. HRQoL was assessed using two validated patient-reported measures, the Personal Evaluation of Transitions in Treatment (PETiT) scale and the Short-Form 12 (SF-12). Total and domain scores (psychosocial function and adherence-related attitude) were assessed using the PETiT scale; patients' mental and physical component summary scores (MCS and PCS) were assessed using the SF-12. Changes in HRQoL from baseline to study endpoint were compared using ANCOVA, with baseline score, treatment, and pooled site as covariates. Changes were assessed among all patients and those switched from specific antipsychotics to lurasidone. RESULTS: The analysis included 235 patients with data on the PETiT and SF-12 who had received ≥ 1 dose of lurasidone. Statistically significant improvements were observed from baseline to study endpoint on the PETiT total (mean change [SD]: 3.2 [8.5]) and psychosocial functioning (2.5 [6.9]) and adherence-related attitude (0.7 [2.6]) domain scores (all p ≤ 0.002). When examined by preswitch antipsychotic, significant improvements in PETiT total scores were observed in patients switched from quetiapine, risperidone, aripiprazole, and ziprasidone (all p < 0.03) but not olanzapine (p = 0.893). Improvements on the SF-12 MCS score were observed for all patients (mean change [SD]: 3.7 [11.5], p < 0.001) and for those switched from quetiapine or aripiprazole (both p < 0.03). The SF-12 PCS scores remained comparable to those at baseline in all patient groups. CONCLUSIONS: These findings indicate that patients switching from other antipsychotics to lurasidone experienced statistically significant improvement of HRQoL, based on PETiT scores, within six weeks of treatment. Patient health status remained stable with respect to the SF-12 physical component and showed improvement on the mental component. Changes in HRQoL varied based on the antipsychotic used before switching to lurasidone. TRIAL REGISTRATION: NCT01143077.

Ocular Mucoadhesive and Biodegradable Sponge-Like Inserts for the Sustained and Controlled Delivery of Voriconazole; Preparation, D-optimal Factorial Optimization and in-vivo Evaluation.

The aim of this study was to formulate and optimize by statistical means mucoadhesive and biodegradable sponge-like inserts loaded with voriconazole (VCZ) which increases the contact time of the drug with the eye and sustain its release from the formula in a controlled manner. This avoids the pulsed effect reported for the drug suspension and results in reducing the number of drug instillations in the eye with the result of enhancing the patient compliance. Also, the sponge like nature of the insert reduces the foreign body sensation caused by other ocular solid dosage forms. They were prepared using casting/freeze-drying technique using five polymers namely high molecular weight chitosan (CH), sodium alginate (AL), sodium carboxy methyl cellulose (CMC), gellan gum (GG) and xanthan gum (XG). The prepared inserts were subjected to evaluations of their visual appearance, weight variation, drug content, surface pH, in-vitro release (percent drug released after 1h (Q1 (%)), mean dissolution time (MDT) and dissolution efficiency (DE)) in addition to kinetic analysis of the release data, water uptake, mucoadhesion and rheology of the forming plain polymer solution at the maximum rate of shear. The independent variables of the D-optimal factorial design were the polymer type and concentration while Q1 (%), MDT, DE, % water uptake after 15 minutes and rheology at the maximum rate of shear were chosen as dependant variables. The performed optimization process using design expert software showed an optimum formula consisting of 2 % GG. It showed slow release behavior compared to the drug suspension. FTIR and DSC studies showed that there is no interaction between VCZ and GG. The optimum formula has good in-vitro mucoadhesive properties and pH in the safe ocular range. Moreover, it showed promising in-vivo results of rapid hydration and gelling in addition to good mucoadhesive behavior when instilled in the eye, high ocular safety and biocompatibility, sustained antifungal activity in comparison to the drug suspension and finally biodegradation. So, it may be taken into consideration as an outstanding carrier for the ocular delivery of VCZ.

The role of dietitian follow-ups on nutritional outcomes post-bariatric surgery.

BACKGROUND: Current evidence recommends dietary counselling with a registered dietitian (RD) for successful weight loss after metabolic bariatric surgery; however, there are limited data on the effect of RD follow-ups on micronutrient deficiencies. This study evaluated the effects of the number of postoperative RD visits on nutritional outcomes, including weight loss and micronutrient deficiencies. OBJECTIVES: The aim of this study was to evaluate the effects of the number of postoperative registered dietitian visits on nutritional outcomes, including weight loss and micronutrient deficiencies after metabolic and bariatric surgery. SETTING: Cleveland Clinic Abu Dhabi, United Arab Emirates METHODS: This retrospective study included patients who underwent bariatric surgery between September 2015 and June 2020. Demographics, weight loss, micronutrients, and the number of postoperative RD visits were evaluated. Baseline and 12-month postsurgery outcomes were compared based on the number of RD follow-ups. RESULTS: A total of 174 primary and 46 revisions were included. Patients were 73.6% female, with a mean age of 40 years. The initial mean body mass index was 42.8 kg/m2. Number of RD visits were as follows: 0-1 (39 patients), 2 (59 patients), 3 (55 patients), and 4 or more (67 patients). Baseline (pre-operative) micronutrient values were within normal range. In comparison with the reference group (REF = 0-1 post-op RD visits), patients with 3 RD visits had 7% higher total body weight loss (P < .001) and maintained micronutrients within the normal range at 12 months postoperative. Mean differences in postoperative values were statistically significant (P < .05) for weight, vitamin B12, and vitamin D but not for hemoglobin, ferritin, calcium, folate, vitamin B1, copper, and zinc. CONCLUSION: Our study suggests that three or more RD visits during the first 12 months after bariatric surgery are associated with improved outcomes, including significant percent total body weight loss and lower rates of micronutrient deficiencies.

A Comparative Analysis of Polysaccharides and Ethanolic Extracts from Two Egyptian Sweet Potato Cultivars, Abees and A 195: Chemical Characterization and Immunostimulant Activities.

Sweet potato (Ipomoea batatas (L.) Lam.) belongs to family Convolvulaceae. The plant is distributed worldwide and consumed, especially for its edible tubers. Many studies have proved that the plant has variable biological activities such as antidiabetic, anti-cancer, antihypertensive, antimicrobial, and immunostimulant activities. The roots of sweet potatoes are rich in valuable phytochemical constituents that vary according to the flesh color. Our investigation focused on the chemical profiling of two Egyptian sweet potato cultivars, Abees and A 195, using UPLC-QTOF and the analysis of their polysaccharide fractions by GC-MS. Furthermore, we assessed the immunostimulant properties of these extracts in immunosuppressed mice. The study revealed that sweet potato roots contain significant concentrations of phenolic acids, including caffeoylquinic, caffeic, caffeoyl-feruloyl quinic, and p-coumaric acids, as well as certain flavonoids, such as diosmin, diosmetin, and jaceosidin, and coumarins, such as scopoletin and umbelliferone. Moreover, polysaccharides prepared from both studied cultivars were analyzed using GC-MS. Further biological analysis demonstrated that all the tested extracts possessed immunostimulant properties by elevating the level of WBCs, IL-2, TNF, and IFN-γ in the immunosuppressed mice relative to the control group with the highest values in polysaccharide fractions of A195 (the ethanolic extract showed a higher effect on TNF and IFN-γ, while its polysaccharide fraction exhibited a promising effect on IL-2 and WBCs). In conclusion, the roots of the Egyptian sweet potato cultivars Abees and A 195 demonstrated significant immunostimulant activities, which warrants further investigation through clinical studies.

Nanocomposite alginate hydrogel loaded with propranolol hydrochloride kolliphor® based cerosomes as a repurposed platform for Methicillin-Resistant Staphylococcus aureus-(MRSA)-induced skin infection; in-vitro, ex-vivo, in-silico, and in-vivo evaluation.

Nanocomposite alginate hydrogel containing Propranolol hydrochloride (PNL) cerosomes (CERs) was prepared as a repurposed remedy for topical skin Methicillin-Resistant Staphylococcus aureus (MRSA) infection. CERs were formed via an ethanol injection technique using different ceramides, Kolliphores® as a surfactant, and Didodecyldimethylammonium bromide (DDAB) as a positive charge inducer. CERs were optimized utilizing 13. 22 mixed-factorial design employing Design-Expert® software, the assessed responses were entrapment efficiency (EE%), particle size (PS), and zeta potential (ZP). The optimum CER, composed of 5 mg DDAB, ceramide VI, and Kolliphor® RH40 showed tubular vesicles with EE% of 92.91 ± 0.98%, PS of 388.75 ± 18.99 nm, PDI of 0.363 ± 0.01, and ZP of 30.36 ± 0.69 mV. Also, it remained stable for 90 days and manifested great mucoadhesive aspects. The optimum CER was incorporated into calcium alginate to prepare nanocomposite hydrogel. The ex-vivo evaluation illustrated that PNL was permeated in a more prolonged pattern from PNL-loaded CERs nanocomposite related to PNL-composite, optimum CER, and PNL solution. Confocal laser scanning microscopy revealed a perfect accumulation of fluorescein-labeled CERs in the skin. The in-silico investigation illustrated that the PNL was stable when mixed with other ingredients in the CERs and confirmed that PNL is a promising candidate for curing MRSA. Moreover, the PNL-loaded CERs nanocomposite revealed superiority over the PNL solution in inhibiting biofilm formation and eradication. The PNL-loaded CERs nanocomposite showed superiority over the PNL-composite for treating MRSA infection in the in-vivo mice model. Histopathological studies revealed the safety of the tested formulations. In conclusion, PNL-loaded CERs nanocomposite provided a promising, safe cure for MRSA bacterial skin infection.