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Methicillin-resistant Staphylococcus aureus (MRSA) mastitis poses a significant threat to dairy herds worldwide, given its resistance to methicillin and other β-lactam antibiotics, which often leads to treatment failure. Consequently, there is an urgent need for safe and effective alternative therapeutic approaches. Recent investigations have highlighted the potential of baicalein, a natural flavonoid known for its potent anti-inflammatory and antibacterial properties, especially its synergistic effects with β-lactam antibiotics against MRSA. However, the limited solubility and bioavailability of baicalein hinder its biomedical utility. The present study assessed the therapeutic efficacy of encapsulated baicalein in chitosan, forming a tricomplex with a β-lactam antibiotic, using a murine model of MRSA-induced mastitis. The experimental design comprised seven groups, each consisting of six mice. We evaluated the ability of various treatment regimens to mitigate histopathological alterations and bacterial burden induced by MRSA infection, aiming to elucidate underlying mechanisms. Our results revealed that tricomplex treatment significantly reduced bacterial load in mammary tissue and preserved tissue integrity, resulting in decreased inflammatory responses post-MRSA inoculation. In addition, tricomplex treatment markedly reduced mean leukocyte and neutrophil counts in blood and suppressed the matrix metalloproteinase-9 (MMP-9) concentration and C-reactive protein (CRP) response. Notably, the synergistic interaction between baicalein and amoxicillin was particularly pronounced. Our findings suggest that chitosan-encapsulated baicalein combined with a β-lactam antibiotic holds promise as a therapeutic option for MRSA-induced mastitis. Further investigations, particularly in target animal species, are warranted to comprehensively evaluate its clinical feasibility.

Abstract Background Extreme Risk Protection Orders (ERPOs) are civil court orders that prohibit firearm purchase and possession when someone is behaving dangerously and is at risk of harming themselves and/or others. As of June 2024, ERPOs are available in 21 states and the District of Columbia to prevent firearm violence. This paper describes the design and protocol of a six-state study of ERPO use. Methods The six states included are California, Colorado, Connecticut, Florida, Maryland, and Washington. During the 3-year project period (2020–2023), ERPO case files were obtained through public records requests or through agreements with agencies with access to these data in each state. A team of over four dozen research assistants from seven institutions coded 6628 ERPO cases, abstracting 80 variables per case under domains related to respondent characteristics, events and behaviors leading to ERPO petitions, petitioner types, and court outcomes. Research assistants received didactic training through an online learning management system that included virtual training modules, quizzes, practice coding exercises, and two virtual synchronous sessions. A protocol for gaining strong interrater reliability was used. Research assistants also learned strategies for reducing the risk of experiencing secondary trauma through the coding process, identifying its occurrence, and obtaining help. Discussion Addressing firearm violence in the U.S. is a priority. Understanding ERPO use in these six states can inform implementation planning and ERPO uptake, including promising opportunities to enhance safety and prevent firearm-related injuries and deaths. By publishing this protocol, we offer detailed insight into the methods underlying the papers published from these data, and the process of managing data abstraction from ERPO case files across the multi-state and multi-institution teams involved. Such information may also inform future analyses of this data, and future replication efforts. Registration This protocol is registered on Open Science Framework ( https://osf.io/kv4fc/ ).

Purpose: To compare the clinical outcomes and surgical safety between femtosecond laser-assisted cataract surgery (FLACS) and conventional phacoemulsification cataract surgery (CPCS) in vitrectomized eyes. Methods: A prospective interventional comparative study was conducted at a tertiary eye care center. Sixty consecutive cases requiring cataract surgery following pars plana vitrectomy were allocated into Group 1 (n = 30), who underwent FLACS with intraocular lens implantation, and Group 2 (n = 30), who underwent CPCS with intraocular lens implantation, and followed up for 3 months. Primary outcome measures were intraoperative ultrasonic cumulative dissipated energy (CDE) and intraoperative and postoperative complications. The secondary outcome measures were postoperative changes in endothelial cell count (ECC) and central corneal thickness (CCT). Results: Baseline corrected distance visual acuity (CDVA), ECC, and CCT were comparable. Intraoperative CDE was significantly less in the FLACS group (8.11 vs. 15.83 percentage seconds; P = 0.012) with no intraoperative complication in either group. The postoperative CDVA was comparable between the groups with a trend toward earlier visual recovery in the FLACS group. The postoperative day (POD) 1 endothelial cell loss was higher in the CPCS group (7.54% vs. 2.05%), with the mean endothelial cell density being significantly higher in the FLACS group throughout the follow-up period (P < 0.05). POD-1 corneal edema was higher in the CPCS group compared to FLACS with no significant difference on follow-up. Intraoperative migration of silicone oil to the anterior chamber was observed in 40% versus 0% in the CPCS versus FLACS groups, respectively. Conclusion: FLACS can be safely performed in post-vitrectomy eyes with lesser intraoperative ultrasonic energy used, postoperative endothelial cell loss, and change in CCT compared to CPCS.

Background: Post-spinal anesthesia shivering in cesarean section is a common complication owing to sympatholysis, resulting in vasodilation and heat redistribution from the core to peripheral parts of the body. The physiological consequences of shivering include an increase in cardiac and systemic energy expenditure, oxygen consumption, and carbon dioxide production. Ketamine, a N-methyl D-aspartate (NMDA) receptor antagonist, has been reported to have anti-shivering effects. The aim of this study is to determine the effectiveness of prophylactic low-dose intravenous (IV) ketamine (0.25 mg/kg) in preventing shivering after spinal anesthesia as compared to placebo in elective cesarean sections. Methods: A randomized, double-blind study was conducted on 80 patients aged 18 to 40 years and American Society of Anesthesiologists grade II undergoing elective cesarean section under spinal anesthesia. Groups K and group S received IV ketamine 0.25 mg/kg diluted to 5 ml in normal saline and 5 ml normal saline IV, respectively, 10 minutes after spinal anesthesia. The incidence and duration of shivering, tympanic membrane temperature, sedation score, hemodynamic parameters, and side effects were recorded. Results: The incidence of shivering in group K was 12.5% compared to 32.5% in group S (P = 0.030). The mean duration of shivering was only 0.75 ± 2.02 min in group K as compared to 2.38 ± 3.57 min in group S (P = 0.014). Mean arterial pressure and heart rate were stable in group K without any significant sedative effect. Conclusion: The use of prophylactic low-dose ketamine (0.25 mg/kg) significantly reduces the incidence and duration of spinal anesthesia-induced shivering compared to placebo.

Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is dose dependent nerve damaging adverse reaction with prevalence rate of 68.1% at the 1st month; 60.0 % at the 3rd month; and 30% at the 6th month of chemotherapy. Objective: to determine the effectiveness of an Intervention (Effleurage and Petrissage) on severity of CIPN among patients receiving chemotherapy Methods: 60 patients either having third or fourth cycle of platinum based chemotherapy were subjected to quantitative approch. Random assignment were used among two groups with a pre- and post-test design. Interventional group received effleurage and petrissage prior to chemotherapy for a period of one month and comparison of CIPN level among both groups were done at 7th, 14th, 21st day & 1st month by using FACT/GOG-Ntx subscale. Results: Pretest Mean+SD of CIPN in Intervention (17.17+4.907) and in Conventional care (17.10+ 4.421) group at t valve .055 and p value .956NS as measured by FACT/GOG-Ntx subscale. Posttest Mean+SD of CIPN in intervention (10.70±2.855) and conventional care (16.27±3.039) group after receiving effleurage and petrissage for one month at p value 0.000*. Conclusions: Study concludes that Intervention (Effleurage and Petrissage) is effective, lucrative for decline in CIPN level among patients.

Contexte : La neuropathie périphérique induite par la chimiothérapie est un effet secondaire du traitement qui dépend de la dose reçue et qui endommage les nerfs; les taux de prévalence rapportés sont de 68,1 % après 1 mois de traitement, de 60,0 % après 3 mois et de 30,0 % après 6 mois. But de l’étude : Déterminer l’efficacité d’une intervention de massothérapie (par effleurage et pétrissage) sur l’intensité de la neuropathie périphérique chez les patients recevant de la chimiothérapie à base de platine. Méthodologie : Soixante (60) patients qui en étaient à leur troisième ou quatrième cycle de chimiothérapie à base de platine ont été assignés de façon aléatoire à l’un des deux groupes selon un devis de type pré-test/post-test. Pendant un mois, le groupe expérimental a reçu des massages par effleurage et pétrissage avant les séances de chimiothérapie. La comparaison entre les niveaux d’intensité de la neuropathie périphérique a été effectuée à l’aide de la sous-échelle FACT/GOG-Ntx pour Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity subscale (échelle d’évaluation fonctionnelle du traitement du cancer/groupe d’oncologie gynécologique – sous-échelle de neurotoxicité) après 7 jours, 14 jours, 21 jours et 28 jours, Résultats : Avant l’intervention, le score moyen (+ÉT) d’intensité de la neuropathie périphérique induite par la chimiothérapie était de 17,17 (+4,907) dans le groupe expérimental et de 17,10 (+4,421) dans le groupe témoin (t = 0,055, p = 0,956). Les scores moyens post-test (+ÉT) après 28 jours étaient de 10,70 (±2,855) dans le groupe expérimental et de 16,27 (±3,039) dans le groupe témoin (p = 0,000). Conclusion : Les résultats du présent essai clinique pilote confirment l’efficacité de l’intervention (massage par effleurage et pétrissage) pour réduire l’intensité de la neuropathie périphérique induite par la chimiothérapie à base de platine.

Introduction: Breast cancer is the second most prevalent disease among women in India and one of the most dangerous and lethal. Chemotherapy-treated breast cancer patients may have perceived stress, which is defined as emotions of mental or physical exhaustion that make them feel angry or anxious. Mindfulness-based intervention (MBI) gives some ideas in line with the conventional mindfulness technique. Purposes: (i) To assess the effect of MBI on perceived stress among breast cancer patients undergoing chemotherapy. (ii) To determine the association between perceived stress with selected demographic variables among breast cancer patients undergoing chemotherapy. Methods: The current quantitative pre- and postexperimental study was carried out in two oncology departments of selected cancer hospitals, Bhubaneswar. A total number of 40 breast cancer patients of perceived stress receiving chemotherapy and data were gathered by using a self-structured socio-demographic proforma and a structured Perceived Stress Scale 10. The experimental group received MBI, and a posttest was conducted on the 17th day on both the groups after 10 days of the termination of intervention. This MBI was provided to breast cancer patients for five sessions over five days continuously, each session for 45 min with mindfulness breathing exercises, progressive muscle relaxation techniques, practising meditation, and guided imagery technique. Results: The study findings illustrated that reduction of perceived stress among female breast cancer patients undergoing chemotherapy with (t = 2.2463) (P = 0.0306) at the P < 0.05; furthermore, there is one socio-demographic variable which had association with perceived stress that is history of psychiatric illness (χ2 = 14.1176) (P = 0.0009) and others had no association with perceived stress. Conclusion: MBI was an effective therapy for reducing the perceived stress of breast cancer patients undergoing chemotherapy.

Practical reason is the use of reason to decide how to act and perform in a social reality. When someone deliberates about what to do, one puts all the reasons for the action, and then all the reasons against the action will determine the outcome of the action. In that situation, we can describe that practical action with reason because we will determine reason with the weight of different reasons not on the weighing reasons. In this paper, we analyze that reasons have weight against the theory that weights of reasons have no role in a theory of reasoning, and defend that reasons have weight with the evidence of practical reasons. The aim of this paper is to argue that weight of reasons has a role in the process of reasoning. In every situation of life, we can use have reason and weight of reason according to the practical situation of life.

Abstract The present study was aimed at showing the importance of HPV DNA status and the clinical history of the patients required by the cytologist for accurate reporting. A total of 1250 symptomatic women who attended the gynaecology outpatient department of the Mahavir Cancer Sansthan and Nalanda Medical College, Patna, for pap smear examinations were screened and recruited for the study. Due to highly clinical symptoms out of the negative with inflammatory smears reported, one hundred and ten patients were randomly advised for biopsy and HPV 16/18 DNA analysis by a gynaecologist to correlate negative smears included in the study. Pap smear reports revealed that 1178 (94.24%) were negative for intraepithelial lesions (NILM) with inflammatory smears, 23 (1.84%) smears showed low-grade squamous intraepithelial lesions (LSIL), 12 (0.96%) smears showed high-grade squamous intraepithelial lesions, and 37 (2.96%) smears showed an atypical squamous cell of undetermined significance (ASC-US). A biopsy of 110 out of 1178 (NILM) patients revealed that 15 (13.63%) women had cervical cancer, 29 women had CIN I, 17 women had CIN II + CIN III, 35 women had benign cervical changes, and 14 women had haemorrhages. On the other hand, HPV 16/18 DNA was detected as positive in 87 out of 110. The high positivity of HPV in biopsied cases where frank cervical cancer and at-risk cancer were also observed in the negative smear-screened patients reveals that the HPV status and clinical history of the patients will be quite helpful to the cytologist for accurate reporting, and suggests that a negative HPV DNA result may be a stronger predictor of cervical cancer risk than a negative Pap test.

Aim: Synthetic inorganic materials are commonly used as reinforcing agents in polyetheretherketone (PEEK) composite, whereas natural organic plant-based reinforcing agents are negligible. Surface hardness, roughness, and wettability are indicative factors of osseointegration behavior to be used as an implant material. This study evaluated micro surface hardness (MSH), nano surface hardness (NSH), surface roughness (SR), and contact angle (CA) of PEEK-Azadirachta indica reinforced at 10 wt%, 20 wt%, and 30 wt%. Settings and Design: This was an in vitro study. Materials and Methods: Neem (A. indica) leaf nanoparticles were prepared and reinforced with PEEK powder at 10%, 20%, and 30% weight ratios by injection molding. Sixty specimens underwent the microhardness and CA testing using a digital microhardness tester, and CA goniometer, respectively, and later nanoindentation test to analyze the nanohardness and SR. Statistical Analysis Used: A one-way ANOVA test with a 95% confidence interval for MSH and NSH, SR, and CA was performed on the samples. A post hoc Bonferroni test was conducted (α = 0.05) to compare the groups. Results: There was a significant increase in nanohardness (P = 0.000) with zero difference in microhardness (P = 0.514). The addition of 10 wt%, 20 wt%, and 30 wt% nanoparticles increased the SR value of the pure PEEK from 273.19 nm to 284.10 (3.99%), 296.91 (8.68%), and 287.54 (5.24%), respectively. In the analysis of the CA, CA 20% shows the lowest angle (63.69) with the highest for control specimens (82.39). There is an increase in the PEEK composite SR with a decrease in CA. Conclusions: The addition of plant-derived nanoparticles into the PEEK matrix has a significant impact on the hardness and hydrophobicity enhancing cell growth and osteoblastic differentiation during osseointegration of dental implants.

Abstract Background Prognosis of DKA has improved over time with the availability of evidence-based protocols and resources. However, in Kenya, there are limited resources for the appropriate diagnosis and management of DKA, mostly limited to tertiary-level referral facilities. This study aimed to review the clinical presentation, management, and outcomes of adult patients admitted with DKA and assess differences in these parameters before and during the COVID-19 pandemic. Methods This was a retrospective study of DKA admissions from January 2017 to December 2021. Patient data were retrieved from the medical records department using ICD-10 codes, and individual details were abstracted on clinical presentation, management, and outcomes of DKA. Comparisons were made between pre-COVID-19 and during COVID-19 durations. Results 150 patients admitted with DKA were included (n = 48 pre- COVID-19, n = 102 during COVID-19 (n = 23 COVID-19 positive, n = 79 COVID-19 negative)). Median age was 47 years (IQR 33.0, 59.0), median HbA1C was 12.4% [IQR 10.8, 14.6]), and most patients had severe DKA (46%). Most common DKA precipitants were infections (40.7%), newly diagnosed diabetes (33.3%) and missed medication (25.3%). There was a significant difference in pulmonary infections as a DKA precipitant, between the pre- COVID and during COVID-19 pandemic (21.6% during COVID-19 versus 6.3% pre- COVID-19; p = 0.012). Median total insulin dose used was 110.0 units [IQR 76.0, 173.0], and a 100% of patients received basal insulin. Median length of hospital stay was 4.0 days [IQR 3.0, 6.0] and time to DKA resolution was 30.0 h [IQR 24.0, 48.0]. There were 2 deaths (1.3%), none directly attributable to DKA. Severity of DKA significantly differed between pre- COVID-19, COVID-19 positive and COVID-19 negative DKA (52.2% of COVID-19 positive had moderate DKA compared to 26.6% of COVID-19 negative and 22.9% of Pre-COVID-19 (p = 0.006)). Conclusion Even in developing regions, good outcomes can be achieved with the appropriate facilities for DKA management. Clinician and patient education is necessary to ensure early detection and prompt referral to avoid patients presenting with severe DKA. Exploratory studies are needed to assess reasons for prolonged time to DKA resolution found in this study.

Abstract Due to the increasing importance of exposome in environmental epidemiology, feasibility and usefulness of an Environmental Data Management System (EDMS) using Open Data was evaluated. The EDMS includes data from 10 European cities (Celje (Slovenia), Łódź (Poland), Manchester (UK), Palermo (Italy), Paris (France), Porto (Portugal), Regensburg (Germany), Reus (Spain), Rijeka (Croatia), Thessaloniki (Greece)) about external non-specific and specific exposome factors at the city or country level (2017–2020). Findings showed that the highest values of life expectancy were in Reus females (86 years) and Palermo males (81 years). UK had the highest obesity rate (28%), Croatia the highest prescribed drug consumption (62%), Greece and Portugal the highest smoking rates (37%, 42%) and daily alcohol consumption (21%), respectively. The most polluted cities were Thessaloniki for PM10 (38 µg/m3), Łódź for PM2.5 (25 µg/m3), Porto for NO2 (62 µg/m3) and Rijeka for O3 (92 µg/m3). Thessaloniki had the highest grey space (98%) and Łódź the highest cumulative amount of pollen (39,041 p/m3). The highest daily noise levels ≥ 55 dB was in Reus (81% to traffic) and Regensburg (21% to railway). In drinking water, arsenic had the highest value in Thessaloniki (6.4 µg/L), boron in Celje (24 mg/L) and lead in Paris (46.7 µg/L). Portugal and Greece showed the highest pesticide residues in food (7%). In conclusion, utilizing open-access databases enables the translation of research findings into actionable strategies for public health interventions.

Abstract Background Mercury (Hg) is highly toxic and has the potential to cause severe health problems for humans and foraging animals when transported into edible plant parts. Soil rhizobia that form symbiosis with legumes may possess mechanisms to prevent heavy metal translocation from roots to shoots in plants by exporting metals from nodules or compartmentalizing metal ions inside nodules. Horizontal gene transfer has potential to confer immediate de novo adaptations to stress. We used comparative genomics of high quality de novo assemblies to identify structural differences in the genomes of nitrogen-fixing rhizobia that were isolated from a mercury (Hg) mine site that show high variation in their tolerance to Hg. Results Our analyses identified multiple structurally conserved merA homologs in the genomes of Sinorhizobium medicae and Rhizobium leguminosarum but only the strains that possessed a Mer operon exhibited 10-fold increased tolerance to Hg. RNAseq analysis revealed nearly all genes in the Mer operon were significantly up-regulated in response to Hg stress in free-living conditions and in nodules. In both free-living and nodule environments, we found the Hg-tolerant strains with a Mer operon exhibited the fewest number of differentially expressed genes (DEGs) in the genome, indicating a rapid and efficient detoxification of Hg from the cells that reduced general stress responses to the Hg-treatment. Expression changes in S. medicae while in bacteroids showed that both rhizobia strain and host-plant tolerance affected the number of DEGs. Aside from Mer operon genes, nif genes which are involved in nitrogenase activity in S. medicae showed significant up-regulation in the most Hg-tolerant strain while inside the most Hg-accumulating host-plant. Transfer of a plasmid containing the Mer operon from the most tolerant strain to low-tolerant strains resulted in an immediate increase in Hg tolerance, indicating that the Mer operon is able to confer hyper tolerance to Hg. Conclusions Mer operons have not been previously reported in nitrogen-fixing rhizobia. This study demonstrates a pivotal role of the Mer operon in effective mercury detoxification and hypertolerance in nitrogen-fixing rhizobia. This finding has major implications not only for soil bioremediation, but also host plants growing in mercury contaminated soils.

Irrespective of medical technology improvements, cancer ranks among the leading causes of mortality worldwide. Although numerous cures and treatments exist, creating alternative cancer therapies with fewer adverse side effects is vital. Since ancient times, plant bioactive compounds have already been used as a remedy to heal cancer. These plant bioactive compounds and their anticancer activity can also deregulate the microRNAs (miRNAs) in the cancerous cells. Therefore, the deregulation of miRNAs in cancer cells by plant bioactive compounds and the usage of the related miRNA could be a promising approach for cancer cure, mainly to prevent cancer and overcome chemotherapeutic side effect problems. Hence, this review highlights the function of plant bioactive compounds as an anticancer agent through the underlying mechanism that alters the miRNA expression in cancer cells, ultimately leading to apoptosis. Moreover, this review provides insight into using plant bioactive compounds -driven miRNAs as an anticancer agent to develop miRNA-based cancer gene therapy. They can be the potential resource for gene therapy and novel strategies targeting cancer therapeutics.

ABSTRACTDesmosomes are intercellular junctions that regulate mechanical integrity in epithelia and cardiac muscle. Dynamic desmosome remodeling is essential for wound healing and development, yet the mechanisms governing junction assembly remain elusive. While we and others have shown that cadherin ectodomains are highly organized, how this ordered architecture emerges during assembly is unknown. Using fluorescence polarization microscopy, we show that desmoglein 2 (Dsg2) ectodomain order gradually increases during 8 h of assembly, coinciding with increasing adhesive strength. In a scratch wound assay, we observed a similar increase in order in desmosomes assembling at the leading edge of migratory cells. Together, our findings indicate that cadherin organization is a hallmark of desmosome maturity and may play a role in conferring adhesive strength.

Background: Molecular detection is considered benchmark criteria for SARS-CoV-2 diagnosis. Both computer tomography (CT) chest imaging and reverse transcriptase polymerase chain reaction (RTPCR) can give false-negative test results in the initial state of coronavirus infection. This study aimed to assess the precision of computer tomography (CT) chest imaging and RTPCR assay and to compare the role of CT chest imaging and molecular testing (RTPCR) in the early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Methods: Retrospective analysis of 588 clinically suspected coronavirus disease cases was performed over from April 2021 to June 2021. RTPCR test result was compared with chest computer tomography and diagnostic precision of computer tomography (CT) scan was determined using RTPCR as reference standard. Categorical variables were statistically analyzed as frequencies and percentages. Results: Out of 465 patients who tested positive by chest computer tomography (CT) scan findings, 132 (28.39%) tested RTPCR positive and 333 (71.61%) tested RTPCR negative. 306/465 (65.81%) cases showed moderate-to-severe infection and 159/465 (34.19%) had mild infection. Diagnostic precision of imaging chest computer tomography (CT) scan was observed to be 38.44%. Low sensitivity of RTPCR detection method in the early identification of coronavirus disease was observed. Conclusion: The use of computer tomography (CT) scan in the early detection of coronavirus disease is supplemental to RTPCR assay and is limited to the detection of laboratory-confirmed coronavirus disease cases as imaging characteristics of SARS-CoV-2 pneumonia superimposed with other types of pneumonia.

Formulating a research question and selecting an appropriate study design for answering that question are crucial initial steps in the research process. The population, intervention, control group, and outcomes measures (PICO time and setting [TS]) framework provides a practical guide in this regard, which stands for population, intervention, control, outcome, type of research question, and study design. The various study designs have their own merits and demerits, and implementing the methodology meticulously requires knowledge of all of these. Similarly, different methods of sample size calculation are warranted based on the most appropriate study design and outcome variables of interest. Sometimes, a post hoc power analysis can be performed after the sample size calculation, to check whether the study was adequately powered or not. There are multiple validated free software tools for sample size calculation, including Open-Epi, R, StatCalc, etc. The practice by most researchers of reporting significant P values is to be replaced by reporting effect sizes, as the latter is a much better estimate of the strength of association. This review provides a comprehensive, ready reckoner for busy family physicians to quickly identify the appropriate study design for answering any applied research questions in their minds and estimating the sample size required for the same.

Background: Laryngoscopy, endotracheal intubation, and creation of pneumoperitoneum during laparoscopic cholecystectomy cause sympathetic stimulation manifesting as hypertension, tachycardia, arrhythmia, and myocardial ischemia. Methods: We undertook this study to determine the effect of oral clonidine premedication on perioperative hemodynamics, postoperative pain, and sedation for patients undergoing laparoscopic cholecystectomy. In this double-blinded randomized controlled trial, 100 American Society of Anesthesiologists Grades I and II patients scheduled for laparoscopic cholecystectomy were randomized into 2 groups to receive 100 μg tablet clonidine in Group I and ranitidine 150 mg tablet in Group II (control group) 90 min before induction of general endotracheal anesthesia. Effect on hemodynamic parameters, duration of analgesia, requirement of rescue analgesic, and sedation score was assessed. Data were expressed as mean ± standard deviation or number (proportion). Unpaired t-test and Chi-square test were applied wherever indicated. P < 0.05 was considered statistically significant. Results: Patients in the clonidine group had lower systolic blood pressure, diastolic blood pressure, mean arterial pressure, and heart rate values as compared to control group at all measured time intervals (P < 0.05). The duration of analgesia was prolonged in the clonidine group (256.6 ± 34.97 min vs. 103.4 ± 10.94 min, P = 0.000). Total amount (88.50 ± 29.11 mg vs. 165.00 ± 30.31 mg, P = 0.000) and number of doses (1.18 ± 0.39 vs. 2.20 ± 0.40, P = 0.000) of rescue analgesic requirement in 1st 24 h postoperative period were also lesser in clonidine group. The sedation score was higher in clonidine group just after extubation (2.24 ± 0.43) as compared to the placebo group (1.92 ± 0.40, P = 0.000) at 1 h of postoperative period. Conclusion: Premedication with 100 μg clonidine provides stable hemodynamics against stress response triggered by the creation of pneumoperitoneum, laryngoscopy, and endotracheal intubation in patients undergoing laparoscopic cholecystectomy and also prolongs the duration of postoperative analgesia with reduced requirement of rescue analgesics without causing prolonged postoperative sedation.

ABSTRACT: The pressing issue of the moment affecting public health is antimicrobial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is an emerging pathogen that is proven to be resistant to a range of antibiotics like penicillins, cephalosporins, other β ββ-lactam antibiotics, and carbapenems. Baicalein, a phytochemical of the traditional Chinese herb, Scutellaria baicalensis has an inhibitory effect on different bacteria. The current study aimed to investigate the synergistic effect of baicalein and β ββlactam antibiotics (amoxicillin and ampicillin) against methicillin-resistant S. aureus (MRSA). The minimum inhibitory concentrations (MICs) of baicalein and β-lactam antibiotics (amoxicillin and ampicillin) against the MRSA were determined through the broth dilution method. The determination of synergism was tested by checkerboard tube dilution and time-kill assay procedure. The combination of baicalein with amoxicillin showed more potent synergy against MRSA strain compared to the combination of baicalein and ampicillin. The fractional inhibitory concentration indices (FICI) of amoxicillin + baicalein varied from 0.19 to 0.50. The fractional inhibitory concentration (FIC) indices of ampicillin + baicalein varied from 0.19 to 0.25. These findings offer significant evidence that the amoxicillin combined with baicalein showed potent synergistic activity against MRSA in vitro and might offer promising therapeutic implications for MRSA infections.

Abstract Background Untreated hepatitis C virus (HCV) infection can result in cirrhosis and hepatocellular cancer. Direct-acting antiviral (DAA) therapies are highly effective and have few side effects compared to older interferon-based therapy. Despite the Australian government providing subsidised and unrestricted access to DAA therapy for chronic HCV infection, uptake has not been sufficient to meet the global target of eliminating HCV as a public health threat by 2030. This study will offer people with HCV financial incentives of varying values in order to evaluate its effect on initiation of DAA therapy in primary care. Methods Australian adults (18 years or older) who self-report as having current untreated HCV infection can register to participate via an automated SMS-based system. Following self-screening for eligibility, registrants are offered a financial incentive of randomised value (AUD 0 to 1000) to initiate DAA therapy. Study treatment navigators contact registrants who have consented to be contacted, to complete eligibility assessment, outline the study procedures (including the requirement for participants to consult a primary care provider), obtain consent, and finalise enrolment. Enrolled participants receive their offered incentive on provision of evidence of DAA therapy initiation within 12 weeks of registration (primary endpoint). Balanced randomisation is used across the incentive range until the first analysis, after which response-adaptive randomisation will be used to update the assignment probabilities. For the primary analysis, a Bayesian 4-parameter EMAX model will be used to estimate the dose–response curve and contrast treatment initiation at each incentive value against the control arm (AUD 0). Specified secondary statistical and economic analyses will evaluate the effect of incentives on adherence to DAA therapy, virological response, and cost-effectiveness. Discussion This project seeks to gain an understanding of the dose–response relationship between incentive value and DAA treatment initiation, while maximising the number of people treated for HCV within fixed budget and time constraints. In doing so, we hope to offer policy-relevant recommendation(s) for the use of financial incentives as a pragmatic, efficient, and cost-effective approach to achieving elimination of HCV from Australia. Trial registration ANZCTR (anzctr.org.au), Identifier ACTRN12623000024640, Registered 11 January 2023 ( https://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=384923&isReview=true ).

Background The keystone design perforator island flap (KDPIF) is unique among local flaps because of its high potential for adaptation. We describe our experience with the use of the keystone flap for the reconstruction of a variety of defects in different regions of the body concerning its versatility, surgical outcomes, complications, postoperative pain, operative time, and esthetic outcomes.

Introduction: The Sunderban area of West Bengal is home to tribal and religious minorities inhabiting various islands. There is a high prevalence of thalassemia among poverty-stricken residents of this region living with meagre health care facilities. This work was planned to determine the proportion of four viral transfusion-transmitted infections (TTIs): HIV-1, HIV-2, hepatitis B virus (HBV) and hepatitis C virus (HCV) among thalassemia patients attending the sole rural medical college in the region. Materials and Methods: Thalassemia patients (n = 359, age ranging from 1 year to 60 years) attending the thalassemia clinic or being admitted to the indoor facilities for better management were included in the study. Only patients diagnosed with high-performance liquid chromatography (HPLC) and with classical clinical features were included in the study. Blood samples of these patients were tested for HIV as per NACO protocol. For HBV and HCV, samples were first tested serologically; reactive samples were collected and sent in the cold chain to a higher centre for nucleic acid amplification testing (NAAT) for qualitative and quantitative estimation. Clinical and laboratory data was collected, patients were followed up for complications and hospitalisation during the study period, and statistical analysis was performed. Results: Majority of our patients had E-beta-thalassemia (245, 59.81%), followed by beta-thalassemia major (102, 28.30%). NAAT-confirmed HCV infection (14.21%) infection was the most common, followed by HBV (2.51%), and lastly by HIV-1 (0.58%) infection. Among infected thalassemia patients, the mean HCV RNA was 741063 ± 438514.67 IU/ml while the mean HBV DNA level was 4082863 ± 7298514 IU/ml. Co-infections of HIV-1 and HCV and that of HBV and HCV were noted in one patient each (0.28%). HCV-related liver disease (14.21%) and growth retardation (10.31%) were the most typical complication noted, and death occurred in five patients (1.39%) during the study period. Conclusion: Primary care physicians should know HCV infection is the most common TTI among thalassemia patients in rural eastern India.

Abstract The ever-growing threats in cybersecurity growing with the rapid development of quantum computing, necessitates the development of robust and quantum-resistant cryptographic systems. This paper introduces a novel cryptosystem, Public Key Cryptosystem based on Systematic Polar Encoding (PKC-SPE), based on the combination of systematic polar encoding and public-key cryptographic principles. The Systematic Polar Encoding (SPE), derived from the well-established field of polar codes, serves as the foundation for this proposed cryptographic scheme. Here, we have used MATLAB Software to introduce and implement the PKC-SPE Cryptosystem. The paper examines key generation, encryption, and decryption algorithms, providing insights into the adaptability and efficiency of systematic polar encoding in public-key cryptography. We assess the efficiency of the PKC-SPE Cryptosystem in three aspects: key size, computational complexity, and system implementation timings. In addition, we compare the PKC-SPE Cryptosystem with PKC-PC cryptosystem and find that it has reduced key sizes ( $$P_{r}$$ P r = 0.8436 kbytes). The results obtained through simulations validate the effectiveness of the proposed cryptosystem and highlighting its potential for integration into real-world communication systems. Thus, in the paradigm shift to quantum computing, the PKC-SPE cryptosystem emerges as a promising candidate to secure digital communication in the quantum computing era.

Introduction: Although numerous syndromic and non-syndromic odontogenic lesions of the jaws have been documented in the literature, there are very few cases of simultaneous benign and malignant jaw lesions. Patient Concerns: We present a case of right maxillary squamous cell carcinoma along with several benign odontogenic cystic lesions of the jaws and skeletal abnormalities that meet the criteria for Gorlin-Goltz syndrome. Take-Away Lessons: With a review of the literature, the specifics of management and follow-up are discussed.

ABSTRACT Background: Pre-cytoreduction refers to the administration of initial chemotherapy to reduce tumor burden prior to initiating definitive multi-agent chemotherapy. This study assessed the safety and efficacy of pre-cytoreduction prior to definitive multi-agent chemotherapy in aggressive lymphomas. Methods: A prospective cohort study was done at Ziauddin Hospital, Karachi for six months. Patients of either gender, aged between 18-80 years diagnosed with aggressive lymphoma (Stage II-IV) were included. Patients having stage-I lymphoma, primary CNS lymphoma, HIV-linked Diffuse Large B Cell Lymphoma (DLBCL) transformed lymphoma, and other malignancies were excluded. The pre-cytoreduction group received a low dose of chemotherapeutic drug on the −6th day and prednisolone 100mg daily for 7 days (−6th day to day 0) followed by standard chemotherapy on day 1. Non-pre-cytoreduction group received chemotherapy without pre-cytoreduction. After chemotherapy’s first cycle, follow-up was done for 30 days. Anxiety assessment was done using the Hamilton Anxiety Rating Scale (HAM-A). For data analysis, SPSS v27 was used. Results: From 120 patients, 27(22.5%) were diagnosed with Burkitt Lymphoma while 93(77.5%) with DLBCL. Pre-cytoreduction included prednisone, in 17(14.2%) patients, while 12(10%), 13(11%), and 10(8%) were given Vincristine, Prednisolone (VP), Cyclophosphamide, Prednisolone (CP) and Cyclophosphamide, Vincristine, and Prednisolone (CVP) respectively. There was a significant difference between both groups’ tumor lysis syndrome, bone marrow suppression, ECOG PS (Eastern Cooperative Oncology Group Performance Status), and other post-treatment complications (p

Cancer stem cells (CSCs) are a unique population of tumor cells with stem cell-like properties. They are believed to be involved in drug resistance, potential therapy failure, tumor relapse after treatment, and ultimately reduced overall survival of cancer patients. One of the causal factors that may lead to CSC formation is chromosomal instability (CIN), a dynamic event leading to numerical and structural changes in the chromosomes. The CIN is also proposed to aid the maintenance of CSCs, contribute towards their heterogeneity, and facilitate their immune escape. However, the role of CIN in the modulation of the immune system in tumors remains contradictory. Studies have revealed that it can lead to both activation and suppression of the immune system. Previous literature suggests that the CIN, CSCs, and cancer immunity (3Cs), interact with and complement each other to create a pro-tumor environment. However, the mechanisms underlying such an interaction are poorly understood. So, in this review article, an attempt has been made to understand the nature of the interaction between the triad of CIN, CSC, and the immune response in tumors and some of the pathways governing the same. Understanding the above may be a positive step towards the complete cure for malignant diseases.

Tänapäeva hariduses on kirjutamisel keskne roll ja seetõttu on oluline ka see, kuidas kirjutamist toetatakse ja juhendatakse. Artiklis anname ülevaate Eesti gümnaasiumide ja ülikoolide uurimis- ning lõputööde juhenditest. Kogusime uurimiseks 60 juhendit ja analüüsisime neid, et näha, mida juhendid tavapäraselt sisaldavad ning millist abi need (üli)õpilasele kirjutamisprotsessi eri etappides pakuvad. Analüüsist selgus, et juhendites moodustasid sisuteemad ((üli)õpilastööde liigid; teema valik; kavandamine; allikate valik ja käsitlemine; ülesehitus; keel ja stiil; eetilised põhimõtted) vaid 22% juhendite kogumahust, ülejäänud 78% oli pühendatud vormistusele jm formaalsetele aspektidele. Sisuteemadest käsitleti kõige sagedamini töö ülesehitust, vähim räägiti töö kavandamisest. Rõhuasetused juhendites viitavad kirjutamise mõtestamisele Eesti haridussüsteemis üldisemalt: tähelepanu pööratakse eelkõige lõpptulemusele ja selle nõuetekohasusele, samas tulemuseni jõudmise protsess jäetakse sageli tagaplaanile. *** "Academic writing guidelines: TNR, 12, 1.5 and done?" In the article, we introduce an analysis of guidelines for theses and other written assignments in Estonian high schools and universities. We have collected 60 guidelines and analyzed them quantitatively to see what topics they contain and in which proportions, and qualitatively to see how those topics are presented and explained. The goal of this study was to understand how guidelines assist students throughout the process of writing longer assignments. First of all, it is important to emphasize that written guidelines are only a part of the guidance students receive (in addition to writing courses, seminars etc), yet they are regulated and more centralized at the institutional level compared to other options (e.g selective courses or Bachelor’s/Master’s seminars which can vary by teacher). Our analysis of the guidelines shows that they mainly focus on formal aspects. Only 22% of the total volume of guidelines (in pages) is dedicated to aspects related to the actual writing process and the content of the paper (planning, structure, working with sources, use of language). The rest is concerned with requirements on formatting, citation styles, submitting and defending the thesis etc. Of the content and process-related topics, the most attention is paid to the structure of the paper, which is mentioned in all guidelines, whereas the planning and drafting stage is discussed only in 14 guidelines out of 60. It can thus be concluded from our analysis that the guidelines for writing in Estonian high schools and universities appear to be oriented more toward form than content. The students receive thorough and detailed instructions on what the final text must look like, but the process of creating the text itself is often neglected. Our suggestion is to keep that tendency towards form in mind while creating or updating guidelines in order to make them more content-rich and therefore encouraging and motivating – all that to support (university) students in creation of meaningful texts.

Abstract Background Varicose vein is a chronic condition that affects the lower extremities of the human body. Several factors have been implicated in the development of this disease, viz age, gender, weight, height and prolonged standing. Recently, genome-wide studies have identified genetic biomarkers that are associated with varicose veins in different ethnic groups. Such genetic studies are lacking in South Asians specifically in Indians where the prevalence of varicose veins is high, and it is important to replicate these variants in the stated population. The study aimed to replicate the association of genetic variants associated with varicose veins in this target population, which were found to be associated with the other ethnic groups. Methodology The studied cohort is of the Indian population comprising unrelated 104 varicose veins cases and 448 non-varicose vein controls. The samples were genotyped using the Illumina Global Screening Array. Using the genomic data from UK BioBank and 23andMe studied cohorts; eight genetic variants were selected to replicate in our dataset. The allelic association was performed to identify the effective allele and risk was estimated using odds ratio and p-value as level of significance. Multifactor Dimensionality Reduction was used to estimate the cumulative effect of variants in Indians. Result Variant rs3791679 of EFEMP1 was found to be associated with varicose veins in Indians. After observing the association of the EFEMP1 with varicose veins, we further ensued to identify all genetic variants within EFEMP1 to uncover the additional variants associated with this trait. Interestingly, we identified six new variants of EFEMP1 gene that have shown association. Moreover, the cumulative effect of all associated variations was estimated and the risk was 2.7 times higher in cases than controls whereas independently their effect ranges from 0.37–1.58. Conclusion This study identifies EFEMP1 as a potential gene related to the risk of varicose veins in Indians. It also highlights that evaluating the maximum number of variants of a gene rather than focusing solely on replicating single variations offers a more comprehensive and nuanced understanding of the genetic factors contributing to a complex trait like varicose veins.

Abstract Background Various studies have demonstrated gender disparities in workplace settings and the need for further intervention. This study identifies and examines evidence from randomized controlled trials (RCTs) on interventions examining gender equity in workplace or volunteer settings. An additional aim was to determine whether interventions considered intersection of gender and other variables, including PROGRESS-Plus equity variables (e.g., race/ethnicity). Methods Scoping review conducted using the JBI guide. Literature was searched in MEDLINE, Embase, PsycINFO, CINAHL, Web of Science, ERIC, Index to Legal Periodicals and Books, PAIS Index, Policy Index File, and the Canadian Business & Current Affairs Database from inception to May 9, 2022, with an updated search on October 17, 2022. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension to scoping reviews (PRISMA-ScR), Sex and Gender Equity in Research (SAGER) guidance, Strengthening the Integration of Intersectionality Theory in Health Inequality Analysis (SIITHIA) checklist, and Guidance for Reporting Involvement of Patients and the Public (GRIPP) version 2 checklist. All employment or volunteer sectors settings were included. Included interventions were designed to promote workplace gender equity that targeted: (a) individuals, (b) organizations, or (c) systems. Any comparator was eligible. Outcomes measures included any gender equity related outcome, whether it was measuring intervention effectiveness (as defined by included studies) or implementation. Data analyses were descriptive in nature. As recommended in the JBI guide to scoping reviews, only high-level content analysis was conducted to categorize the interventions, which were reported using a previously published framework. Results We screened 8855 citations, 803 grey literature sources, and 663 full-text articles, resulting in 24 unique RCTs and one companion report that met inclusion criteria. Most studies (91.7%) failed to report how they established sex or gender. Twenty-three of 24 (95.8%) studies reported at least one PROGRESS-Plus variable: typically sex or gender or occupation. Two RCTs (8.3%) identified a non-binary gender identity. None of the RCTs reported on relationships between gender and other characteristics (e.g., disability, age, etc.). We identified 24 gender equity promoting interventions in the workplace that were evaluated and categorized into one or more of the following themes: (i) quantifying gender impacts; (ii) behavioural or systemic changes; (iii) career flexibility; (iv) increased visibility, recognition, and representation; (v) creating opportunities for development, mentorship, and sponsorship; and (vi) financial support. Of these interventions, 20/24 (83.3%) had positive conclusion statements for their primary outcomes (e.g., improved academic productivity, increased self-esteem) across heterogeneous outcomes. Conclusions There is a paucity of literature on interventions to promote workplace gender equity. While some interventions elicited positive conclusions across a variety of outcomes, standardized outcome measures considering specific contexts and cultures are required. Few PROGRESS-Plus items were reported. Non-binary gender identities and issues related to intersectionality were not adequately considered. Future research should provide consistent and contemporary definitions of gender and sex. Trial registration Open Science Framework https://osf.io/x8yae .

Background: Proton therapy (PT) has unique biologic properties with excellent clinical outcomes for the management of localized prostate cancer. Here, we aim to characterize the toxicity of PT for patients with localized prostate cancer and propose mitigation strategies using a large institutional database. Methods: We reviewed medical records of 2772 patients with localized prostate cancer treated with definitive PT between May 2006 through January 2020. Disease risk was stratified according to National Comprehensive Cancer Network guidelines as low [LR, n = 640]; favorable-intermediate [F-IR, n = 849]; unfavorable-intermediate [U-IR, n = 851]; high [HR, n = 315]; or very high [VHR, n = 117]. Descriptive statistics and Kaplan-Meier estimates assessed toxicity and freedom from biochemical relapse (FFBR). Results: Median follow-up was 7.0 years. The median dose was 78 Gy(RBE)(range: 72–79.2 Gy) in 2.0 Gy(RBE) fractions; 63 % of patients received 78 Gy(RBE) in 39 fractions, and 29 % received 76 Gy(RBE) in 38 fractions. Overall rates of late grade ≥3 GU and GI toxicity were 0.87 % and 1.01 %, respectively. Two patients developed grade 4 late GU toxicity and seven patients with grade 4 late GI toxicity. All patients experiencing severe late grade 4 toxicities were treated to 78 Gy(RBE) in 39 fractions with 80 Gy(RBE) dose to the anterior rectal wall and/or bladder neck. The 10-year FFBR rates for patients with LR to U-IR disease were compared between those treated with 76 and 78 Gy(RBE); the rates were 94.5 % (95 % confidence interval [CI] 92.4–96.0 %) and 93.2 % (95 % CI 91.3–95.7 %), respectively (log-rank p = 0.22). Conclusions: Proton therapy is associated with low rates of late grade ≥3 GU and GI toxicity. While rare, late grade 4 toxicities occurred in nine (0.3 %) patients. De-escalation to a total dose of 76 Gy(RBE) yields excellent clinical outcomes for patients with LR to U-IR disease with the potential for significant reductions in grade ≥3 late toxicity.

Striae distensae (SD), commonly known as Stretch marks or striae, are one of the most common benign dermal lesions frequently seen in females that often cause a significant physical and psychological impact. A number of treatment modalities ranging from topicals to invasive approaches are commercially available, however, none of the available options is capable of complete eradication of SD. As effectiveness of most of the available topical formulations for SD is attributed to the combined effects of their antioxidant, anti-inflammatory and proliferative effects, allicin and probiotic based topical formulations are hypothesized to be effective in treatment and prevention of SD. Both allicin and probiotics are able to reduce the inflammatory response via suppression of transcription factor i.e., nuclear factor (NF)-κB, and pro-inflammatory cytokines and chemokines levels. Moreover, the antioxidant effect of allicin and probiotics is considered to decrease the reactive oxygen species induced fragmentation of collagen. Also, the effects of allicin on the collagen and elastin tissue as well as beneficial effects of probiotics and their metabolites on skin elasticity and skin hydration are expected to provide multiple target approach for the management of SD. Altogether, a combination formulation containing both allicin and probiotics is considered to be novel approach for the prevention and management of SD.

Background and Objectives: Cervical cancer global burden is highly skewed towards poor countries primarily due to lack of awareness, poor screening, and low uptake of prophylactic vaccines. The purpose of our study is to educate and raise awareness among young girls and women about the importance of cervical screening and HPV vaccination. Materials and Methods: The present study, conducted from January 2023 to December 2023, focused on students, teachers, housewives, and healthcare professionals in the Jammu region to assess their awareness of cervical cancer and the HPV vaccine. HPV DNA testing was carried out using the Truenat Real-Time PCR method at Swastik Diagnostic Laboratory, Jammu. Results: Knowledge of cervical cancer, awareness of the HPV virus, and the vaccination status of women were assessed in survey. In the HPV screening test, out of 2,400 women, 106 tested positive for HPV. Among these 106 women, 19% had a high viral load (Ct < 20), 11% had a low viral load (25 ≤ Ct < 30), indicating a low relative concentration of HPV viruses, 40% had a medium viral load (20 ≤ Ct < 25), and 30% had very low viral loads (Ct ≥ 30). Conclusion: These findings highlight the importance of routine cervical screenings, such as Pap smears and HPV tests, for the early detection of cervical cancer. There is an urgent need to implement cervical cancer screening and vaccination programs in the Jammu region.

Introduction Chronic respiratory morbidity from bronchopulmonary dysplasia (BPD) remains the most common complication of preterm birth and has consequences for later respiratory, cardiovascular and neurodevelopmental outcomes. The early phases of respiratory illness are characterised by rapid consumption of endogenous surfactant and slow replenishment. Exogenous surfactant is routinely administered to infants born before 28 weeks of gestation as prophylaxis. Endogenous surfactant includes four proteins, known as surfactant proteins (SPs) A, B, C and D. Current bovine-derived and porcine-derived surfactant preparations only contain SPs B and C. SP-D has a key role in lung immune homeostasis as part of the innate immune system. Laboratory studies using recombinant SP-D have demonstrated reduced inflammation, which may be a pathway to reducing the associated morbidity from BPD. RESPONSE uses a recombinant fragment of human SP D (rfhSP-D), in a phase I safety and dose-escalation trial as the first stage in determining its effect in humans.Methods and analysis This is a single-centre, dose-escalation, phase I safety study aiming to recruit 24 infants born before 30 weeks gestation with respiratory distress syndrome. In addition to routine surfactant replacement therapy, participants will receive three doses of rfhSP-D via endotracheal route at either 1 mg/kg, 2 mg/kg or 4 mg/kg. The study uses a Bayesian continual reassessment method to make dose escalation decisions. Dose-limiting events (DLE) in this trial will be graded according to the published Neonatal Adverse Event Severity Score. The primary outcome of this study is to evaluate the safety profile of rfhSP-D across each dose level based on the profile of DLE to establish the recommended phase 2 dose (RP2D) of rfhSP-D.Ethics and dissemination The RESPONSE study has received ethical approval from London-Brent NHS Research Health Authority ethics committee. Results from the study will be published in peer-reviewed journals and presented at national and international conferences.Trial registration numbers ISRCTN17083028, NCT05898633.Protocol version RESPONSE Protocol V.4.0 24th July 2024.

Background: The molecular and epidemiological landscape of C. difficile infection (CDI) has evolved markedly in the last decade; however, limited information is available contrasting differences between adult and pediatric populations. We describe a multicenter study evaluating healthcare-associated (HA) and community-associated (CA) adult and pediatric-CDI identified in the Canadian Nosocomial Infection Surveillance Program (CNISP) network from 2015 to 2022. Methods: Hospitalized patients with CDI were identified from up to 84 hospitals between 2015–2022 using standardized case definitions. Cases were confirmed by PCR, cultured, and further characterized using ribotyping and E-test. We used two-tailed tests for significance (p≤0.05). Results: Of 30,817 cases reported, 29,245 were adult cases [HA-CDI (73.2%), CA-CDI (26.8%)] and 1,572 were pediatric cases [HA-CDI (77.7%), CA-CDI (22.3%)]. From 2015 to 2022, HA-CDI rates decreased 19.7% (p=0.007) and 29.4% (p=0.004) in adult and pediatric populations, respectively (Figure 1). CA-CDI rates remained relatively stable in the adult population (p=0.797), while decreasing 60.7% in the pediatric population (p=0.013). Median ages of adult and pediatric patients were 70 (interquartile range (IQR), 58–80) and seven (IQR, 3–13) years, respectively. Thirty-day all-cause mortality was significantly higher among adult vs. Pediatric CDI patients (11.0% vs 1.4%, p < 0.0001). No significant differences in other severe outcomes were found. Ribotyping and susceptibility data were available for 4,620 samples: 3,558 adult (77.0%) and 1,062 pediatric (23.0%). The predominant adult and pediatric ribotypes (RT) were 106 (12.2/16.2%), 027 (11.4/3.2%), and 014 (8.8/8.2%). Overall, RT027 prevalence significantly decreased from 17.9% in 2015 to 3.2% in 2022 (p=0.003), while RT106 increased from 8.5% to 14.4%. Resistance rates among adult and pediatric isolates were similar for all antimicrobials tested except moxifloxacin (16.2% vs. 6.2%, p < 0.0001, respectively). Adult moxifloxacin resistance decreased from 30% to 6.3% from 2015 to 2022 (p=0.006). Adults with moxifloxacin-resistant CDI were older (median: 74 vs. 69 years, p < 0.001) and had higher thirty-day all-cause mortality (13% vs. 9.8%, p=0.041) and recurrence (10% vs. 5.7%, p < 0.001) compared to those with moxifloxacin non-resistant CDI, while these trends were not observed in pediatric patients. Among RT027 strains, moxifloxacin resistance decreased from 91.0% in 2015 to 7.1% in 2022. There was one metronidazole-resistant pediatric sample in 2018 and no resistance to vancomycin or tigecycline in either population. Conclusion: We have found differences in the epidemiological and molecular characteristics of adult and pediatric CDI, with higher thirty-day all-cause mortality among adults. Overall, RT106 has replaced RT027 as the predominant ribotype with a concomitant decrease in fluoroquinolone resistance.

Background The updated Shape of Training curriculum has shortened the duration of specialty training. We present the potential role of out of programme clinical fellowships.Method An electronic online survey was sent to all current fellows to understand their experiences, training opportunities and motivations.Data were collected on fellows’ endoscopic experiences and publications using PubMed for all previous doctors who have completed the Sheffield Fellowship Programme.Results Since 2004, 39 doctors have completed the Sheffield Fellowship.Endoscopic experience: current fellows completed a median average of 350 (IQR 150–500) gastroscopies and 150 (IQR 106–251) colonoscopies per year. Fellows with special interests completed either 428 hepato-pancreato-biliary procedures or 70 endoscopic mucosal resections per year.Medline publications: Median average 9 publications(IQR 4–17). They have also received multiple national or international awards and 91% achieved a doctoral degree.The seven current fellows in the new Shape of Training era (57% male, 29% Caucasian, aged 31–40 years) report high levels of enjoyment due to their research projects, supervisory teams and social aspects. The most cited reasons for undertaking the fellowship were to develop a subspecialty interest, take time off the on-call rota and develop endoscopic skills. The most reported drawback was a reduced income.All current fellows feel that the fellowship has enhanced their clinical confidence and prepared them to become consultants.Conclusion Out of programme clinical fellowships offer the opportunity to develop the required training competencies, subspecialty expertise and research skills in a supportive environment.

Introduction Central venous catheterization is a common tool widely used in medical treatment for long-term intravenous administration of medication (e.g. chemotherapy or antibiotics) or parenteral nutrition. Here, we present a case of a missing peripherally inserted central catheter (PICC) which was detected on computed tomography (CT) scan thorax.

Abstract Background Point-of-care testing (POCT) devices are diagnostic tools that can provide quick and accurate results within minutes, making them suitable for diagnosing non-communicable diseases (NCDs). However, these devices are not widely implemented in healthcare systems and for this reason is relevant to understand the implementation process. Aim To describe the process and define a strategy to implement a multiparameter POCT device for diagnosing and managing NCDs in one region of Peru. Methods A descriptive and non-experimental study, using the participatory methodologies of co-creation process. It was conducted in one region of Peru (Tumbes) to design an intervention for implementing a multiparameter POCT device. Two co-creation sessions were conducted involving five groups: community members, primary healthcare workers, these groups in both rural and urban settings, and regional decision-makers. These sessions included activities to understand patient journeys in receiving care for NCDs, identify facilitators and barriers to POCT devices usage, and define an implementation strategy for POCT devices in both rural and urban settings of Tumbes. The research team analysed the data and summarized key topics for discussion after each session. Results A total of 78 participants were enrolled across the five groups. Among community members: 22.2% had only diabetes, 24.1% had only hypertension, and 18.5% had both diagnoses. In the patient journey, community members mentioned that it took at least three days to receive a diagnosis and treatment for an NCD. Most of the participants agreed that the POCT devices would be beneficial for their communities, but they also identified some concerns. The strategy for POCT devices implementation included healthcare workers training, POCT devices must be placed in the laboratory area and must be able to perform tests for glucose, glycated haemoglobin, cholesterol, and creatinine. Advertising about POCT devices should be displayed at the healthcare centres and the municipality using billboards and flyers. Conclusions The co-creation process was useful to develop strategies for the implementation of multiparameter POCT devices for NCDs, involving the participation of different groups of stakeholders guided by moderators in both, rural and urban, settings in Peru.

Abstract Focal adhesions (FAs) connect inner workings of cell to the extracellular matrix to control cell adhesion, migration and mechanosensing. Previous studies demonstrated that FAs contain three vertical layers, which connect extracellular matrix to the cytoskeleton. By using super-resolution iPALM microscopy, we identify two additional nanoscale layers within FAs, specified by actin filaments bound to tropomyosin isoforms Tpm1.6 and Tpm3.2. The Tpm1.6-actin filaments, beneath the previously identified α-actinin cross-linked actin filaments, appear critical for adhesion maturation and controlled cell motility, whereas the adjacent Tpm3.2-actin filament layer beneath seems to facilitate adhesion disassembly. Mechanistically, Tpm3.2 stabilizes ACF-7/MACF1 and KANK-family proteins at adhesions, and hence targets microtubule plus-ends to FAs to catalyse their disassembly. Tpm3.2 depletion leads to disorganized microtubule network, abnormally stable FAs, and defects in tail retraction during migration. Thus, FAs are composed of distinct actin filament layers, and each may have specific roles in coupling adhesions to the cytoskeleton, or in controlling adhesion dynamics.

Abstract Computing binding affinities is of great importance in drug discovery pipeline and its prediction using advanced machine learning methods still remains a major challenge as the existing datasets and models do not consider the dynamic features of protein-ligand interactions. To this end, we have developed PLAS-20k dataset, an extension of previously developed PLAS-5k, with 97,500 independent simulations on a total of 19,500 different protein-ligand complexes. Our results show good correlation with the available experimental values, performing better than docking scores. This holds true even for a subset of ligands that follows Lipinski’s rule, and for diverse clusters of complex structures, thereby highlighting the importance of PLAS-20k dataset in developing new ML models. Along with this, our dataset is also beneficial in classifying strong and weak binders compared to docking. Further, OnionNet model has been retrained on PLAS-20k dataset and is provided as a baseline for the prediction of binding affinities. We believe that large-scale MD-based datasets along with trajectories will form new synergy, paving the way for accelerating drug discovery.

Abstract Background The infection of the liver by Plasmodium parasites is an obligatory step leading to malaria disease. Following hepatocyte invasion, parasites differentiate into replicative liver stage schizonts and, in the case of Plasmodium species causing relapsing malaria, into hypnozoites that can lie dormant for extended periods of time before activating. The liver stages of Plasmodium remain elusive because of technical challenges, including low infection rate. This has been hindering experimentations with well-established technologies, such as electron microscopy. A deeper understanding of hypnozoite biology could prove essential in the development of radical cure therapeutics against malaria. Results The liver stages of the rodent parasite Plasmodium berghei, causing non-relapsing malaria, and the simian parasite Plasmodium cynomolgi, causing relapsing malaria, were characterized in human Huh7 cells or primary non-human primate hepatocytes using Correlative Light-Electron Microscopy (CLEM). Specifically, CLEM approaches that rely on GFP-expressing parasites (GFP-CLEM) or on an immunofluorescence assay (IFA-CLEM) were used for imaging liver stages. The results from P. berghei showed that host and parasite organelles can be identified and imaged at high resolution using both CLEM approaches. While IFA-CLEM was associated with more pronounced extraction of cellular content, samples’ features were generally well preserved. Using IFA-CLEM, a collection of micrographs was acquired for P. cynomolgi liver stage schizonts and hypnozoites, demonstrating the potential of this approach for characterizing the liver stages of Plasmodium species causing relapsing malaria. Conclusions A CLEM approach that does not rely on parasites expressing genetically encoded tags was developed, therefore suitable for imaging the liver stages of Plasmodium species that lack established protocols to perform genetic engineering. This study also provides a dataset that characterizes the ultrastructural features of liver stage schizonts and hypnozoites from the simian parasite species P. cynomolgi. Graphical Abstract

Abstract Background Plasmodium vivax remains a major challenge for malaria control and elimination due to its ability to cause relapsing illness. To prevent relapses the Indian National Center for Vector Borne Diseases Control (NCVBDC) recommends treatment with primaquine at a dose of 0.25 mg/kg/day provided over 14 days. Shorter treatment courses may improve adherence and treatment effectiveness. Methods This is a hospital-based, randomised, controlled, open-label trial in two centres in India. Patients above the age of 16 years, with uncomplicated vivax malaria, G6PD activity of ≥ 30% of the adjusted male median (AMM) and haemoglobin levels ≥ 8 g/dL will be recruited into the study and randomised in a 1:1 ratio to receive standard schizonticidal treatment plus 7-day primaquine at 0.50 mg/kg/day or standard care with schizonticidal treatment plus 14-day primaquine at 0.25 mg/kg/day. Patients will be followed up for 6 months. The primary endpoint is the incidence risk of any P. vivax parasitaemia at 6 months. Safety outcomes include the incidence risk of severe anaemia (haemoglobin < 8 g/dL), the risk of blood transfusion, a > 25% fall in haemoglobin and an acute drop in haemoglobin of > 5 g/dL during primaquine treatment. Discussion This study will evaluate the efficacy and safety of a 7-day primaquine regimen compared to the standard 14-day regimen in India. Results from this trial are likely to directly inform national treatment guidelines. Trial registration Trial is registered on CTRI portal, Registration No: CTRI/2022/12/048283.

Aim: This study aimed to evaluate the role of chest radiographs and electrocardiograms in predicting the hemodynamics of congenital heart disease (CHD). Methods: This retrospective study included 50 patients with a diagnosis of CHD who had undergone any form of cardiac intervention, either surgical or nonsurgical between September 2019 and September 2020. Chest radiographs and electrocardiograms were evaluated and compared with the diagnostic gold standard echocardiography. Results: Chest radiographs had the highest sensitivity, specificity, and accuracy, with all being 100%, in detecting situs and cardiac position. There was a very good agreement between chest radiographs and echocardiography in the detection of both situs and cardiac position (κ = 1.00, P < 0.001), while moderate agreement was observed for the detection of cardiomegaly, position of the aortic knuckle, main pulmonary artery dilation, and right pulmonary artery dilation. Electrocardiograms had a high sensitivity (100.00%), but modest specificity and accuracy for the detection of left ventricle pressure overload. For the detection of left atrial enlargement and left ventricle volume overload, electrocardiograms had high specificity (94.12% and 94.29%, respectively) but low sensitivity and modest accuracy. There was a moderate agreement between electrocardiograms and echocardiography in the detection of right ventricle pressure overload (κ = 0.43, P = 0.002) and left ventricle volume overload (κ = 0.46, P < 0.001). Conclusions: The study findings indicate that chest radiographs and electrocardiograms alone are not adequate for the assessment of hemodynamics of CHD and reinstates the recommendation that in addition to routine chest radiographs and electrocardiograms, echocardiography should be performed.

Recent developments in cloud technology enable one to dynamically deploy heterogeneous resources as and when needed. This dynamic nature of the incoming workload causes fluctuations in the cloud environment, which is currently addressed using traditional reactive scaling techniques. Simple reactive approaches affect elastic system performance either by over-provisioning resources which significantly increases the cost, or by under-provisioning, which leads to starvation. Hence automated resource provisioning becomes an effective method to deal with such workload fluctuations. The aforementioned problems can also be resolved by using intelligent resource provisioning techniques by dynamically assigning required resources while adapting to the environment. In this paper, a reinforcement learning-based proactive resource allocation framework (RLPRAF) is proposed. This framework simultaneously learns the environment and distributes the resources. The proposed work presents a paradigm for the optimal allocation of resources by merging the notions of automatic computation, linear regression, and reinforcement learning. When tested with real-time workloads, the proposed RLPRAF method surpasses previous auto-scaling algorithms considering CPU usage, response time, and throughput. Finally, a set of tests demonstrate that the suggested strategy lowers overall expense by 30% and SLA violation by 77.7%. Furthermore, it converges at an optimum timing and demonstrates that it is feasible for a wide range of real-world service-based cloud applications.

Abstract Background India has the most significant number of children with thalassemia major worldwide, and about 10,000-15,000 children with the disease are born yearly. Scaling up e-health initiatives in rural areas using a cost-effective digital tool to provide healthcare access for all sections of people remains a challenge for government or semi-governmental institutions and agencies. Methods We compared the performance of a recently developed formula SCS $$_{BTT}$$ BTT and its web application SUSOKA with 42 discrimination formulae presently available in the literature. 6,388 samples were collected from the Postgraduate Institute of Medical Education and Research, Chandigarh, in North-Western India. Performances of the formulae were evaluated by eight different measures: sensitivity, specificity, Youden’s Index, AUC-ROC, accuracy, positive predictive value, negative predictive value, and false omission rate. Three multi-criteria decision-making (MCDM) methods, TOPSIS, COPRAS, and SECA, were implemented to rank formulae by ensuring a trade-off among the eight measures. Results MCDM methods revealed that the Shine & Lal and SCS $$_{BTT}$$ BTT were the best-performing formulae. Further, a modification of the SCS $$_{BTT}$$ BTT formula was proposed, and validation was conducted with a data set containing 939 samples collected from Nil Ratan Sircar (NRS) Medical College and Hospital, Kolkata, in Eastern India. Our two-step approach emphasized the necessity of a molecular diagnosis for a lower number of the population. SCS $$_{BTT}$$ BTT along with the condition MCV $$\le$$ ≤ 80 fl was recommended for a higher heterogeneous population set. It was found that SCS $$_{BTT}$$ BTT can classify all BTT samples with 100% sensitivity when MCV $$\le$$ ≤ 80 fl. Conclusions We addressed the issue of how to integrate the higher-ranked formulae in mass screening to ensure higher performance through the MCDM approach. In real-life practice, it is sufficient for a screening algorithm to flag a particular sample as requiring or not requiring further specific confirmatory testing. Implementing discriminate functions in routine screening programs allows early identification; consequently, the cost will decrease, and the turnaround time in everyday workflows will also increase. Our proposed two-step procedure expedites such a process. It is concluded that for mass screening of BTT in a heterogeneous set of data, SCS $$_{BTT}$$ BTT and its web application SUSOKA can provide 100% sensitivity when MCV $$\le$$ ≤ 80 fl.

Abstract Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant’s effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.

Abstract Background Breast cancer is the most common cancer in women. Radiotherapy is an important part of breast cancer treatment after surgery. Breast cancer radiotherapy is usually delivered in 3–5 weeks. This is a long duration for women with breast cancer to stay away from the family and work. We wanted to reduce this duration so that the wages loss and the logistics can be minimised for these patients. Hypofractionation, i.e. high dose per fraction, is delivered in a smaller number of days. In this study, we will compare a 1-week schedule of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy against 2 weeks for locoregional disease control, toxicities, quality of life (QoL), survival and second cancers after primary surgery in patients with breast cancer. Methods Eligible patients with breast cancer after mastectomy or breast conserving surgery (BCS) will be treated with a radiotherapy dose of 26 Gy in 5 fractions over 1 week in the study arm and 34 Gy in 10 fractions over 2 weeks in the control arm. The primary endpoint of this noninferiority study will be locoregional tumour control. Secondary endpoints will be early and late radiation toxicities, quality of life, contralateral primary tumours, regional and distant metastases, survival and second cancers. A total of 1018 patients will be randomised (1:1) to receive 1 week or 2 weeks of radiotherapy. An event-driven analysis will be performed after at least 94 patients have documented locoregional recurrences. Acute radiation toxicity will be assessed and scaled according to the RTOG grading system. Late radiation toxicity will be assessed with the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer late radiation morbidity scale. Cosmetic assessment will be done using Harvard/NSABP/RTOG breast cosmesis grading scale at baseline and 3 and 5 years. QoL will be assessed with EORTC QLQ-30 and EORTC QLQ-BR 23 at baseline and 3 and 5 years. Discussion Hypofractionation reduces treatment time to half while maintaining breast cosmesis and gives control rates equal to conventional fractionation. This is possible because breast tissue can tolerate high dose per fraction. In this study, we presume that 1-week radiotherapy will be non-inferior to 2 week radiotherapy, i.e. disease control will be similar with both the schedules without additional side effects, and QoL of these patients will be maintained. If we are able to achieve these outcomes, then patients will be able to complete their radiotherapy in less duration. There is not much data on regional nodal irradiation with hypofraction in breast cancer. We have used hypofraction for regional nodal irradiation in the past and not encountered any safety issue. If we are able to prove that late-term effects are comparable in the two schedules, it will make the radiation oncologist confident about hypofractionation in breast cancer. As breast cancer is a leading cancer in females and radiation therapy is an integral part of its local management, hypofractionation will help radiation centres worldwide to meet the growing need for radiation treatment in breast cancer, particularly in developing countries where resources are limited. It will also reduce the financial burden on the patient and family. Since we will treat these patients with both simple and complex radiotherapy techniques, it will also be possible for the low-income countries to follow this trial without needing a high-end or expensive radiotherapy equipment as the planning and treatment process will be very simple. Trial registration The trial is registered with ClinicalTrials.gov ID NCT04472845 and CTRI with REF/2020/09/037050.

Background: The European Organization for the Research and Treatment of Cancer (EORTC) has developed a commonly used validated questionnaire specific to anal cancer (EORTC QLQ-ANL27). It is used as an adjunct to the core EORTC quality-of-life (QoL) questionnaire QLQ-C30. This validated questionnaire was not available in any Indian language, and therefore, Indian patients not familiar with English could not fill it. Objective: We aimed to translate and validate the EORTC QLQ-ANL27 module in Hindi, Marathi, and Bangla languages. Materials and Methods: This study was conducted in the Department of Radiation Oncology at the Tata Memorial Hospital, a tertiary cancer center in Mumbai, India, from September 01, 2022, to March 31, 2023. The QLQ-ANL27 questionnaire was translated into Hindi, Marathi, and Bangla languages using the standard EORTC guidelines. The overall process comprised two independent forward translations of the original English questionnaire into the target languages, followed by reconciliation between the two forward translations. The reconciled version was then back translated to English. The report generated was sent to the EORTC translation unit (TU) for review. Once approved by the EORTC TU, these translated versions were pilot tested on 30 patients (10 for each language) with cancer of the rectum or anal canal. After responding to the questionnaires, each patient was individually interviewed to explore any difficulty encountered while answering the QoL questionnaire. The interviewer specifically asked whether the patients found any words or sentences difficult to answer, confusing, or upsetting, and for suggestions on better phrasing. Results: The EORTC QLQ-ANL27 was translated to Hindi, Marathi, and Bangla, followed by back translation into English within a period of 2 months between September 2022 and October 2022. The translated versions were approved by the EORTC TU in October 2022. Validation of the translated versions was conducted between December 2022 and March 2023 in 30 patients diagnosed with anorectal cancer. The median age of the patients was 55 (interquartile range, 29–77); the male-to-female ratio was 2:1. There were no suggestions or doubts in the Hindi, Marathi, and Bangla questionnaires during the pilot testing. After reviewing the pilot testing reports, the EORTC TU approved the translated versions of QLQ-ANL27. The reliability of the translated questionnaires was confirmed using Cronbach's alpha, which were 0.838, 0.743, and 0.808 for the Hindi, Marathi, and Bangla versions, respectively. Conclusions: The Hindi, Marathi, and Bangla translations of the QLQ-ANL27 module have been validated and approved by the EORTC and are now available for use (Clinical Trials Registry-India, CTRI/2022/12/047970).

Background: Coronavirus disease 2019 (COVID-19) is a contagious infection characterized by severe acute respiratory syndrome (SARS-CoV-2). Safe and effective vaccines are game-changers in the global vision of marking an end to the challenges posed by the COVID-19 pandemic. However, vaccine hesitancy due to perceived stigma and misinformation is a grave cause of concern. Objectives: To assess pre-university students' self-expressed stigma regarding COVID-19 vaccination and its association with their knowledge. Materials and Methods: A cross-sectional study was adopted for this research. A structured questionnaire approach was used to gather data from 384 students purposively at the selected pre-university college. The structured questionnaire consisted of three sections that explored the socio-demographic characteristics of the study participants, knowledge of vaccination, and self-expressed stigma, respectively. A total of 384 respondents took part in the study. Results: The study observes a low positive relationship (r = 0.25, P < 0.01) between knowledge and self-expressed stigma toward vaccination. Further, it was observed that participants from rural backgrounds had lower knowledge and self-expressed stigma scores than participants from urban settings. It is pertinent to note that participants with other sources of information had higher knowledge than those who used the internet, friends/peers, or newspapers. Both of the aforementioned findings are statistically significant. Conclusion: The interventions should revive trust in national health authorities, structured awareness campaigns by government agencies, and media coverage about the safety and efficacy of vaccines. In addition, it is also important to support citizens in ensuring that they have access to the right information from authentic sources in times of crisis.