Highlights on the Development, Related Patents, and Prospects of Lenacapavir: The First-in-Class HIV-1 Capsid Inhibitor for the Treatment of Multi-Drug-Resistant HIV-1 Infection.

The multidrug-resistant (MDR) human immunodeficiency virus 1 (HIV-1) infection is an unmet medical need. HIV-1 capsid plays an important role at different stages of the HIV-1 replication cycle and is an attractive drug target for developing therapies against MDR HIV-1 infection. Lenacapavir (LEN) is the first-in-class HIV-1 capsid inhibitor approved by the USFDA, EMA, and Health Canada for treating MDR HIV-1 infection. This article highlights the development, pharmaceutical aspects, clinical studies, patent literature, and future directions on LEN-based therapies. The literature for this review was collected from PubMed, authentic websites (USFDA, EMA, Health Canada, Gilead, and NIH), and the free patent database (Espacenet, USPTO, and Patent scope). LEN has been developed by Gilead and is marketed as Sunlenca (tablet and subcutaneous injection). The long-acting and patient-compliant LEN demonstrated a low level of drug-related mutations, is active against MDR HIV-1 infection, and does not reveal cross-resistance to other anti-HIV drugs. LEN is also an excellent drug for patients having difficult or limited access to healthcare facilities. The literature has established additive/synergistic effects of combining LEN with rilpivirine, cabotegravir, islatravir, bictegravir, and tenofovir. HIV-1 infection may be accompanied by opportunistic infections such as tuberculosis (TB). The associated diseases make HIV treatment complex and warrant drug interaction studies (drug-drug, drug-food, and drug-disease interaction). Many inventions on different aspects of LEN have been claimed in patent literature. However, there is a great scope for developing more inventions related to the drug combination of LEN with anti-HIV/anti-TB drugs in a single dosage form, new formulations, and methods of treating HIV and TB co-infection. Additional research may provide more LEN-based treatments with favorable pharmacokinetic parameters for MDR HIV-1 infections and associated opportunistic infections such as TB.

Evaluating the effect of gargling with hydrogen peroxide and povidone-iodine on salivary viral load of SARS-CoV-2: A pilot randomized clinical trial.

Background and Aim: This study evaluates the salivary viral load of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in hospitalized patients and outpatients before and after gargling with 1% hydrogen peroxide and 0.25% povidone-iodine in comparison with normal saline. Patients and Methods: This clinical trial was conducted on 120 participants with laboratory-confirmed coronavirus disease 2019 (COVID-19) in two groups: outpatients (n = 60) and hospitalized patients (n = 60). In each group, the patients were randomly divided into three subgroups of 20 based on their given mouthwash for gargling (hydrogen peroxide, povidone-iodine, or normal saline). Two saliva samples were taken from each patient: the first one before gargling and the second one 10 minutes after gargling 10 ml of the respected mouthwashes for 30 seconds. The TaqMan real-time polymerase chain reaction (PCR) amplification of SARS-CoV-2 was used to measure the viral load. Results: Saliva samples from 46% of patients were positive for coronavirus before gargling the mouthwashes. The percentage of patients with an initial positive saliva sample was significantly higher in the outpatient group (83.3%) than in the hospitalized group (5.4%) (P = 0.01). According to the findings, gargling any mouthwash similar to saline did not reduce the viral load (P > 0.05). Conclusion: The saliva of COVID-19 patients in the initial stage of the disease was more likely to contain SARS-CoV-2 than the saliva of the hospitalized patients. Gargling hydrogen peroxide or povidone-iodine did not reduce the salivary SARS-CoV-2 viral load.

Transgender Youth's Perspectives on Factors Influencing Intended and Unintended Pregnancies.

Drawing on data from focus groups with 152 trans youth aged 14-18 years in the United States, this article explores the factors that the participants understood as contributing to adolescent pregnancy among trans youth. Youth posited that unintended pregnancies occur due to barriers to contraceptives; a lack of gender-affirming sexual health education; sexual assault and dating violence; and mental health-influenced sexual risk-taking. Participants suggested that intended pregnancies may be a self-development strategy; a self-directed effort to repress/change gender modality or identity; and due to the perceived incompatibility between pregnancy and transition, where pregnancy must occur prior to transitioning.

A Systematic Review on the Relationship Between Physical Activity and Sexual Function in Adults.

Sexual function is a vital component of overall well-being and quality of life. Physical activity is known to have a profound influence on various aspects of health, but its impact on sexual function in the general population remains an under-explored area. This systematic review seeks to thoroughly examine existing evidence, aiming to establish the correlation between physical activity and sexual function in both male and female adults. We conducted a comprehensive search of electronic databases and relevant sources, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eligible studies were those that investigated the effects of physical activity on sexual function using the International Index of Erectile Dysfunction (IIEF-5) questionnaire and the Female Sexual Function Index (FSFI). Quality assessment was performed on the included studies, and the findings were synthesized through qualitative analysis. The review identified 12 randomized controlled trials, primarily focusing on males, with interventions ranging from home-based walking to structured exercise training. Only two studies were conducted among females. The most recommended exercise was aerobic exercise. Consistent aerobic exercise proves to be a hopeful and efficient non-drug intervention for enhancing erectile function in men. However, when considering the effects of physical exercise programs on sexual function and the quality of sexual life of females, the results present challenges in drawing clear conclusions. Health policymakers play an important role in providing guidelines and recommendations to healthcare professionals, encouraging them to prescribe exercise as a preferable alternative to pharmacological treatments for enhancing sexual functions in both men and women.

Molecular Investigation of Brucella Species Belongs to Sheep and Goats in Seropositive Samples from an Endemic Area of Hamedan Province; Famenin Brucellosis Cohort Study.

Brucellosis is a zoonotic infectious disease in western regions of Iran, especially in Hamedan province. Following the Famenin brucellosis cohort study, the main aim of the current study was the molecular detection of Brucella species (spp.) in sheep and goats from Famenin, Hamedan, Iran. A total of 23 Brucella-seropositive samples (sheep=21 and goats=2), which had been screened from 1,660 animals in the Famenin cohort study, were used to detect Brucella-DNA using the BCSP31 target gene and IS711 locus. In total, 20 of 23 samples were positive for Brucella infection by using specific primers. Additionally, Brucella melitensis (B. melitensis) and Brucella abortus (B. abortus) were confirmed in 90% (n=18) and 10% (n=2) of positive samples, respectively. There was no sample with the co-infection of B. abortus and B. melitensis. In this study, B. abortus was isolated from one of the goat samples. This is the first report on Brucella spp. in animals in the region. It was found that B. melitensis is the dominant spp. responsible for brucellosis in animals from Famenin. Molecular techniques are reliable tools to detect Brucella infection, especially in cases without serology findings and conclusive results.

Regulation of mitochondrial temperature in health and disease.

Mitochondrial temperature is produced by various metabolic processes inside the mitochondria, particularly oxidative phosphorylation. It was recently reported that mitochondria could normally operate at high temperatures that can reach 50℃. The aim of this review is to identify mitochondrial temperature differences between normal cells and cancer cells. Herein, we discussed the different types of mitochondrial thermosensors and their advantages and disadvantages. We reviewed the studies assessing the mitochondrial temperature in cancer cells and normal cells. We shed the light on the factors involved in maintaining the mitochondrial temperature of normal cells compared to cancer cells.

Personality, density and habitat drive the dispersal of invasive crayfish.

There is increasing evidence that personality traits may drive dispersal patterns of animals, including invasive species. We investigated, using the widespread signal crayfish Pacifastacus leniusculus as a model invasive species, whether effects of personality traits on dispersal were independent of, or affected by, other factors including population density, habitat, crayfish size, sex and limb loss, along an invasion gradient. Behavioural traits (boldness, activity, exploration, willingness to climb) of 310 individually marked signal crayfish were measured at fully-established, newly-established and invasion front sites of two upland streams. After a period at liberty, recaptured crayfish were reassessed for behavioural traits (newly-established, invasion front). Dispersal distance and direction of crayfish movement, local population density, fine-scale habitat characteristics and crayfish size, sex and limb loss were also measured. Individual crayfish exhibited consistency in behavioural traits over time which formed a behavioural syndrome. Dispersal was both positively and negatively affected by personality traits, positively by local population density and negatively by refuge availability. No effect of size, sex and limb loss was recorded. Personality played a role in promoting dispersal but population density and local habitat complexity were also important determinants. Predicting biological invasion in animals is likely to require better integration of these processes.

Fish community and abundance response to improved connectivity and more natural hydromorphology in a post-industrial subcatchment.

Barrier removal and fish pass construction are increasingly used as tools to restore river connectivity and improve habitat quality, but the effectiveness of subcatchment-scale connectivity restoration on recovery of fish communities is poorly understood. We used a before-after-downstream-upstream methodology to determine the effects of subcatchment-scale connectivity restoration on fishes in a fragmented tributary of the River Wear, Northeast England, between 2013 and 2019. Following restoration (three barriers removed, five barriers fitted with fish passes, two barriers unaltered), riffle habitat increased, fine sediment decreased, and most fish species benefitted. Total fish abundance, comprising seven native species, increased 3 years after the restoration and remained elevated to the end of the study. Mean brown trout (Salmo trutta) density increased from 20.9 ±â€¯6.3 to 33.8 ±â€¯16.8 per 100m2 from 2013 to 2019, with Young-of-Year trout increasing from 10.6 ±â€¯4.6 to 19.8 ±â€¯11.8 per 100m2. Connectivity restoration reduced the mean age of trout, suggesting a change to an increased migratory component of the population. Density of bullhead (Cottus perifretum), a species with poor dispersal ability, increased from 4.6 ±â€¯2.7 to 32.6 ±â€¯17.9 per 100m2 over 2013 to 2019. Stone loach (Barbatula barbatula), also a less mobile species but tolerant to fine sediment, decreased in abundance where barriers were removed. Atlantic salmon (Salmo salar) were absent over the study timescale, despite being common in the Wear, and despite suitable habitat and water quality in the restored subcatchment, suggesting a hysteresis effect. Our findings indicate that, where good water quality exists, restoring river connectivity and hydromorphology at a subcatchment scale is beneficial for most native resident and migratory fishes. However, the ecological benefits of connectivity restoration, especially in rivers with many barriers, may take several years to develop. We encourage well-controlled long-term studies reporting the outcomes of large-scale connectivity restoration.

Evaluation of different haematoxylin stain subtypes for the optimal microscopic interpretation of cutaneous malignancy in Mohs frozen section histological procedure.

BACKGROUND: The Mohs technique employs mainly H&E-stained frozen sections for surgical margin assessment of cutaneous excisions, utilising microscopic evaluation of the complete, circumferential, peripheral and deep margins. This study aimed to determine which mordant based haematoxylin (Ehrlich's, Cole's, Mayer's, Gill's I, Gill's II, Gill's III, Weigert's, Harris' or Carazzi's) produced the optimal morphological clarity of staining for the identification of cellular and tissue morphology of cutaneous basal cell carcinoma (BCC). MATERIAL AND METHODS: In total, 100 anonymised patient cases were selected, sectioned and stained with each haematoxylin subtype. The slides were independently evaluated microscopically by two assessors. A combined score was generated to determine the sensitivity (defined as the intensity of haematoxylin staining being too weak or too strong and the colour appearance of the haematoxylin not being blue/black) and specificity (defined as the appearance of background staining with haematoxylin, uneven staining and staining deposits) for each of the nine haematoxylin subtypes. The scoring criteria were based on the UKNEQAS CPT Mohs procedure assessment criteria. RESULTS: The scores generated for specificity identified Carazzi's haematoxylin as best performing (99.2%) followed by Gill's III (98.4%), Ehrlich's (98.2%) and Harris' (85.0%). The sensitivity score again identified Carazzi's as producing the best result (85.0%) followed by Weigert's (83.4%), Ehrlich's (81.6%) and Gill's III (80.4%). DISCUSSION: Carazzi's haematoxylin is the most optimal staining dye for the identification of BCC tumour for use as part of the Mohs micrographic surgery procedure.

Relationship between wetting and capillary pressure in a crude oil/brine/rock system: From nano-scale to core-scale.

HYPOTHESIS: The wetting behaviour is a key property of a porous medium that controls hydraulic conductivity in multiphase flow. While many porous materials, such as hydrocarbon reservoir rocks, are initially wetted by the aqueous phase, surface active components within the non-wetting phase can alter the wetting state of the solid. Close to the saturation endpoints wetting phase fluid films of nanometre thickness impact the wetting alteration process. The properties of these films depend on the chemical characteristics of the system. Here we demonstrate that surface texture can be equally important and introduce a novel workflow to characterize the wetting state of a porous medium. EXPERIMENTS: We investigated the formation of fluid films along a rock surface imaged with atomic force microscopy using ζ-potential measurements and a computational model for drainage. The results were compared to spontaneous imbibition test to link sub-pore-scale and core-scale wetting characteristics of the rock. FINDINGS: The results show a dependency between surface coverage by oil, which controls the wetting alteration, and the macroscopic wetting response. The surface-area coverage is dependent on the capillary pressure applied during primary drainage. Close to the saturation endpoint, where the change in saturation was minor, the oil-solid contact changed more than 80%.

Semi-automated standardisation of melanin bleaching procedures of heavily pigmented melanocytic lesions for immunohistochemical analysis on an automated platform.

Background: The diagnosis of heavily pigmented melanocytic lesions is problematic. This is often compounded by lack of visibility of nuclear detail of tumour cells due to physical masking by melanin pigment. Similarly, there can be colour merging of chromogenic final reaction products with melanin, making an evidence of antigenic localisation problematic. There are a number of melanin bleaching techniques available for immunohistochemical assessments.Material and methods: All methods to date have involved the bleaching of melanin as a manually performed primary step before loading subsequently bleached slides onto automated immunohistochemical platforms. Here we define a semi-automated bleaching procedure that allows full integration on one of the most widely employed automated IHC staining platforms (Roche Ventana BenchMark Ultra). The bleaching protocol was defined on the BenchMark Ultra and involved the assessment of 24 histological cases of heavily pigmented malignant melanoma lesions (13 cutaneous and 11 metastatic) routinely fixed processed and paraffin wax embedded.Results: Completion of the bleaching was assessed on H&E preparations performed following the semi-automated bleaching step and employing the Roche Ventana BenchMark Ultra machine for 60 min at 42°C. Complete immunohistochemical staining was achieved on the automated platform within 5-6 h including the bleaching step. Results were consistent across all tissue evaluated.Discussion: This data provides evidence that the hydrogen peroxide bleaching procedure can be adapted for integration on one of the most widely employed automated IHC staining platforms and as a result, improve the efficiency and reproducibility of the technique.

Artery targeted photothrombosis widens the vascular penumbra, instigates peri-infarct neovascularization and models forelimb impairments.

The photothrombotic stroke model generates localized and reproducible ischemic infarcts that are useful for studying recovery mechanisms, but its failure to produce a substantial ischemic penumbra weakens its resemblance to human stroke. We examined whether a modification of this approach, confining photodamage to arteries on the cortical surface (artery-targeted photothrombosis), could better reproduce aspects of the penumbra. Following artery-targeted or traditional photothrombosis to the motor cortex of mice, post-ischemic cerebral blood flow was measured using multi-exposure speckle imaging at 6, 48, and 120 h post-occlusion. Artery-targeted photothrombosis produced a more graded penumbra at 48 and 120 h. The density of isolectin B4+ vessels in peri-infarct cortex was similarly increased after both types of infarcts compared to sham at 2 weeks. These results indicate that both models instigated post-ischemic vascular structural changes. Finally, we determined whether the strength of the traditional photothrombotic approach for modeling upper-extremity motor impairments extends to the artery-targeted approach. In adult mice that were proficient in a skilled reaching task, small motor-cortical infarcts impaired skilled-reaching performance for up to 10 days. These results support that artery-targeted photothrombosis widens the penumbra while maintaining the ability to create localized infarcts useful for modeling post-stroke impairments.

Resveratrol reduces albuminuria in diabetic nephropathy: A randomized double-blind placebo-controlled clinical trial.

AIM: Albuminuria is the most important indicator of diabetic nephropathy (DN). Resveratrol, a natural compound found in grape skins and red wine, has antioxidant effects. This study aimed to evaluate the effects of resveratrol on DN. METHODS: In this randomized, double-blind, placebo-controlled clinical trial, 60 patients with type 2 diabetes and albuminuria were randomly assigned to receive either resveratrol (500mg/day) or placebo for 90 days. Losartan (12.5mg/day) was also administered to all participants. Primary outcomes were urinary albumin/creatinine ratio, estimated glomerular filtration rate (eGFR) and serum creatinine levels. Secondary outcomes were oxidative stress markers, and anthropometric and biochemical measures. RESULTS: Mean urine albumin/creatinine ratio was significantly reduced in the resveratrol group vs placebo (-46.4mg/g, 95% CI: -64.5 to -28.3 vs 29.9mg/g, 95% CI: 4.9 to 54.9; P<0.001), whereas eGFR (1.7mL/min/1.73m2, 95% CI: -3.4 to 6.8 vs -4.0, 95% CI: -8.2 to 0.2; P=0.08) and serum creatinine (-0.3mg/dL, 95% CI: -0.1 to 0.1 vs 0.1mg/dL, 95% CI: -0.0 to 0.1; P=0.13) were unchanged. Serum antioxidant enzymes were significantly increased with resveratrol. After adjusting for confounding variables, the effect of resveratrol in reducing urinary albumin excretion was still significant (P<0.001). Regression analysis revealed that every 1-cm decrease in waist circumference and 1-µmol/L increase in nitric oxide (NO) was associated with 9.4mg/g and 4.0mg/g reductions, respectively, of urine albumin/creatinine ratio. CONCLUSION: This clinical trial has shown that resveratrol may be an effective adjunct to angiotensin receptor blockers (ARBs) for reducing urinary albumin excretion in patients with DN (ClinicalTrials.gov: NCT02704494).

Use of a novel 1-hour protocol for rapid frozen section immunocytochemistry, in a case of squamous cell carcinoma treated with Mohs micrographic surgery.

For squamous cell carcinoma (SCC) treated using Mohs micrographic surgery (MMS), interpretation of haematoxylin and eosin-stained frozen sections can be challenging. In these situations, ancillary use of immunostaining is a useful tool for the Mohs surgeon. However, use of immunostaining in MMS laboratories is limited, mainly because current manual immunostaining platforms are subject to operator error, and automated immunostaining, albeit accurate, is too slow for inclusion in MMS. In this report, we describe a novel 1-hour protocol for rapid frozen section immunocytochemistry, using the pancytokeratin markers AE1/AE3. This protocol has been specifically designed to integrate the speed of manual techniques and the accuracy of automated platforms, making it a valuable addition to the MMS laboratory. We propose that in selected or histologically challenging cases, there is a role for the use of this novel protocol, allowing the Mohs surgeon to more confidently declare tumour clearance, thus preventing further unnecessary surgery and preserving healthy tissue.

Prenatal diagnosis in rare bleeding disorders-An unresolved issue?

Intracranial haemorrhage (ICH) is the most dreadful complication, and the main cause of death among patients with rare bleeding disorders (RBD) and prenatal diagnosis (PND) is a preventative lifesaving program. A total of 39 PNDs were reported in the literature through a search on PubMed, EMBASE, SCOPUS and Web of Science databases, most often for congenital factor (F) XIII and FVII deficiencies and rarely in FX, FV deficiencies and afibrinogenemia. The main cause to request a PND is ICH and related morbidity and mortality. Different molecular methods including direct sequencing and linkage analysis as well as polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for a specific mutation are the most common used methods for PND, while factor assay and combination of molecular and factor assay also were used. In this research, 7 severely affected foetuses were identified during PND including 3 foetuses with FXIII deficiency, 3 with FVII deficiency and 1 with FX deficiency. Out of these 7 cases, intrauterine ICH occurred in 1 case with FXIII deficiency, 1 was electively aborted and 1 case with severe FVII deficiency received intrauterine factor transfusion. Postdelivery ICH was reported for 1 patient with severe FVII deficiency within the first month of life. All other pregnancies were uneventful.

ABO blood grouping in Egyptian children with rotavirus gastroenteritis.

INTRODUCTION: Rotavirus gastroenteritis is an important public health problem all over the world, causing a notable economic burden in both developing and developed countries. AIM: To explore the relationship between blood group typing, rotavirus gastroenteritis, and its severity in Egyptian children. MATERIAL AND METHODS: A cross sectional case control study was conducted on 231 cases of acute gastroenteritis attending the outpatient clinic of Al-Zahraa University Hospital. Full history taking, clinical examination, and clinical data collection were done. Blood samples were collected for an ABO grouping. Stool samples were tested for viral gastroenteritis agents. RESULTS: Rota positive cases of GE were significantly more prevalent among cases with blood group A (p < 0.05) and significantly less among cases with blood group B (p < 0.05). The rate of hospitalisation was highly significantly greater among cases with group A (p < 0.005), and significantly lower among cases with group AB and O (p < 0.05). As regards the degree of dehydration, moderate and severe cases were highly significant in groups A and O (p < 0.005). Rota-positive gastroenteritis showed significant positive correlations with indicators of severity such as hospitalisation, degree of dehydration, and duration of fever (p < 0.005). CONCLUSIONS: Blood group A is highly associated with paediatric rotavirus gastroenteritis. This could highlight an important risk factor, which could play a significant role for the pathogenesis of rotavirus gastroenteritis and severity as well. Furthermore, more intervention care could be needed for blood group A paediatric patients, if gastroenteritis especially rotavirus affect this group to avoid comorbidities.

Livestock mortality and offtake in sheep and goat flocks of livestock owners making use of services offered by paravets in West Afghanistan.

In the present study, we quantified the effect of livestock services provided through paravets (intermediate-level training in veterinary medicine) on mortality and offtake of small ruminants in Western Afghanistan for the years 2010, 2011 and 2013. We compared mortality in adult and in young stock, and offtake of young stock of 120 livestock owners that made use of the paravet services (Users) with 120 livestock owners who did not make use of these services (Non-users). Security issues in the districts under study influenced the choice of villages. Within villages, livestock owners were purposively selected based on their known use of the services, including the provision of biologicals such as anthelmintics and vaccines. In addition, we subdivided both categories into 'partial' and 'full' based on the intensity of use of biologicals. Paravets were not only trained on preventive and curative veterinary medicine, they were also trained in extension and trained on adhering to a cold-chain and applying quality biologicals. For Non-users there was the possibility to buy biologicals through a local market or bazaar. In Afghanistan, local markets have an extensive supply of vaccines, anthelmintics, and medicines from a variety of sources, often not handled appropriately and therefore of varying quality. The results indicated that livestock owners making partial or full use of the paravet services had statistically significant better animal health and production results. The mortalities in adult stock, expressed as Incidence Rate Ratios (IRRs), for the partial-Users and full-Users categories were estimated to be respectively 0.80 and 0.73 times the mortality observed in the partial Non-users', the reference category. A similar result was observed for young stock mortality with estimated IRRs of 0.81 and 0.77 for partial and full-Users category respectively. The offtake for partial- and full-Users category livestock owners were 1.24 and 1.21 times higher compared with the reference category. In conclusion, we demonstrated significant improvement of health and production parameters in small ruminants' flocks of owners making use of the services of the DCA-trained paravets, emphasizing the importance of this sustainable and effective system of private veterinary service delivery in Afghanistan.