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The use of granulocyte colony-stimulating factor (GCSF) to control febrile neutropenia (FN) caused by anti-cancer chemotherapy is well documented but it still needs to evaluated with respect to the specific type of cancer and chemotherapeutic agents. The present study evaluates the efficacy of adjunctive GCSF for treating FN after taking anticancer therapy by measuring clinical, hematological and microbiological outcomes. It is a single center study conducted at Hayatabad Medical Complex (HMC), Peshawar, Pakistan. Adult patients of both genders, suffering from different types of sarcomas and taking anticancer chemotherapy were included in the study. The study was conducted between January 2023 and January 2024. Baseline data including demographic data, medication history and hematological evaluation of all the patients was recorded at the time of enrolment. Primary outcomes of the study were the extent of absolute neutrophil count (ANC) recovery, duration and severity of neutropenia (grade IV), period to fever resolution. After the therapy (with and without adjunctive GCSF) clinical outcomes, hematological evaluation and microbiological data was compared and evaluated. All the data was statistically analyzed by SPSS (IBMS, version 20). A total number of 120 patients were investigated out of which data of 109 patients was included. Out of 109 patients, 64 (58.72%) received adjunctive GCSF therapy, and 45 (41.28%) did not receive adjunctive GCSF. Comparison of the data showed that the patients receiving adjunctive GCSF had a significant improvement ANC recovery time, better recovery of fever and patients were free of infections. This study concluded that adjunctive GCSF therapy benefits the patients undergoing anticancer treatment for different types of carcinoma., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Kakar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The study's primary objectives encompass the following: (i) To implement the object detection of ovarian follicles using you only look once (YOLO)v8 and subsequently segment the identified follicles using a hybrid fuzzy c-means-based active contour technique. (ii) To extract statistical features and evaluate the effectiveness of both machine learning (ML) and deep learning (DL) classifiers in detecting polycystic ovary syndrome (PCOS). The research involved a two different dataset in which dataset1 comprising both normal (N = 50) and PCOS (N = 50) subjects, dataset 2 consists of 100 normal and 100 PCOS affected subjects for classification. The YOLOv8 method was employed for follicle detection, whereas statistical features were derived using Gray-level co-occurrence matrices (GLCM). For PCOS classification, various ML models such as Random Forest (RF), k- star, and stochastic gradient descent (SGD) were employed. Additionally, pre-trained models such as MobileNet, ResNet152V2, and DenseNet121 and Vision transformer were applied for the categorization of PCOS and healthy controls. Furthermore, a custom model named Follicles Net (F-Net) was developed to enhance the performance and accuracy in PCOS classification. Remarkably, the F-Net model outperformed among all ML and DL classifiers, achieving an impressive classification accuracy of 95% for dataset1 and 97.5% for dataset2 respectively in detecting PCOS. Consequently, the custom F-Net model holds significant potential as an effective automated diagnostic tool for distinguishing between normal and PCOS., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 S. et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The Coronavirus disease 2019 pandemic increased global psychological distress, emotional distress, and sleep disturbances, all known risk factors for compromised oral health. Despite this, there is limited understanding of the impacts of these psychological factors on oral health in certain populations, including Iranians. Thus, the present study investigates the associations between sociodemographic characteristics, emotional distress, sleep pattern changes, tooth brushing frequency, and oral ulcer reports in a sample of Iranian adults during the Coronavirus disease 2019 pandemic., Materials and Methods: This cross-sectional, web-based study collected data from Iranian adults between July and September 2022 using respondent-driven sampling. The Mental Health and Wellness questionnaire was used to gather information on sociodemographic characteristics, emotional distress, sleep pattern changes, toothbrushing frequency, and oral ulcer reports. Simple and multiple logistic regression served for statistical analysis., Results: Among the 240 participants, comprising 164 females and 76 males, with a mean age of 35.3 years (±13.3), 28 individuals (11.7%) reported reduced tooth brushing frequency, and 35 individuals (14.6%) reported oral ulcers. Male gender (OR = 2.75, p = 0.016) and sleep patterns changes (OR = 2.93, p = 0.01) increased the likelihood of reduced tooth brushing frequency. Additionally, being younger than 30 (OR = 2.87, p = 0.025) and fearing coronavirus transmission (OR = 3.42, p = 0.009) increased the odds of oral ulcers., Conclusions: Male gender and sleep pattern changes were risk factors for reduced tooth brushing frequency among the present sample of Iranian adults during the Coronavirus disease 2019 pandemic. Additionally, being under 30 and fearing coronavirus transmission were identified as risk factors for oral ulcers in this population. To preserve and promote adults' oral health during public health crises, targeted educational initiatives, public health awareness campaigns, and integrated mental and oral healthcare approaches are encouraged., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Karimi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Residents of rural areas have poorer health status, less healthy behaviours and higher mortality than urban dwellers, issues which are commonly addressed in primary care. Strengthening primary care may be an important tool to improve the health status of rural populations., Objective: Synthesize and categorize studies that examine interventions to improve rural primary care., Eligibility Criteria: Experimental or observational studies published between January 1, 1996 and December 2022 that include an historical or concurrent control comparison., Sources of Evidence: Pubmed, CINAHL, Cochrane Library, Embase., Charting Methods: We extracted and charted data by broad category (quality, access and efficiency), study design, country of origin, publication year, aim, health condition and type of intervention studied. We assigned multiple categories to a study where relevant., Results: 372 papers met our inclusion criteria, divided among quality (82%), access (20%) and efficiency (13%) categories. A majority of papers were completed in the USA (40%), Australia (15%), China (7%) or Canada (6%). 35 (9%) papers came from countries in Africa. The most common study design was an uncontrolled before-and-after comparison (32%) and only 24% of studies used randomized designs. The number of publications each year has increased markedly over the study period from 1-2/year in 1997-99 to a peak of 49 papers in 2017., Conclusions: Despite substantial inequity in health outcomes associated with rural living, very little attention is paid to rural primary care in the scientific literature. Very few studies of rural primary care use randomized designs., Competing Interests: KAB and JR are family physicians who previously practiced in rural areas. KAB, JR, and SA are rural health services researchers with an interest in the equity of health service distribution. The authors have no other disclosures to report., (Copyright: © 2024 Aubrey-Basler et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The impression technique highly influences the adaptation of ceramic restorations. Not enough information is available to compare the marginal (MF) and internal fit (IF) of endocrowns fabricated with various digitization techniques. Therefore, this in-vitro study aimed to compare the MF and IF of lithium disilicate (LDS) endocrowns fabricated through direct and indirect digital scanning methods., Materials and Methods: One extracted maxillary molar was used to fabricate endocrowns. The digitization of the model was performed with (G1) direct scanning (n = 10) utilizing an intraoral scanner (IOS), (G2) indirectly scanning the conventional impression taken from the model using the same IOS (n = 10), (G3) indirectly digitalizing the obtained impression using an extraoral scanner (EOS) (n = 10), and (G4) scanning the poured cast using the same EOS (n = 10). The MF and IF of the endocrowns were measured using the replica method and a digital stereomicroscope. The Kruskal-Wallis test was used to analyze data., Results: The studied groups differed significantly (p<0.001). G2 (130.31±7.87 μm) and G3 (48.43±19.14 μm) showed the largest and smallest mean vertical marginal gap, respectively. G2 and G3 led to the highest and lowest internal gaps in all regions, respectively. With significant differences among the internal regions (p<0.001), the pulpal area demonstrated the most considerable misfit in all groups., Conclusions: Scanning the impression using an extraoral scanner showed smaller marginal and internal gaps., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Akhlaghian et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

People's Dietary Patterns (DPs) are influenced by culture and ethnicity, and their identification requires a holistic assessment of diet. DP reflects dietary behaviors, and its analysis may provide further details about the dietary etiology of chronic diseases. By examining people's DP and related factors, more practical solutions can be proposed to prevent overweight, obesity, and related diseases. This study aimed to describe DP, Eating Restrictions (ER), Food Involvement (FI), Nutrition Knowledge (NK), and anthropometric indices in Iranian adults and determine the mediating role of FI in the relationship between ER, NK, and DP. A descriptive cross-sectional study was conducted using the structural equation modeling approach. The study was conducted on 2421 adults in Mazandaran Province, northern Iran. The Eating Restrictions Questionnaire (ERQ), the Food Involvement Inventory (FII), the komPAN questionnaire, and a demographic characteristics and anthropometric indices questionnaire were used to collect data. We also measured the seven major food groups, the Diet Quality Scores (DQS), and the six dietary indices, including the pro-Healthy-Diet-Index (pHDI-15), non-Healthy Diet-Index (nHDI-16), high-Glycemic-Diet-Index-7 (hGIDI-7), low-Glycaemic-Diet-Index-4 (lGIDI-4), high-Sugar-Diet-Index-4 (hSDI-4), and high-sugar product (hSFDI-6) and compared their values by gender and four BMI groups. The prevalence of ER and FI was 6.25% and 49.1%, respectively. NK was insufficient for 43.1% of the participants. Most participants (71.2%) had low DQS scores on pHDI-15 and moderate scores (52.9%) on nHDI-16. DQS scores were low in 64.8% of participants in the lGIDI-4 food group, while 71.7%, 92.6%, and 77.2% possessed moderate scores in the hGIDI-7, hSFDI-6, and hSDI-4 food groups, respectively. The mean pHDI-15 and lGIDI-4 indices were higher in women than in men. The amount of unhealthy food indices (nHDI-16, hGIDI-7, hSDI-4, and hSFDI-6) was higher in lean, overweight, and obese people than in people with a normal BMI. The structural model assumed between ER and DP and the mediating role of FI fit well with Iranian adults. Moreover, FI had a mediating role in the relationship between NK and pHDI&#95;15 (Indirect Effects = 0.05, P<0.05) and nHDI&#95;16 (Indirect Effects = -0.07, P<0.01). Most participants are small portions of the healthy food groups and the low glycemic foods, and FI plays a mediating role in the relationship between NK and ER with DP. Therefore, it is necessary to pay attention to the role of FI as a mediating variable in interventions based on reducing ER, increasing NK, and shifting DP from unhealthy to healthy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Saadati et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Early in the COVID-19 pandemic, Canadian primary care practices rapidly adapted to provide care virtually. Most family physicians lacked prior training or expertise with virtual care. In the absence of formal guidance, they made individual decisions about in-person versus remote care based on clinical judgement, their longitudinal relationships with patients, and personal risk assessments. Our objective was to explore Canadian family physicians' perspectives on the strengths and limitations of virtual care implementation for their patient populations during the COVID-19 pandemic and implications for the integration of virtual care into broader primary care practice., Methods: We conducted semi-structured qualitative interviews with family physicians working in four Canadian jurisdictions (Vancouver Coastal health region, British Columbia; Southwestern Ontario; the province of Nova Scotia; and Eastern Health region, Newfoundland and Labrador). We analyzed interview data using a structured applied thematic approach., Results: We interviewed 68 family physicians and identified four distinct themes during our analysis related to experiences with and perspectives on virtual care: (1) changes in access to primary care; (2) quality and efficacy of care provided virtually; (3) patient and provider comfort with virtual modalities; and (4) necessary supports for virtual care moving forward., Conclusions: The move to virtual care enhanced access to care for select patients and was helpful for family physicians to better manage their panels. However, virtual care also created access challenges for some patients (e.g., people who are underhoused or living in areas without good phone or internet access) and for some types of care (e.g., care that required access to medical devices). Family physicians are optimistic about the ongoing integration of virtual care into broader primary care delivery, but guidance, regulations, and infrastructure investments are needed to ensure equitable access and to maximize quality of care., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hedden et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The ability of the fungus Candida albicans to filament and form biofilms contributes to its burden as a leading cause of hospital-acquired infections. Biofilm development involves an interconnected transcriptional regulatory network (TRN) consisting of nine transcription factors (TFs) that bind both to their own regulatory regions and to those of the other network TFs. Here, we show that seven of the nine TFs in the C. albicans biofilm network contain prion-like domains (PrLDs) that have been linked to the ability to form phase-separated condensates. Construction of PrLD mutants in four biofilm TFs reveals that these domains are essential for filamentation and biofilm formation in C. albicans. Moreover, biofilm PrLDs promote the formation of phase-separated condensates in the nuclei of live cells, and PrLD mutations that abolish phase separation (such as the removal of aromatic residues) also prevent biofilm formation. Biofilm TF condensates can selectively recruit other TFs through PrLD-PrLD interactions and can co-recruit RNA polymerase II, implicating condensate formation in the assembly of active transcriptional complexes. Finally, we show that PrLD mutations that block the phase separation of biofilm TFs also prevent filamentation in an in vivo model of gastrointestinal colonization. Together, these studies associate transcriptional condensates with the regulation of filamentation and biofilm formation in C. albicans, and highlight how targeting of PrLD-PrLD interactions could prevent pathogenesis by this species., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ganser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Toxoplasmosis is a worldwide disease of various animals and human and results from infection with the Toxoplasma gondii parasite. Abortion and congenital defects are important consequences of the T. gondii infection. The aim of this study was to determine the Toxoplasma-induced abortions among women with miscarriage and the presence of T. gondii in their aborted fetuses in Urmia, the northwest of Iran. This cross-sectional study was conducted with 215 women with abortion and their aborted fetuses, from 2020 to 2021. Seroprevalence of anti-Toxoplasma IgG and IgM were determined using the sera of the aforesaid women. Nested PCR was carried out using RE-529 gene sequences, and sequencing was performed using the T. gondii GRA6 gene on the remnant of pregnancy after abortion. The tissue positive samples were then subjected to another PCR on GRA6 gene and sequenced for genotyping. Among 215 serum samples of women with abortion, 70 (32.6%) were positive for anti-Toxoplasma IgG, and three (1.4%) were positive for IgM. The RE-529 sequence of T. gondii was positive in three (1.4%) of the aborted fetuses. The analysis of GRA6 gene indicated that all three positive samples carried a GRA6 allele (GRA6I) of T. gondii type I genotype. Our findings suggest that T. gondii is one of the causative agents of spontaneous abortion in West Azerbijan Province, the northwest of Iran., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zeinali et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The aim of this study was to examine the quality of care by age and gender in oesophageal cancer using Global Burden of Disease (GBD) database., Methods: Patients aged 20 and over with oesophageal cancer were included in this longitudinal study using GBD 1990-2019 data. We used the Socio-Demographic Index (SDI) to classify the regions. We used Principal Component Analysis (PCA) method to calculate the Quality of Care Index (QCI). The QCI was rescaled into a 0-100 single index, demonstrating that the higher the score, the better the QC., Results: The age-standardized QCI for oesophageal cancer dramatically increased from 23.5 in 1990 to 41.1 in 2019 for both sexes, globally. The high SDI regions showed higher QCI than the rest of the regions (45.1 in 1990 and 65.7 in 2019) whereas the low SDI regions had the lowest QCI, which showed a 4.5% decrease through the years (from 13.3 in 1990 to 12.7 in 2019). Globally, in 2019, the QCI showed the highest scores for patients aged 80-84, reported 48.2, and the lowest score for patients aged 25-29 reported 31.5, for both sexes. Globally, in 2019, age-standardized Gender Disparity Ratio (GDR) was 1.2, showing higher QCI in females than males., Conclusion: There were fundamental differences in the QCI both globally and regionally between different age groups as well as between males and females. To achieve the goal of providing high-quality services equally to people in need in all over the world, health systems need to invest in effective diagnostic services, treatments, facilities, and equipment and to plan for screening and surveillance of high-risk individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Iezadi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: To identify the costs of hospital care for patients with COVID-19 and the amount of out-of-pocket payments., Methods: We conducted a systematic review using Scopus and WEB OF SCIENCE and PubMed databases in April 5, 2022 and then updated in January 15, 2023. English articles with no publication year restrictions were included with study designs of cost-of-illness (COI) studies, cost analyses, and observational reports (cross-sectional studies and prospective and retrospective cohorts) that calculated the patient-level cost of care for COVID-19. Costs are reported in USD with purchasing power parity (PPP) conversion in 2020. The PROSPERO registration number is CRD42022334337., Results: The results showed that the highest total cost of hospitalization in intensive care per patient was 100789 USD, which was reported in Germany, and the lowest cost was 5436.77 USD, which was reported in Romania. In the present study, in the special care department, the highest percentage of total expenses is related to treatment expenses (42.23 percent), while in the inpatient department, the highest percentage of total expenses is related to the costs of hospital beds/day of routine services (39.07 percent). The highest percentage of out-of-pocket payments was 30.65 percent, reported in China, and the lowest percentage of out-of-pocket payments was 1.12 percent, reported in Iran. The highest indirect cost per hospitalization was 16049 USD, reported in USA, and the lowest was 449.07 USD, reported in India., Conclusion: The results show that the COVID-19 disease imposed a high cost of hospitalization, mainly the cost of hospital beds/day of routine services. Studies have used different methods for calculating the costs, and this has negatively impacted the comparability costs across studies. Therefore, it would be beneficial for researchers to use a similar cost calculation model to increase the compatibility of different studies. Systematic review registration: PROSPERO CRD42022334337., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gholipour et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: This study appraises the psychometrics properties of the Inflammatory bowel disease-fatigue (IBD-F) Persian version questionnaire., Methods: The original IBD-F questionnaire was translated into the Persian version in a standard forward-back manner. The validation was performed through the face, content, and construct validity. Fifteen experts scored each item's necessity on an ordinal Likert scale of three; then, the content validity ratio was calculated using the Lawshe formula. Eight judges from pre-defined panel rated each item on an ordinal 4-point Likert scale concerning its relevancy, clarity, and simplicity for individual-CVI calculation. The mean individual-CVI was considered as the Scale-CVI for each domain. Twenty lay experts (selected from the target population) were asked to express their opinion on each item's importance by scoring on a 5-point Likert scale; subsequently, face validity was determined by the impact score formula. The questions that had minimum values of CVR, CVI, and impact score were retained in the final version of the questionnaire for reliability evaluation. Construct validity was evaluated via Confirmatory Factor Analysis. Internal consistency and test-retest reliability were checked using Cronbach's α and intraclass correlation coefficients (ICC). Fifty-four patients recruited based on inclusion and exclusion criteria to participate in the reliability analysis., Results: All the questions received the qualified values of CVR (exceeding 0.49 points) and impact score (more than 1.5 points) and were retained in the questionnaire; however, revisions were made for questions with a CVI 0.7-0.9 for clarity and simplicity. The result demonstrated relative goodness CFA and proper internal consistency, as Cronbach's α coefficient was 0.964 for the test (0.845 and 0.963 for the first and second part of the questionnaire, respectively (and 0.888 for the re-test (0.793 and 0.876 for the first and second section of the questionnaire, respectively). The ICC values between test and re-test for the first and second part and the whole questionnaire were obtained as 0.904, 0.922, and 0.921, respectively., Conclusion: The Persian version of the IBD-F questionnaire was valid and reliable; thus, an appropriate scale was deemed to measure fatigue (severity, frequency, and impact on daily activities)., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Hatamnejad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background and Objective: Estimating the contribution of risk factors of mortality due to COVID-19 is particularly important in settings with low vaccination coverage and limited public health and clinical resources. Very few studies of risk factors of COVID-19 mortality used high-quality data at an individual level from low- and middle-income countries (LMICs). We examined the contribution of demographic, socioeconomic and clinical risk factors of COVID-19 mortality in Bangladesh, a lower middle-income country in South Asia., Methods: We used data from 290,488 lab-confirmed COVID-19 patients who participated in a telehealth service in Bangladesh between May 2020 and June 2021, linked with COVID-19 death data from a national database to study the risk factors associated with mortality. Multivariable logistic regression models were used to estimate the association between risk factors and mortality. We used classification and regression trees to identify the risk factors that are the most important for clinical decision-making., Findings: This study is one of the largest prospective cohort studies of COVID-19 mortality in a LMIC, covering 36% of all lab-confirmed COVID-19 cases in the country during the study period. We found that being male, being very young or elderly, having low socioeconomic status, chronic kidney and liver disease, and being infected during the latter pandemic period were significantly associated with a higher risk of mortality from COVID-19. Males had 1.15 times higher odds (95% Confidence Interval, CI: 1.09, 1.22) of death compared to females. Compared to the reference age group (20-24 years olds), the odds ratio of mortality increased monotonically with age, ranging from an odds ratio of 1.35 (95% CI: 1.05, 1.73) for ages 30-34 to an odds ratio of 21.6 (95% CI: 17.08, 27.38) for ages 75-79 year group. For children 0-4 years old the odds of mortality were 3.93 (95% CI: 2.74, 5.64) times higher than 20-24 years olds. Other significant predictors were severe symptoms of COVID-19 such as breathing difficulty, fever, and diarrhea. Patients who were assessed by a physician as having a severe episode of COVID-19 based on the telehealth interview had 12.43 (95% CI: 11.04, 13.99) times higher odds of mortality compared to those assessed to have a mild episode. The finding that the telehealth doctors' assessment of disease severity was highly predictive of subsequent COVID-19 mortality, underscores the feasibility and value of the telehealth services., Conclusions: Our findings confirm the universality of certain COVID-19 risk factors-such as gender and age-while highlighting other risk factors that appear to be more (or less) relevant in the context of Bangladesh. These findings on the demographic, socioeconomic, and clinical risk factors for COVID-19 mortality can help guide public health and clinical decision-making. Harnessing the benefits of the telehealth system and optimizing care for those most at risk of mortality, particularly in the context of a LMIC, are the key takeaways from this study., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sania et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The Hepatitis B virus (HBV) core protein is an attractive target for preventing capsid assembly and viral replication. Drug repurposing strategies have introduced several drugs targeting HBV core protein. This study used a fragment-based drug discovery (FBDD) approach to reconstruct a repurposed core protein inhibitor to some novel antiviral derivatives. Auto Core Fragment in silico Screening (ACFIS) server was used for deconstruction-reconstruction of Ciclopirox in complex with HBV core protein. The Ciclopirox derivatives were ranked based on their free energy of binding (ΔGB). A quantitative structure affinity relationship (QSAR) was established on the Ciclopirox derivatives. The model was validated by a Ciclopirox-property-matched decoy set. A principal component analysis (PCA) was also assessed to define the relationship of the predictive variable of the QSAR model. 24-derivatives with a ΔGB (-16.56±1.46 Kcal.mol-1) more than Ciclopirox was highlighted. A QSAR model with a predictive power of 88.99% (F-statistics = 9025.78, corrected df(25), Pr > F = 0.0001) was developed by four predictive descriptors (ATS1p, nCs, Hy, F08[C-C]). The model validation showed no predictive power for the decoy set (Q2 = 0). No significant correlation was observed between predictors. By directly attaching to the core protein carboxyl-terminal domain, Ciclopirox derivatives may be able to suppress HBV virus assembly and subsequent viral replication inhibition. Hydrophobic residue Phe23 is a critical amino acid in the ligand binding domain. These ligands share the same physicochemical properties that lead to the development of a robust QSAR mode. The same strategy may also be used for future drug discovery of viral inhibitors., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Mohebbi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Hospital-acquired infections (HAIs) are significant problems as public health issues which need attention. Such infections are significant problems for society and healthcare organizations. This study aimed to carry out a systematic review and a meta-analysis to analyze the prevalence of HAIs globally., Methods: We conducted a comprehensive search of electronic databases including EMBASE, Scopus, PubMed and Web of Science between 2000 and June 2021. We found 7031 articles. After removing the duplicates, 5430 studies were screened based on the titles/ abstracts. Then, we systematically evaluated the full texts of the 1909 remaining studies and selected 400 records with 29,159,630 participants for meta-analysis. Random-effects model was used for the analysis, and heterogeneity analysis and publication bias test were conducted., Results: The rate of universal HAIs was 0.14 percent. The rate of HAIs is increasing by 0.06 percent annually. The highest rate of HAIs was in the AFR, while the lowest prevalence were in AMR and WPR. Besides, AFR prevalence in central Africa is higher than in other parts of the world by 0.27 (95% CI, 0.22-0.34). Besides, E. coli infected patients more than other micro-organisms such as Coagulase-negative staphylococci, Staphylococcus spp. and Pseudomonas aeruginosa. In hospital wards, Transplant, and Neonatal wards and ICU had the highest rates. The prevalence of HAIs was higher in men than in women., Conclusion: We identified several essential details about the rate of HAIs in various parts of the world. The HAIs rate and the most common micro-organism were different in various contexts. However, several essential gaps were also identified. The study findings can help hospital managers and health policy makers identify the reason for HAIs and apply effective control programs to implement different plans to reduce the HAIs rate and the financial costs of such infections and save resources., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Raoofi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We introduced a brand-new member of the family that is going to be referred to as the New Power Topp-Leone Generated (NPTL-G). This new member is one of a kind. Given the major functions that created this new member, important mathematical aspects are discussed in as much detail as possible. We derived some functions for the new one, included the Rényi entropy, the qf, series development, and moment weighted probabilities. Moreover, to estimate the values of the parameters of our model that were not known, we employed the maximum likelihood technique. In addition, two actual datasets from the real world were investigated in order to bring attention to the possible applications of this novel distribution. This new model performs better than three key rivals based on the measurements that were collected., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Atchadé et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: As a country's future leaders and pioneers, University students must live with healthy habits. In order to achieve a healthy lifestyle, Physical activity and Quality of Life can serve as suitable indices to study. The purpose of the study was to clarify how physical activity (PA), Body mass index (BMI) and gender relate to the quality of life (QOL) of students of Medical Sciences University by using a structural equation model., Methods: The research was a cross-sectional study. The number of participants was 225 students of the University. The participants answered three questionnaires, including Demographic, International Physical Activity Questionnaire (IPAQ short form), and Quality of Life Questionnaire (SF-12), BMI was calculated by anthropometric measures, as well. The Structural equation model (SEM) method was employed. The Fitness of the proposed pattern was measured using the following indexes: chi-square/degree of freedom ratio (CMIN/DF), Normed Fit Index (NFI), comparative fit index (CFI), the goodness of fit index (GFI), and standardized root mean squared residual (SRMR). In the analysis the significant level was considered as P < 0.05., Results: PA (r = -0.726, P<0.001) and QOL (r = -0.405, P<0.001) have significantly inverse relationship with BMI, whereas the QOL and PA were proven to be positively related (r = 0.357, P<0.001). Moreover, the results signify gender as a moderator in the relationship between PA and QOL (Δχ2 (10) = 19.903, P = 0.030) and also the mediatory role of BMI among students. BMI affects the QOL in men (P < 0.001, β = -0.307) more in compare to women women (P = 0.324, β = -0.158)., Conclusion: Study findings supported the research hypothesis. Gender exhibited moderating role in the relationship between PA and QOL, considering the mediating role of BMI., Competing Interests: The authors have declared that no competing interests exist.

A growing body of theoretical and experimental evidence suggests that intramolecular epistasis is a major determinant of rates and patterns of protein evolution and imposes a substantial constraint on the evolution of novel protein functions. Here, we examine the role of intramolecular epistasis in the recurrent evolution of resistance to cardiotonic steroids (CTS) across tetrapods, which occurs via specific amino acid substitutions to the α-subunit family of Na,K-ATPases (ATP1A). After identifying a series of recurrent substitutions at two key sites of ATP1A that are predicted to confer CTS resistance in diverse tetrapods, we then performed protein engineering experiments to test the functional consequences of introducing these substitutions onto divergent species backgrounds. In line with previous results, we find that substitutions at these sites can have substantial background-dependent effects on CTS resistance. Globally, however, these substitutions also have pleiotropic effects that are consistent with additive rather than background-dependent effects. Moreover, the magnitude of a substitution's effect on activity does not depend on the overall extent of ATP1A sequence divergence between species. Our results suggest that epistatic constraints on the evolution of CTS-resistant forms of Na,K-ATPase likely depend on a small number of sites, with little dependence on overall levels of protein divergence. We propose that dependence on a limited number sites may account for the observation of convergent CTS resistance substitutions observed among taxa with highly divergent Na,K-ATPases (See S1 Text for Spanish translation)., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Common mental disorders in combination with work-related stress are widespread in the western world, not least in Sweden. Various interactive factors, primarily work-related, have impact on the return to work process, for example; a supportive communicative function between the person on sick leave and the employer may facilitate this process. The aim was to investigate experiences of being part of a collaborative care model including a person-centered dialogue meeting with the employer and with a rehabilitation coordinator as the moderator., Methods: A qualitative design based on individual interviews with 13 persons diagnosed with common mental disorders who participated in an extensive collaborative care model, called the Co-Work-Care model. Persons were recruited as a heterogeneous sample with respect to age, gender, work background, and time since the intervention. All interviews were analyzed with Systematic Text Condensation., Results: Five codes synthesized the results: 1) A feeling of being taken care of, 2) Collaboration within the team was perceived as supportive, 3) An active and sensitive listener, 4) Structure and planning in the dialogue meeting, 5) The person-centered dialogue meeting was supportive and provided increased understanding., Conclusions: Participants experienced the close collaborative contact with the care manager and the rehabilitation coordinator as highly valuable for their rehabilitation process. Participants valued a well-structured dialogue meeting that included initial planning and a thorough communication involving the patient, the employer, and coordinator. Further, participants appreciated having an active role during the meeting, also empowering the return to work process., Competing Interests: The authors have declared that no competing interests exist.

Background: Amongst the pre-analytical, analytical, and post-analytical phase of laboratory testing, pre-analytical phase is the most error-prone. Knowledge gaps in understanding of pre-analytical factors are identified in the clinical years amongst undergraduate students due to lack of formal teaching modules on the pre-analytical phase. This study was conducted to seek experts' consensus in Clinical Chemistry on learning objectives and contents using the Delphi technique with an aim to develop an asynchronous virtual classroom for teaching pre-analytical factors of laboratory testing., Methods: A mixed method study was conducted at the Aga Khan University. A questionnaire comprising of 16 learning objectives and their associated triggers was developed on Google Docs for developing the case vignettes. A four-point Likert Scale, which included strongly agree, agree, disagree and strongly disagree, was utilized for the learning objectives. An open-ended question was included for experts to suggest new items for inclusion. A cut off of at least 75% agreement was set to establish consensus on each item. A total of 17 Chemical Pathology faculty from 13 institutions across Pakistan were invited to participate in the first round of Delphi. Similar method of response was used in round two to establish consensus on the newly identified items suggested by the faculty in round 1. Later, the agreed-upon objectives and triggers were used to develop interactive scenarios over Moodle to concurrently test and teach medical students in a nonchalant manner., Results: A total of 17 responses were received in Round 1 of the Delphi process (response rate = 100%), while 12 responses were received in Round 2 (response rate = 71%). In round 1, all 16 learning objectives reached the required consensus (≥ 75%) with no additional learning objectives suggested by the experts. Out of 75 triggers in round 1, 61 (81.3%) reached the consensus to be included while 39 were additionally suggested. In 2nd round, 17 out of 39 newly suggested triggers met the desired consensus. 14 triggers did not reach the consensus after two rounds, and were therefore eliminated. The virtual classroom developed using the agreed-upon learning objectives and triggers consisted of 20 items with a total score of 31 marks. The questions included multiple choice questions, fill in the blanks, drag and drop sequences and read-and-answer comprehensions. Specific learning points were included after each item and graphs and pictures were included for a vibrant experience., Conclusion: We developed an effective and interactive virtual session with expert consensus on the pre-analytical phase of laboratory testing for undergraduate medical students which can be used for medical technologist, graduate students and fellows in Chemical Pathology., Competing Interests: The authors have declared that no competing interests exist.

The Pacific Islands Families (PIF) study is a birth cohort study designed to increase knowledge about the growth and development of Pacific children living in Auckland, New Zealand. Adolescence is a critical time of growth and development, yet the roles of physical function and body composition in metabolic health at this life stage are not clear. We aimed to investigate associations between measures of physical function (the 6-minute-walk-test (6MWT)), heart rate changes before and after the 6MWT, handgrip strength, body composition including appendicular skeletal muscle mass (ASMM) measured by dual-energy X-ray absorptiometry and biomarkers of metabolic health from a fasting blood sample.A total of 200 youth (98 girls, 102 boys) aged 14-15 years, from the birth-cohort of children in the Pacific Islands families study were measured. In girls, the proportion of ASMM was lower and fat higher than in boys. Controlling for age, a 1% increase in ASMM predicted a longer walk distance (+6.3, 95%CI 2.2, 10.4 m in girls; +7.1, 95%CI 4.4, 9.1 m in boys) and lower heart rate following the 6MWT. ASMM and fat mass were independently predictive of maximal handgrip strength which was increased by 1.4 (1.0,1.8) kg in girls and 1.7 (1.3, 2.0) kg in boys for each kg increase in ASMM and reduced by 0.23 (0.08, 0.38) kg in girls and 0.26 (0.14, 0.37) kg in boys for each kg increase in fat mass. Lower total cholesterol and LDL were associated with an increase in distance walked in boys only. For each year of age, distance walked was reduced by 34 (15, 53) m in girls and 59 (36,84) m in boys. These findings should be explored further in the context of other influences such as food security, opportunities for physical activity and cultural expectations., Competing Interests: The authors have declared that no competing interests exist.

Neonatal brain injury may impact brain development and lead to lifelong functional impairments. Hypoxic-ischemic encephalopathy (HIE) and congenital heart disease (CHD) are two common causes of neonatal brain injury differing in timing and mechanism. Maturation of whole-brain neural networks can be quantified during development using diffusion magnetic resonance imaging (dMRI) in combination with graph theory metrics. DMRI of 35 subjects with CHD and 62 subjects with HIE were compared to understand differences in the effects of HIE and CHD on the development of network topological parameters and functional outcomes. CHD newborns had worse 12-18 month language (P<0.01) and 30 month cognitive (P<0.01), language (P = 0.05), motor outcomes (P = 0.01). Global efficiency, a metric of brain integration, was lower in CHD (P = 0.03) than in HIE, but transitivity, modularity and small-worldness were similar. After controlling for clinical factors known to affect neurodevelopmental outcomes, we observed that global efficiency was highly associated with 30 month motor outcomes (P = 0.02) in both groups. To explore neural correlates of adverse language outcomes in CHD, we used hypothesis-based and data-driven approaches to identify pathways with altered structural connectivity. We found that connectivity strength in the superior longitudinal fasciculus (SLF) tract 2 was inversely associated with expressive language. After false discovery rate correction, a whole connectome edge analysis identified 18 pathways that were hypoconnected in the CHD cohort as compared to HIE. In sum, our study shows that neonatal structural connectivity predicts early motor development after HIE or in subjects with CHD, and regional SLF connectivity is associated with language outcomes. Further research is needed to determine if and how brain networks change over time and whether those changes represent recovery or ongoing dysfunction. This knowledge will directly inform strategies to optimize neurologic functional outcomes after neonatal brain injury., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Dawn Gano received grant funding from the following organizations within a 5 year period of this article: - Cerebral Palsy Alliance - UCSF preterm birth initiative funded by Marc & Lynne Benioff.

Background: Domestic violence (DV) is a universal issue and an important public health priority. Establishing a DV Registry System (DVRS) can help to systematically integrate data from several sources and provide valid and reliable information on the scope and severity of harms. The main objective of this study was to develop, validate, and pilot-test a minimum datasheet for a DVRS to register DV victims in medical facilities., Materials and Methods: This study was conducted in two main phases. Phase one includes developing the datasheet for registration of DV in the DVRS. In phase two, the datasheet designed in the previous step was used in a pilot implementation of the DVRS for 12 months to find practical challenges. The preliminary datasheet was first developed using information on similar registry programs and guidelines of the World Health Organization (WHO) and then reviewed by four expert panels. Through a two-round Delphi technique, experts evaluated the instrument using the Content Validity Index (CVI) and Content Validity Ratio (CVR). The consistency of the responses was evaluated by test-retest analysis. Finally, two physicians in two forensic medical clinics registered the victims of physical and/or sexual violence perpetrated by a family member., Results: Preliminary datasheet consisted of 31 items. In the first round of Delphi, fifteen items had good content validity (I-CVI and CVR) and were kept, and seven items were moved to the next round. Also, in the first round of Delphi, experts suggested adding three items, including history of the violence, custody of the child, and custody of the elderly. All items evaluated in the second round were kept due to good CVR and CVI scores. As a result of Test-retest correlation coefficients for self-reprted items, two items including perpetrator's alcohol and drug use status were excluded (r(30) = +.43, and +.38, p< .01, two-tailed, respectively). Finally, 24 items were included in the datasheet including 15 items for individuals' characteristics (victims' characteristics and perpetrators' characteristics), eight items for incidents' characteristics, and one item for past history of violence experience. A total of 369 cases were registered from September 23, 2019, to July 21, 2020. The majority of the reported cases were female (82%) and were 19-40 years old. No physical and/or sexual violence was reported from rural areas, which calls upon researchers to explore how services for detecting and treating the victims can be made accessible to these areas., Conclusion: DVRS can show trends in DV by age, sex, the context of the violence, and incidence characteristics at every point in time. This is particularly valuable in planning and prioritizing research areas and interventions for DV prevention. Additionally, DVRS can be linked to other disease registry programs which can contribute to continuity and coordination of care, and major research in the future. Although a DVRS can be a promising initiative in identifying the areas in need of urgent interventions, there is no guarantee for its proper implementation due to limited resources and other challenges., Competing Interests: The authors have declared that no competing interests exist.

Non-Pharmaceutical Public Health Interventions (NPHIs) have been used by different countries to control the spread of the COVID-19. Despite available evidence regarding the effectiveness of NPHSs, there is still no consensus about how policymakers can trust these results. Studies on the effectiveness of NPHSs are single studies conducted in specific communities. Therefore, they cannot individually prove if these interventions have been effective in reducing the spread of the infection and its adverse health outcomes. In this systematic review, we aimed to examine the effects of NPHIs on the COVID-19 case growth rate, death growth rate, Intensive Care Unit (ICU) admission, and reproduction number in countries, where NPHIs have been implemented. We searched relevant electronic databases, including Medline (via PubMed), Scopus, CINAHL, Web of Science, etc. from late December 2019 to February 1, 2021. The key terms were primarily drawn from Medical Subject Heading (MeSh and Emtree), literature review, and opinions of experts. Peer-reviewed quasi-experimental studies were included in the review. The PROSPERO registration number is CRD42020186855. Interventions were NPHIs categorized as lockdown, stay-at-home orders, social distancing, and other interventions (mask-wearing, contact tracing, and school closure). We used PRISMA 2020 guidance for abstracting the data and used Cochrane Effective Practice and Organization of Practice (EPOC) Risk of Bias Tool for quality appraisal of the studies. Hartung-Knapp-Sidik-Jonkman random-effects model was performed. Main outcomes included COVID-19 case growth rate (percentage daily changes), COVID-19 mortality growth rate (percentage daily changes), COVID-19 ICU admission (percentage daily changes), and COVID-19 reproduction number changes. Our search strategies in major databases yielded 12,523 results, which decreased to 7,540 articles after eliminating duplicates. Finally, 35 articles qualified to be included in the systematic review among which 23 studies were included in the meta-analysis. Although studies were from both low-income and high-income countries, the majority of them were from the United States (13 studies) and China (five studies). Results of the meta-analysis showed that adoption of NPHIs has resulted in a 4.68% (95% CI, -6.94 to -2.78) decrease in daily case growth rates, 4.8% (95 CI, -8.34 to -1.40) decrease in daily death growth rates, 1.90 (95% CI, -2.23 to -1.58) decrease in the COVID-19 reproduction number, and 16.5% (95% CI, -19.68 to -13.32) decrease in COVID-19 daily ICU admission. A few studies showed that, early enforcement of lockdown, when the incidence rate is not high, contributed to a shorter duration of lockdown and a lower increase of the case growth rate in the post-lockdown era. The majority of NPHIs had positive effects on restraining the COVID-19 spread. With the problems that remain regarding universal access to vaccines and their effectiveness and considering the drastic impact of the nationwide lockdown and other harsh restrictions on the economy and people's life, such interventions should be mitigated by adopting other NPHIs such as mass mask-wearing, patient/suspected case isolation strategies, and contact tracing. Studies need to address the impact of NPHIs on the population's other health problems than COVID-19., Competing Interests: The authors have declared that no competing interests exist.

Background: National healthcare financing strategy recommends tax-based equity funds and insurance schemes for the poor and extreme poor living in urban slums and pavements as the majority of these population utilise informal providers resulting in adverse health effects and financial hardship. We assessed the effect of a health voucher scheme (HVS) and micro-health insurance (MHI) scheme on healthcare utilisation and out-of-pocket (OOP) payments and the cost of implementing such schemes., Methods: HVS and MHI schemes were implemented by Concern Worldwide through selected NGO health centres, referral hospitals, and private healthcare facilities in three City Corporations of Bangladesh from December 2016 to March 2020. A household survey with 1,294 enrolees, key-informant interviews, focus group discussions, consultative meetings, and document reviews were conducted for extracting data on healthcare utilisation, OOP payments, views of enrolees, and suggestions of implementers, and costs of services at the point of care., Results: Healthcare utilisation including maternal, neonatal and child health (MNCH) services, particularly from medically trained providers, was higher and OOP payments were lower among the scheme enrolees compared to corresponding population groups in general. The beneficiaries were happy with their access to healthcare, especially for MNCH services, and their perceived quality of care was fair enough. They, however, suggested expanding the benefits package, supported by an additional workforce. The cost per beneficiary household for providing services per year was €32 in HVS and €15 in MHI scheme., Conclusion: HVS and MHI schemes enabled higher healthcare utilisation at lower OOP payments among the enrolees, who were happy with their access to healthcare, particularly for MNCH services. However, they suggested a larger benefits package in future. The provider's costs of the schemes were reasonable; however, there are potentials of cost containment by purchasing the health services for their beneficiaries in a competitive basis from the market. Scaling up such schemes addressing the drawback would contribute to achieving universal health coverage., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Sayem Ahmed – none declared Md. Zahid Hasan – none declared Nausad Ali – none declared Mohammad Wahid Ahmed – none declared Emranul Haq – works at the Concern Worldwide Bangladesh Sadia Shabnam – works at the scheme implementing organization, BRAC Morseda Chowdhury – works at the scheme implementing organization, BRAC Breda Gahan – works at the funding organization, Concern Worldwide Christine Bousquet – works at the funding organization, Concern Worldwide Jahangir A. M. Khan – none declared Ziaul Islam – none declared This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Experimental data about gene functions curated from the primary literature have enormous value for research scientists in understanding biology. Using the Gene Ontology (GO), manual curation by experts has provided an important resource for studying gene function, especially within model organisms. Unprecedented expansion of the scientific literature and validation of the predicted proteins have increased both data value and the challenges of keeping pace. Capturing literature-based functional annotations is limited by the ability of biocurators to handle the massive and rapidly growing scientific literature. Within the community-oriented wiki framework for GO annotation called the Gene Ontology Normal Usage Tracking System (GONUTS), we describe an approach to expand biocuration through crowdsourcing with undergraduates. This multiplies the number of high-quality annotations in international databases, enriches our coverage of the literature on normal gene function, and pushes the field in new directions. From an intercollegiate competition judged by experienced biocurators, Community Assessment of Community Annotation with Ontologies (CACAO), we have contributed nearly 5,000 literature-based annotations. Many of those annotations are to organisms not currently well-represented within GO. Over a 10-year history, our community contributors have spurred changes to the ontology not traditionally covered by professional biocurators. The CACAO principle of relying on community members to participate in and shape the future of biocuration in GO is a powerful and scalable model used to promote the scientific enterprise. It also provides undergraduate students with a unique and enriching introduction to critical reading of primary literature and acquisition of marketable skills., Competing Interests: The authors have declared that no competing interests exist.

Background: COVID-19 is affecting the entire population of India. Understanding district level correlates of the COVID-19's infection ratio (IR) is essential for formulating policies and interventions., Objective: The present study aims to investigate the district level variation in COVID-19 during March-October 2020. The present study also examines the association between India's socioeconomic and demographic characteristics and the COVID-19 infection ratio at the district level., Data and Methods: We used publicly available crowdsourced district-level data on COVID-19 from March 14, 2020, to October 31, 2020. We identified hotspot and cold spot districts for COVID-19 cases and infection ratio. We have also carried out two sets of regression analysis to highlight the district level demographic, socioeconomic, household infrastructure facilities, and health-related correlates of the COVID-19 infection ratio., Results: The results showed on October 31, 2020, the IR in India was 42.85 per hundred thousand population, with the highest in Kerala (259.63) and the lowest in Bihar (6.58). About 80 percent infected cases and 61 percent deaths were observed in nine states (Delhi, Gujarat, West Bengal, Uttar Pradesh, Andhra Pradesh, Maharashtra, Karnataka, Tamil Nadu, and Telangana). Moran's- I showed a positive yet poor spatial clustering in the COVID-19 IR over neighboring districts. Our regression analysis demonstrated that percent of 15-59 aged population, district population density, percent of the urban population, district-level testing ratio, and percent of stunted children were significantly and positively associated with the COVID-19 infection ratio. We also found that, with an increasing percentage of literacy, there is a lower infection ratio in Indian districts., Conclusion: The COVID-19 infection ratio was found to be more rampant in districts with a higher working-age population, higher population density, a higher urban population, a higher testing ratio, and a higher level of stunted children. The study findings provide crucial information for policy discourse, emphasizing the vulnerability of the highly urbanized and densely populated areas., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Health benefits package (HBP) is regarded as one of the main dimensions of health financing strategy. Even with increasing demands for prosthetics and orthotics (P&O) services to approximately 0.5% of the world's population, only 15% of vulnerable groups have the chance to make use of such benefits. Inadequate coverage of P&O services in the HBP is accordingly one of the leading reasons for this situation in many countries, including Iran., Aims: The main objective of this study was to find and prioritize solutions in order to facilitate and promote P&O services in the Iranian HBP., Study Design: A mixed-methods (qualitative-quantitative) research design was employed in this study., Methods: This study was conducted in two phases. First, semi-structured interviews were undertaken to retrieve potential solutions. Then an analytic hierarchy process (AHP) reflecting on seven criteria of acceptability, effectiveness, time, cost, feasibility, burden of disease, and fairness was performed to prioritize them., Results: In total, 26 individuals participated in semi-structured interviews and several policy solutions were proposed. Following the AHP, preventive interventions, infant-specific interventions, inpatient interventions, interventions until 6 years of age, and emergency interventions gained the highest priority to incorporate in the Iranian HBP., Conclusion: A number of policy solutions were explored and prioritized for P&O services in the Iranian HBP. Our findings provide a framework for decision- and policy-makers in Iran and other countries aiming to curb the financial burdens of P&O users, especially in vulnerable groups., Competing Interests: The authors have declared that no competing interests exist.

Mutations in mitochondrial replicative polymerase PolγA lead to progressive external ophthalmoplegia (PEO). While PolγA is the known central player in mitochondrial DNA (mtDNA) replication, it is unknown whether a regulatory process exists on the mitochondrial outer membrane which controlled its entry into the mitochondria. We now demonstrate that PolγA is ubiquitylated by mitochondrial E3 ligase, MITOL (or MARCH5, RNF153). Ubiquitylation in wild-type (WT) PolγA occurs at Lysine 1060 residue via K6 linkage. Ubiquitylation of PolγA negatively regulates its binding to Tom20 and thereby its mitochondrial entry. While screening different PEO patients for mitochondrial entry, we found that a subset of the PolγA mutants is hyperubiquitylated by MITOL and interact less with Tom20. These PolγA variants cannot enter into mitochondria, instead becomes enriched in the insoluble fraction and undergo enhanced degradation. Hence, mtDNA replication, as observed via BrdU incorporation into the mtDNA, was compromised in these PEO mutants. However, by manipulating their ubiquitylation status by 2 independent techniques, these PEO mutants were reactivated, which allowed the incorporation of BrdU into mtDNA. Thus, regulated entry of non-ubiquitylated PolγA may have beneficial consequences for certain PEO patients., Competing Interests: The authors have declared that no competing interests exist.

Several issues have been identified with the current programs for the elimination of onchocerciasis that target only transmission by using mass drug administration (MDA) of the drug ivermectin. Alternative and/or complementary treatment regimens as part of a more comprehensive strategy to eliminate onchocerciasis are needed. We posit that the addition of "prophylactic" drugs or therapeutic drugs that can be utilized in a prophylactic strategy to the toolbox of present microfilaricidal drugs and/or future macrofilaricidal treatment regimens will not only improve the chances of meeting the elimination goals but may hasten the time to elimination and also will support achieving a sustained elimination of onchocerciasis. These "prophylactic" drugs will target the infective third- (L3) and fourth-stage (L4) larvae of Onchocerca volvulus and consequently prevent the establishment of new infections not only in uninfected individuals but also in already infected individuals and thus reduce the overall adult worm burden and transmission. Importantly, an effective prophylactic treatment regimen can utilize drugs that are already part of the onchocerciasis elimination program (ivermectin), those being considered for MDA (moxidectin), and/or the potential macrofilaricidal drugs (oxfendazole and emodepside) currently under clinical development. Prophylaxis of onchocerciasis is not a new concept. We present new data showing that these drugs can inhibit L3 molting and/or inhibit motility of L4 at IC50 and IC90 that are covered by the concentration of these drugs in plasma based on the corresponding pharmacological profiles obtained in human clinical trials when these drugs were tested using various doses for the therapeutic treatments of various helminth infections., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Multidrug-resistant organisms (MDRO) are considered an emerging threat worldwide. Data covering the clinical impact of MDRO colonization in patients with solid malignancies, however, is widely missing. We sought to determine the impact of MDRO colonization in patients who have been diagnosed with Non-small cell lung cancer (NSCLC) who are at known high-risk for invasive infections., Materials and Methods: Patients who were screened for MDRO colonization within a 90-day period after NSCLC diagnosis of all stages were included in this single-center retrospective study., Results: Two hundred and ninety-five patients were included of whom 24 patients (8.1%) were screened positive for MDRO colonization (MDROpos) at first diagnosis. Enterobacterales were by far the most frequent MDRO detected with a proportion of 79.2% (19/24). MDRO colonization was present across all disease stages and more present in patients with concomitant diabetes mellitus. Median overall survival was significantly inferior in the MDROpos study group with a median OS of 7.8 months (95% CI, 0.0-19.9 months) compared to a median OS of 23.9 months (95% CI, 17.6-30.1 months) in the MDROneg group in univariate (p = 0.036) and multivariate analysis (P = 0.02). Exploratory analyses suggest a higher rate of non-cancer-related-mortality in MDROpos patients compared to MDROneg patients (p = 0.002) with an increased rate of fatal infections in MDROpos patients (p = 0.0002)., Conclusions: MDRO colonization is an independent risk factor for inferior OS in patients diagnosed with NSCLC due to a higher rate of fatal infections. Empirical antibiotic treatment approaches should cover formerly detected MDR commensals in cases of (suspected) invasive infections., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: JS reports personal fees from Bristol-Myers & Squibb, personal fees from Novartis, personal fees from Roche, outside the submitted work. RL has nothing to disclose. OB has nothing to disclose. SS has nothing to disclose. WG has nothing to disclose. MJGTV has served at the speakers’ bureau of Akademie für Infektionsmedizin, Ärztekammer Nordrhein, Astellas Pharma, Basilea, Gilead Sciences, Merck/MSD, Organobalance, Pfizer and Uniklinik Freiburg / Kongress und Kommunikation, received research funding from 3M, Astellas Pharma, DaVolterra, Gilead Sciences, MaaT Pharma, Merck/MSD, Morphochem, Organobalance, Seres Therapeutics, and is a consultant to Alb-Fils Kliniken GmbH, Ardeypharm, Astellas Pharma, Berlin Chemie, DaVolterra, Ferring, MaaT Pharma and Merck/MSD. TW has nothing to disclose. CR has nothing to disclose. SG has nothing to disclose. VK reports grants and personal fees from DFG Germany (DFG FG 2251), grants and personal fees from EU Marie Sklodowska-Curie (#765042), during the conduct of the study. PK has nothing to disclose. SS has nothing to disclose. CB has nothing to disclose. MSe reports personal fees from Lilly, personal fees from Astra-Zeneca, personal fees from Bristol-Myers & Squibb, personal fees from Merck Sharp & Dohme, personal fees from Pfizer, personal fees from Takeda, personal fees from Roche, personal fees from AbbVie, personal fees from Boehringer Ingelheim, personal fees from Celgene, personal fees from Novartis, outside the submitted work. SK has nothing to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Onchocerciasis also known as river blindness is a neglected tropical disease and the world's second-leading infectious cause of blindness in humans; it is caused by Onchocerca volvulus. Current treatment with ivermectin targets microfilariae and transmission and does not kill the adult parasites, which reside within subcutaneous nodules. To support the development of macrofilaricidal drugs that target the adult worm to further support the elimination of onchocerciasis, an in-depth understanding of O. volvulus biology especially the factors that support the longevity of these worms in the human host (>10 years) is required. However, research is hampered by a lack of access to adult worms. O. volvulus is an obligatory human parasite and no small animal models that can propagate this parasite were successfully developed. The current optimized 2-dimensional (2-D) in vitro culturing method starting with O. volvulus infective larvae does not yet support the development of mature adult worms. To overcome these limitations, we have developed and applied 3-dimensional (3-D) culture systems with O. volvulus larvae that simulate the human in vivo niche using in vitro engineered skin and adipose tissue. Our proof of concept studies have shown that an optimized indirect co-culture of in vitro skin tissue supported a significant increase in growth of the fourth-stage larvae to the pre-adult stage with a median length of 816-831 μm as compared to 767 μm of 2-D cultured larvae. Notably, when larvae were co-cultured directly with adipose tissue models, a significant improvement for larval motility and thus fitness was observed; 95% compared to 26% in the 2-D system. These promising co-culture concepts are a first step to further optimize the culturing conditions and improve the long-term development of adult worms in vitro. Ultimately, it could provide the filarial research community with a valuable source of O. volvulus worms at various developmental stages, which may accelerate innovative unsolved biomedical inquiries into the parasite's biology., Competing Interests: The authors have declared that no competing interests exist.

Background: Without any pharmaceutical intervention and vaccination, the only way to combat Coronavirus Disease 2019 (COVID-19) is to slow down the spread of the disease by adopting non-pharmaceutical public health interventions (PHIs). Patient isolation, lockdown, quarantine, social distancing, changes in health care provision, and mass screening are the most common non-pharmaceutical PHIs to cope with the epidemic. However, there is neither systematic evidence on the effectiveness of non-pharmaceutical PHIs in controlling the COVID-19 nor on how these interventions work in different contexts. Therefore, in this study we will address two main objectives: 1) to assess the effectiveness of the non-pharmaceutical PHIs in controlling the spread of COVID-19 using a systematic review and meta-analyses; 2) to explore why, how, and for whom these interventions work using a realist review., Materials and Methods: This review study has two main phases. In the first phase of this study, we will extract data from two main types of studies including quasi-experimental studies (such as quasi-randomized trials, controlled before-after studies (CBAs) and interrupted time series studies (ITSs)) and observational studies (such as cohort, case-control, and cross-sectional studies), written in the English language. We will explore effectiveness of the non-pharmaceutical PHIs targeted either suppression or mitigation strategies (or a combination of both) in controlling the COVID-19 epidemics in the community level. Effectiveness will be considered as the changes in mortality rate, incidence rate, basic reproduction number rate, morbidity rate, rates of hospitalization, rates of intensive care unit (ICU) hospitalization, and other health outcomes where possible. We will perform random-effects meta-analyses, if possible, using CMA software. In the second phase, we will conduct a realist review to find out how, why, for whom, and in what circumstances the non-pharmaceutical PHIs work. At the realist review, we will identify and explore Context-Mechanism-Outcome configurations to provide a robust explanation on the effectiveness of the interventions in different contexts using Pawson's 5-step realist review template including: "clarify scope; search for evidence; appraise primary studies and extract data; synthesize evidence and draw conclusions; and disseminate, implement and evaluate". Although the steps are presented in a linear manner, in practice, we will follow them in iterative stages to fill any potential overlap., Discussion: The findings of this research will provide a crucial insight into how and in which context the non-pharmaceutical PHIs work in controlling the spread of COVID-19. Conducting a systematic review and meta-analysis in line with a realist review will allow us to draw a robust conclusion on the effects and the way in which the interventions work. Understanding the role of contextual factors in the effectiveness of non-pharmaceutical PHIs and the mechanism of this process could enable policymakers to implement appropriate policies and manage the COVID-19 epidemics more efficiently., Systematic Review Registration: CRD42020186855., Competing Interests: The authors have declared that no competing interests exist.

Objectives: There is high risk of contamination with COVID-19 virus during routine dental procedures and infection control is crucial. The aim of this study was to determine the factors associated with Covid-19 preventive behaviors among oral health care providers using an extended parallel process model (EPPM)., Methods: In a cross-sectional study, short text message invite surveys were sent to 870 oral health care providers in west part of Iran. Data were collected through validated self-report EPPM questionnaires. Descriptive statistics, Chi-square and Fishers exact tests were used for data analysis., Results: In total, 300 completed questionnaires were received and the mean age of respondents was 29.89 ± 11.17 years (range: 20-75 years). Among the study population, 284 (94.67%) perceived the threat of infection highly. Washing hands frequently with water and soap and use of hand sanitizer was reported by 93.33%, of participants. Age (P = 0.010), sex (P = 0.002) and occupation field (P = 0.010) were significantly associated with danger control responses. Data identified that those oral health care providers that were on the danger control response adopted preventive behaviors more strictly than those on fear control response., Conclusion: The results of this study showed how degrees of perceived threat and perceived efficacy influenced oral health providers' willingness to perform recommended health behaviors. These findings can assist public health agencies in developing educational programs specifically designed for promoting preventive behaviors among oral health providers in pandemic situations., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0232930.].

Introduction: Probiotics are suggested to prevent colorectal cancer (CRC). This study aimed to investigate the anticancer properties of some potential probiotics in vitro and in vivo., Materials and Methods: Anticancer effects of the following potential probiotic groups were investigated in LS174T cancer cells compared to IEC-18 normal cells. 1. a single strain of Bifidobacterium. breve, 2. a single strain of Lactobacillus. reuteri, 3. a cocktail of 5 strains of Lactobacilli (LC), 4. a cocktail of 5 strains of Bifidobacteria (BC), 5. a cocktail of 10 strains from Lactobacillus and Bifidobacterium (L+B). Apoptosis rate, EGFR, HER-2 and PTGS-2 (COX-2 protein) expression levels were assessed as metrics of evaluating anticancer properties. Effect of BC, as the most effective group in vitro, was further assessed in mice models., Results: BC induced ~21% and only ~3% apoptosis among LS174T and IEC-18 cells respectively. BC decreased the expression of EGFR by 4.4 folds, HER-2 by 6.7 folds, and PTGS-2 by 20 folds among the LS174T cells. In all these cases, BC did not interfere significantly with the expression of the genes in IEC-18 cells. This cocktail has caused only 1.1 folds decrease, 1.8 folds increase and 1.7 folds decrease in EGFR, HER-2 and PTGS-2 expression, respectively. Western blot analysis confirmed these results in the protein level. BC significantly ameliorated the disease activity index, restored colon length, inhibited the increase in incidence and progress of tumors to higher stages and grades., Conclusions: BC was the most efficient treatment in this study. It had considerable "protective" anti-cancer properties and concomitantly down regulated EGFR, HER-2 and PTGS-2 (COX-2), while having significant anti-CRC effects on CRC mice models. In general, this potential probiotic could be considered as a suitable nutritional supplement to treat and prevent CRC., Competing Interests: The authors have declared that no competing interests exist.

Human chorionic gonadotropin (hCG) is a glycoprotein hormone that is essential for the maintenance of pregnancy. Glycosylation of hCG is known to be essential for its biological activity. "Hyperglycosylated" variants secreted during early pregnancy have been proposed to be involved in initial implantation of the embryo and as a potential diagnostic marker for gestational diseases. However, what constitutes "hyperglycosylation" is not yet fully understood. In this study, we perform comparative N-glycomic analysis of hCG expressed in the same individuals during early and late pregnancy to help provide new insights into hCG function, reveal new targets for diagnostics and clarify the identity of hyperglycosylated hCG. hCG was isolated in urine collected from women at 7 weeks and 20 weeks' gestation. hCG was also isolated in urine from women diagnosed with gestational trophoblastic disease (GTD). We used glycomics methodologies including matrix assisted laser desorption/ionisation-time of flight (MALDI-TOF) mass spectrometry (MS) and MS/MS methods to characterise the N-glycans associated with hCG purified from the individual samples. The structures identified on the early pregnancy (EP-hCG) and late pregnancy (LP-hCG) samples corresponded to mono-, bi-, tri-, and tetra-antennary N-glycans. A novel finding was the presence of substantial amounts of bisected type N-glycans in pregnancy hCG samples, which were present at much lower levels in GTD samples. A second novel observation was the presence of abundant LewisX antigens on the bisected N-glycans. GTD-hCG had fewer glycoforms which constituted a subset of those found in normal pregnancy. When compared to EP-hCG, GTD-hCG samples had decreased signals for tri- and tetra-antennary N-glycans. In terms of terminal epitopes, GTD-hCG had increased signals for sialylated structures, while LewisX antigens were of very minor abundance. hCG carries the same N-glycans throughout pregnancy but in different proportions. The N-glycan repertoire is more diverse than previously reported. Bisected and LewisX structures are potential targets for diagnostics. hCG isolated from pregnancy urine inhibits NK cell cytotoxicity in vitro at nanomolar levels and bisected type glycans have previously been implicated in the suppression of NK cell cytotoxicity, suggesting that hCG-related bisected type N-glycans may directly suppress NK cell cytotoxicity., Competing Interests: Affiliation with Mologic LTD UK I can confirm that this commercial affiliation does not alter our adherence to PLOS ONE policies on sharing data and materials.” (as detailed online in guide for authors http://journals.plos.org/plosone/s/competing-interests).

Background: Maternal morbidity is common in Bangladesh, where the maternal mortality rate has plateaued over the last 6 years. Maternal undernutrition and micronutrient deficiencies contribute to morbidity, but few interventions have measured maternal outcomes. We compared reported prevalence of antepartum, intrapartum, and postpartum complications among recently delivered women between maternal nutrition intervention and control areas in Bangladesh., Methods and Findings: We conducted a cross-sectional assessment nested within a population-based cluster-randomized trial comparing a nutrition counseling and micronutrient supplement intervention integrated within a structured home-based maternal, newborn, and child health (MNCH) program to the MNCH program alone in 10 sub-districts each across 4 Bangladesh districts. Eligible consenting women, delivering within 42-60 days of enrollment and identified by community-level health workers, completed an interviewer-administered questionnaire detailing the index pregnancy and delivery and allowed review of their home-based care register. We compared pooled and specific reported antepartum, intrapartum, and postpartum complications between study groups using hierarchical logistic regression. There were 594 women in the intervention group and 506 in the control group; overall, mean age was 24 years, 31% were primiparas, and 39% reported facility-based delivery, with no significant difference by study group. There were no significant differences between the intervention and control groups in household-level characteristics, including reported mean monthly income (intervention, 6,552 taka, versus control, 6,017 taka; p = 0.48), having electricity (69.6% versus 71.4%, p = 0.84), and television ownership (41.1% versus 38.7%, p = 0.81). Women in the intervention group had higher recorded iron and folic acid and calcium supplement consumption and mean dietary diversity scores, but reported anemia rates were similar between the 2 groups (5.7%, intervention; 6.5%, control; p = 0.83). Reported antepartum (69.4%, intervention; 79.2%, control; p = 0.12) and intrapartum (41.4%, intervention; 48.5%, control; p = 0.18) complication rates were high and not significantly different between groups. Reported postpartum complications were significantly lower among women in the intervention group than the control group (33.5% versus 48.2%, p = 0.02), and this difference persisted in adjusted analysis (adjusted odds ratio [AOR] = 0.51, 95% CI 0.32-0.82; p < 0.001). For specific conditions, odds of retained placenta (AOR = 0.35, 95% CI 0.19-0.67; p = 0.001), postpartum bleeding (AOR = 0.37, 95% CI 0.15-0.92; p = 0.033), and postpartum fever/infection (AOR = 0.27, 95% CI 0.11-0.65; p = 0.001) were significantly lower in the intervention group in adjusted analysis. There were no significant differences in reported hospitalization for antepartum (49.8% versus 45.1%, p = 0.37), intrapartum (69.9% versus 59.8%, p = 0.18), or postpartum (36.1% versus 29.9%, p = 0.49) complications between the intervention and control groups. The main limitations of this study are outcome measures based on participant report, non-probabilistic selection of community-level workers' catchment areas for sampling, some missing data for variables derived from secondary sources (e.g., dietary diversity score), and possible recall bias for reported dietary intake and supplement use., Conclusions: Reported overall postpartum and specific intrapartum and postpartum complications were significantly lower for women in intervention areas than control areas, despite similar rates of facility-based delivery and hospitalization for reported complications, in this exploratory analysis. Maternal nutrition interventions providing intensive counseling and micronutrient supplements may reduce some pregnancy complications or impact women's ability to accurately recognize complications, but more rigorous evaluation is needed for these outcomes., Competing Interests: The authors have declared that no competing interests exist.

Human parasitic nematodes are the causative agents of lymphatic filariasis (elephantiasis) and onchocerciasis (river blindness), diseases that are endemic to more than 80 countries and that consistently rank in the top ten for the highest number of years lived with disability. These filarial nematodes have evolved an obligate mutualistic association with an intracellular bacterium, Wolbachia, a symbiont that is essential for the successful development, reproduction, and survival of adult filarial worms. Elimination of the bacteria causes adult worms to die, making Wolbachia a primary target for developing new interventional tools to combat filariases. To further explore Wolbachia as a promising indirect macrofilaricidal drug target, the essential cellular processes that define the symbiotic Wolbachia-host interactions need to be identified. Genomic analyses revealed that while filarial nematodes encode all the enzymes necessary for glycolysis, Wolbachia does not encode the genes for three glycolytic enzymes: hexokinase, 6-phosphofructokinase, and pyruvate kinase. These enzymes are necessary for converting glucose into pyruvate. Wolbachia, however, has the full complement of genes required for gluconeogenesis starting with pyruvate, and for energy metabolism via the tricarboxylic acid cycle. Therefore, we hypothesized that Wolbachia might depend on host glycolysis to maintain a mutualistic association with their parasitic host. We did conditional experiments in vitro that confirmed that glycolysis and its end-product, pyruvate, sustain this symbiotic relationship. Analysis of alternative sources of pyruvate within the worm indicated that the filarial lactate dehydrogenase could also regulate the local intracellular concentration of pyruvate in proximity to Wolbachia and thus help control bacterial growth via molecular interactions with the bacteria. Lastly, we have shown that the parasite's pyruvate kinase, the enzyme that performs the last step in glycolysis, could be a potential novel anti-filarial drug target. Establishing that glycolysis is an essential component of symbiosis in filarial worms could have a broader impact on research focused on other intracellular bacteria-host interactions where the role of glycolysis in supporting intracellular survival of bacteria has been reported., Competing Interests: The authors have declared that no competing interests exist.

Diabetic hyperglycemia provokes glycation of haemoglobin (Hb), an abundant protein in red blood cells (RBCs), by increasing its exposure to carbohydrates. Acetylsalicylic acid (ASA; Aspirin) is one of the first agents, which its antiglycation effect was witnessed. Although the precise molecular mechanism of action of ASA on protein glycation is not indisputably perceived, acetylation as its main molecular mechanism has been proposed. This report aims to unravel the meticulous mechanism of action of ASA by using two ASA analogues; benzoic acid (BA) and para-nitrobenzoic acid (NBA), despite their lack of acetyl group. In this regard, the inhibitory effect of these two chemicals in comparison with ASA on Hb fructation is reported. UV-visible spectroscopy, intrinsic advanced glycation end products (AGE) fluorescence spectroscopy, extrinsic thioflavin T (ThT) binding fluorescence spectroscopy, 2,4,6-trinitrobenzenesulfonic acid (TNBSA) assay, and single cell gel electrophoresis (SCGE) were used to explore the effects of BA and NBA in comparison with aforementioned chemicals in the context of protein glycation. In spite of the lack of acetyl substitution, NBA is reported as a novel agent with prominent inhibitory efficacy than ASA on the protein glycation. This fact brings up a possible new mechanism of action of ASA and reconsiders acetylation as the sole mechanism of inhibition of protein glycation., Competing Interests: The authors have declared that no competing interests exist.

Background: The human filarial parasite Onchocerca volvulus is the causative agent of onchocerciasis (river blindness). It causes blindness in 270,000 individuals with an additional 6.5 million suffering from severe skin pathologies. Current international control programs focus on the reduction of microfilaridermia by annually administering ivermectin for more than 20 years with the ultimate goal of blocking of transmission. The adult worms of O. volvulus can live within nodules for over 15 years and actively release microfilariae for the majority of their lifespan. Therefore, protracted treatment courses of ivermectin are required to block transmission and eventually eliminate the disease. To shorten the time to elimination of this disease, drugs that successfully target macrofilariae (adult parasites) are needed. Unfortunately, there is no small animal model for the infection that could be used for discovery and screening of drugs against adult O. volvulus parasites. Here, we present an in vitro culturing system that supports the growth and development of O. volvulus young adult worms from the third-stage (L3) infective stage., Methodology/principal Findings: In this study we optimized the culturing system by testing several monolayer cell lines to support worm growth and development. We have shown that the optimized culturing system allows for the growth of the L3 worms to L5 and that the L5 mature into young adult worms. Moreover, these young O. volvulus worms were used in preliminary assays to test putative macrofilaricidal drugs and FDA-approved repurposed drugs., Conclusion: The culture system we have established for O. volvulus young adult worms offers a promising new platform to advance drug discovery against the human filarial parasite, O. volvulus and thus supports the continuous pursuit for effective macrofilaricidal drugs. However, this in vitro culturing system will have to be further validated for reproducibility before it can be rolled out as a drug screen for decision making in macrofilaricide drug development programs., Competing Interests: Cell Systems- 3D, LLC is a research for-profit contract research organization (CRO) whose focus is the development of 3-D in vitro models of human, veterinary or insect cells/tissues as investigatory platforms for development of successful countermeasures of infectious diseases and/or agents. MTS was the sole employee of Cell Systems-3D, LLC involved in this research effort. The company participation in Cell Systems-3D,LLC nor any current or past employee has a commercial or employment affiliation with the New York Blood Bank or the Bill and Melinda Gates Foundation. The Company participation in this publication is as a research co-investigator. MTS is the founder and Chief Science Officer of the company.

Objective: Gingivitis and poor oral hygiene status are the most prevalent oral diseases among primary school students. Poor oral hygiene status, gingivitis and socio-demographic determinants have been shown to be associated with periodontal diseases. There is limited information on the gingivitis and oral hygiene status among Iranian children. In the present study, the status of gingivitis, oral hygiene status, and their association with socio-demographic determinants among schoolchildren aged 7-12 years old in Hamadan were investigated., Methods: In this cross-sectional study, 988 primary school students aged 7-12 years old were selected. The oral hygiene status was measured through Simplified Oral Hygiene Index (OHI-S) and Community Periodontal Index (CPI) was used to evaluate gingival bleeding and calculus. CPI was measured using a standardized protocol to investigate gum bleeding and calculus. The oral hygiene was classified as good, fair or poor based on calculus and debris measurements. Age, gender, educational level, occupation and residence district of parents, dental pain experience in the last year and whether parents supervised their children while brushing were assessed by the questionnaires. The collected data were analyzed using descriptive statistics and logistic regression analysis., Results: The oral hygiene status was good in 644 students (65.20%), fair in 341 (34.50%) and poor in three (0.30%). Moreover, the results of CPI depicted that 639 students (64.07%) had healthy periodontium, 320 (32.40%) had periodontal bleeding and 29 (2.9%) were with calculus. Higher percentage of the boys in the age group of 12 years old had periodontal bleeding and fewer good oral hygiene. The results of CPI and OHI-S scores depicted that more than half of the primary school students had healthy gums and periodontium (64.1%) and good oral hygiene status (65.2%). There were significant statistical associations between age and residence district with calculus measured by the CPI, also between gender, age, residence district, and mother's occupation with the gingival bleeding measured by the CPI. Furthermore, age and mother's occupation were significantly associated with OHI-S index., Conclusions: In general, the periodontal health status is poorer in students attending suburban schools compared to those in urban schools in Hamadan. Since there are significant associations between gender, school districts and mother's occupation with oral hygiene index among schoolchildren in primary schools, considering them in schools' oral health program design might be useful., Competing Interests: The authors have declared that no competing interests exist.

Objective: To study the effects of customer self-audit on the service quality (SQ) and customer quality (CQ) of maternity care., Design: A community-based cluster-randomized controlled trial., Setting: Twenty-one health centres and health posts in Tabriz, Iran., Participants: Of 21 health centres/health posts, 10 were randomly assigned to the intervention group and 11 randomly assigned to the control group. Participants were 185 pregnant women selected from health centre/post registration lists (intervention group: n = 92; control group: n = 93)., Interventions: The intervention was a customer self-audit based on the CenteringPregnancy® model of prenatal group care. The intervention group attended group support sessions focused on participants' opinions, questions, and self-management concerns. They also received sessions on experiential learning, coping, problem-solving, and goal-setting by a family health expert, a midwife, and a doctor. Control group participants continued to receive individual care., Primary Outcome Measures: SQ and CQ were assessed using questionnaires. Patients rated the importance and performance of non-health quality dimensions. SQ was calculated as: SQ = 10 - (Importance × Performance)., Results: Total mean SQ scores were 7.63 (0.91) and 8.91 (0.76) for the control and intervention groups, respectively, a statistically significant difference (p<0.001). Compared with the control group, the intervention group scored higher on the SQ aspects confidentiality, communication, autonomy, availability of support group, dignity, safety, prevention, and accessibility. Total mean CQ scores for the control and intervention groups were 82.63(7.21) and 87.47 (6.75), respectively, a statistically significant difference (p<0.001). After intervention, 82.6% of intervention group participants and 50.5% of control group participants reached the highest stage of self-management, showing an ability to take care of themselves under stress and financial constraints., Conclusions: The group prenatal care customer self-audit improved the SQ and CQ of maternity care by increased involvement of participants and giving them active roles in the care process., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0197117.].

HIV treatment in Canada has rapidly progressed with the advent of new drug therapies and approaches to care. With this evolution, there is increasing interest in Canada in understanding the current delivery of HIV care, specifically where care is delivered, how, and by whom, to inform the design of care models required to meet the evolving needs of the population. We conducted a cross-sectional survey of Canadian care settings identified as delivering HIV care between June 2015 and January 2016. Given known potential differences in delivery approaches, we stratified settings as primary care or specialist settings, and described their structure, geographic location, populations served, health human resources, technological resources, and available clinical services. We received responses from 22 of 43 contacted care settings located in seven Canadian provinces (51.2% response rate). The total number of patients and HIV patients served by the participating settings was 38,060 and 17,678, respectively (mean number of HIV patients in primary care settings = 1,005, mean number of HIV patients in specialist care settings = 562). Settings were urban for 20 of the 22 (90.9%) clinics and 14 (63.6%) were entirely HIV focused. Primary care settings were more likely to offer preventative services (e.g., cervical smear, needle exchange, IUD insertion, chronic disease self-management program) than specialist settings. The study illustrates diversity in Canadian HIV care settings. All settings were team based, but primary care settings offered a broader range of preventative services and comprehensive access to mental health services, including addictions and peer support., Competing Interests: The authors have declared that no competing interests exist.

Background and Aims: Advanced liver fibrosis is an important predictor of liver disease progression and mortality, and current guidelines recommend screening for complications of cirrhosis once patients develop F3 fibrosis. Our study compared liver disease progression and survival in patients with stage 3 (F3) and stage 4 (F4) fibrosis on liver biopsy., Methods: Retrospective study of patients with F3 or F4 on liver biopsy followed for development of liver disease complications (variceal bleeding, ascites, and hepatic encephalopathy); hepatocellular carcinoma, and survival (overall and transplant free survival)., Results: Of 2488 patients receiving liver biopsy between 01/02 and 12/12, a total of 294 (171 F3) were analyzed. Over a median follow up period of 3 years, patients with F4 (mean age 53 years, 63% male) compared to F3 (mean age 49 years, 43% male) had higher five year cumulative probability of any decompensation (38% vs. 14%, p<0.0001), including variceal bleed (10% vs. 4%, p = 0.014), ascites (21% vs. 9%, p = 0.0014), and hepatic encephalopathy (14% vs. 5%, p = 0.003). F4 patients also had lower overall 5-year survival (80% vs. 93%, p = 0.003) and transplant free survival (80% vs. 93%, p = 0.002). Probability of hepatocellular carcinoma in 5 years after biopsy was similar between F3 and F4 (1.2% vs. 2%, p = 0.54)., Conclusions: Compared to F4 stage, patients with F3 fibrosis have decreased risk for development of liver disease complications and better survival. Prospective well designed studies are suggested with large sample size and overcoming the limitations identified in this study, to confirm and validate these findings, as basis for modifying guidelines and recommendations on follow up of patients with advanced fibrosis and stage 3 liver fibrosis.

[This corrects the article DOI: 10.1371/journal.pone.0191723.].

Repeated cycles of antibody-directed enzyme pro-drug therapy (ADEPT) and the use of glucarpidase in the detoxification of cytotoxic methotrexate (MTX) are highly desirable during cancer therapy but are hampered by the induced human antibody response to glucarpidase. Novel variants of glucarpidase (formal name: carboxypeptidase G2, CPG2) with epitopes not recognized by the immune system are likely to allow repeated cycles of ADEPT for effective cancer therapy. Towards this aim, over two thousand soil samples were collected and screened for folate hydrolyzing bacteria using folate as the sole carbon source. The work led to the isolation and the characterization of three new glucarpidase producing strains, which were designated as: Pseudomonas lubricans strain SF168, Stenotrophomonas sp SA and Xenophilus azovorans SN213. The CPG2 genes of Xenophilus azovorans SN213 (named Xen CPG2) and Stenotrophomonas sp SA (named Sten CPG2) were cloned and molecularly characterized. Both Xen CPG2 and Sten CPG2 share very close amino acid sequences (99%); we therefore, focused on the study of Xen CPG2. Finally, we demonstrated that a polyclonal antibody raised against our new CPG2, Xen CPG2, does not react with the CPG2 from Pseudomonas sp. strain RS-16 (Ps CPG2) that are currently in clinical use. The two enzymes, therefore could potentially be used consecutively in the ADEPT protocol to minimize the effect of the human antibody response that hampers current treatment with Ps CPG2. The identified novel CPG2 in this study will, therefore, pave the way for safer antibody directed enzyme pro-drug therapy for cancer treatment.