Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-Kb and H2-Db (MHCI KbDb-/-), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7-Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7-Fmr1 KO mice, as previously reported in MHCI KbDb-/-mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7-Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

Retrospective cross-sectional study to evaluate outcome of loco-regional flaps in head and neck reconstruction in Sudanese patients.

Introduction: The soft tissue of the head and neck region poses both esthetic and functional aspects and must be retorted simultaneously, as any defect will be easy recognizable and will affect the quality of patient's life. Reconstruction by local- regional flap still the most popular approach used and outcome also better than other options. Objectives: To assess the outcome of loco-regional flaps in head and neck reconstruction in Sudanese patients. Patients and methods: Retrospective cross-sectional, multicenteric study (Soba University Hospital, Khartoum North Teaching Hospital and an associated specialized hospital) - Khartoum, Sudan, 84 patients underwent head/neck reconstruction during the period from 2017 up to 2021 were included. Results: Out of 84 patients, 47.6% were female and 52.4% were male. The etiology of head and neck defects in the majority (69%) was neoplastic, and in 11.9% it was trauma. According to site of defect, in 23.8% of patients was Cheek unit, 21.4% was nasal site, and 16.7% was neck site. Surgery in 85.7% of patients were primary, while in 14.3 was delayed. Fasciocutaneous flaps were used in 64.3%, followed by myocutaneous flap in 28.6%; functional outcome was excellent in 61.9%, adequate in 35.7%, and was inadequate in only 2.4%. The majority of patients 66.2% did not develop any complications. Conclusion: Loco-regional flaps are ideally useful in covering head and neck defects. It has an acceptable esthetic and functional outcome in the majority of cases. It can be considered as a reliable option for reconstruction especially in resource constrained centers.

Frequency and Risk Factors Association with Metabolic Syndrome among the Hypertensive Patients in Jashore, Bangladesh.

Metabolic Syndrome (METS) plays a pivotal role in the development of diabetes mellitus, coronary artery diseases and stroke. Due to the scarcity of data in this issue, this study aims to assess the frequency and risk factors association of METS among the hypertensive patients. This cross-sectional study recruited 667 eligible hypertensive patients aged between 20 and 70 years using non-probability purposive sampling method conducted from 1st January 2019 to 30th June 2019. Hypertensive patients with the known history of diabetes, thyroid, renal, cardiac, or hepatic disease, Cushing syndrome or malignancy and secondary causes of obesity, confirmed pregnancy, bed ridden, taking lipid lowering drugs or drugs that affect lipid and glucose metabolism were excluded from the study. METS among the hypertensive patients (DE novo or established hypertensive patients) of this study was demonstrated by NCEP-ATPIII (National Cholesterol Education Program-Adult Treatment Panel III) criteria having two or more of the following points [a) increased waist circumference ≥102cm in men and ≥88cm in women, b) hypertriglyceridemia: ≥150mg/dl, c) reduced High density lipoprotein cholesterol (HDL-C) <40mg/dL (1.04mmol/L) in men and <50mg/dL (1.29mmol/L) in women, d) high fasting blood glucose: 110mg/dl]. Significantly high frequency (69.9%, p<0.001) of METS was found with a significant female preponderance (52.5%, p<0.001) where the mean age of the study population was 48±11 years. Sex (p<0.001), education (p=0.041), occupation (p<0.001), Body mass index (BMI) (p<0.001) and hypertensive status (p=0.002) showed a highly significant role in the development of METS. Following binary logistic regression analysis after adjusting for confounders, the female sex was 17 times higher than the male [Adjusted odd ratio (AOR) =16.96, 95% CI=4.91-58.66, p<0.001)], obesity 4 times higher than non-obese [BMI (obese AOR=4.24, 95% CI=2.55-7.98, p<0.001)], hypertensive status [established hypertension two times higher than de novo (de-novo AOR=0.60, 95% CI=0.037-0.97, p=0.037)] were significant and independent predictors of METS. Significantly high BMI (27.7±4.2 and p<0.001), high waist circumference (60.4%, p<0.001) and hyper tri-glyceridaemia and reduced HDL (46.0%, p<0.001 and 51.3%, p<0.001) were found in the subjects with METS. In conclusion, high frequency of METS among the hypertensive patients was found in Jashore, Bangladesh with significant risk factors related to female sex, education, occupation, BMI and hypertensive status. So, a holistic evaluation of metabolic components among the hypertensive patients may reduce premature cardiovascular morbidity and mortality.

Mayer-Rokitansky-Kuster-Hauser Syndrome Presented with Diabetes Mellitus and Primary Amenorrhea: A Case Report.

Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome is a rare congenital disorder that affects the female reproductive system and is characterized by an underdeveloped or absent uterus and vagina. A 17-year-old unmarried female was admitted into the Department of Endocrinology, Mymensingh Medical College Hospital, Bangladesh in November 2023 for evaluation of primary amenorrhea and poorly controlled diabetes mellitus. She was the 5th issue of non-consanguineous marriage delivered at term by normal vaginal delivery. Her growth pattern and developmental milestones were normal. She had no history of galactorrhea, chronic or cyclic pelvic pain, thyroid dysfunction, excessive exercise, psychiatric illness, or drug abuse. There was no history of such type of illness in her family. She was diagnosed with diabetes mellitus two years back without classic symptoms, and at that time, her blood glucose was 22 mmol/L. She was prescribed metformin and gliclazide. She had no history of hypoglycemia, hyperglycemic crises, or hospital admission. On examination, her body build and nutritional status were normal. Anemia, jaundice, edema, dehydration, lymphadenopathy, acne, hirsutism, acanthosis nigricans, abdominal striae and vitiligo were absent. Her blood pressure was 110/70 without the postural drop, thyroid gland was not enlarged, anthropometric measurements were normal and BMI was 18.4 kg/m2. Her tanner stage was P5 & B4. Genital examination revealed normal female external genitalia, and a blind vaginal pouch was found. Other systemic examinations revealed no abnormality. On laboratory reports, her blood glucose was uncontrolled (HbA1c-10.2%) with glycosuria. Thyroid function test and gonadal hormones were normal. Ultrasonogram of the abdomen revealed uterus, cervix, and upper part of the vagina are absent, and an ectopic left kidney.

Revision of metal-on-metal hip replacements with dual-mobility bearings and acetabular component retention.

Aims: In metal-on-metal (MoM) hip arthroplasties and resurfacings, mechanically induced corrosion can lead to elevated serum metal ions, a local inflammatory response, and formation of pseudotumours, ultimately requiring revision. The size and diametral clearance of anatomical (ADM) and modular (MDM) dual-mobility polyethylene bearings match those of Birmingham hip MoM components. If the acetabular component is satisfactorily positioned, well integrated into the bone, and has no surface damage, this presents the opportunity for revision with exchange of the metal head for ADM/MDM polyethylene bearings without removal of the acetabular component. Methods: Between 2012 and 2020, across two centres, 94 patients underwent revision of Birmingham MoM hip arthroplasties or resurfacings. Mean age was 65.5 years (33 to 87). In 53 patients (56.4%), the acetabular component was retained and dual-mobility bearings were used (DM); in 41 (43.6%) the acetabulum was revised (AR). Patients underwent follow-up of minimum two-years (mean 4.6 (2.1 to 8.5) years). Results: In the DM group, two (3.8%) patients underwent further surgery: one (1.9%) for dislocation and one (1.9%) for infection. In the AR group, four (9.8%) underwent further procedures: two (4.9%) for loosening of the acetabular component and two (4.9%) following dislocations. There were no other dislocations in either group. In the DM group, operating time (68.4 vs 101.5 mins, p < 0.001), postoperative drop in haemoglobin (16.6 vs 27.8 g/L, p < 0.001), and length of stay (1.8 vs 2.4 days, p < 0.001) were significantly lower. There was a significant reduction in serum metal ions postoperatively in both groups (p < 0.001), although there was no difference between groups for this reduction (p = 0.674 (cobalt); p = 0.186 (chromium)). Conclusion: In selected patients with Birmingham MoM hips, where the acetabular component is well-fixed and in a satisfactory position with no surface damage, the metal head can be exchanged for polyethylene ADM/MDM bearings with retention of the acetabular prosthesis. This presents significant benefits, with a shorter procedure and a lower risk of complications.

Early and rapid development of bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplantation.

Bronchiolitis obliterans (BO) is a form of graft-versus-host disease (GVHD) in the lung and manifests as moderate to severe airflow obstruction after hematopoietic stem cell transplantation (HCT). New-onset airflow obstruction on spirometry is considered diagnostic of bronchiolitis obliterans syndrome (BOS). BOS affects about 5% of all HCT recipients. In general, BO is thought of as a late complication of HCT, usually occurring after day 100 post-transplantation. However, the onset of airflow obstruction can be rapid and is most often irreversible even with treatment. We describe a patient who rapidly developed severe airflow obstruction less than one month after transplantation following the development of upper airway symptoms. Despite aggressive immunosuppression, the patient had no improvement in airflow obstruction. We hypothesize that early screening and treatment may help prevent BOS after HCT.

Lower intensity therapy with cladribine/low dose cytarabine/venetoclax in older patients with acute myeloid leukemia compares favorably with intensive chemotherapy among patients undergoing allogeneic stem cell transplantation.

BACKGROUND: Allogeneic stem cell transplantation (SCT) remains the best consolidative modality in most patients with acute myeloid leukemia (AML). Along with factors directly pertaining to SCT, pretransplantation disease control, performance status, and prior treatment-related complications are important factors that affect posttransplantation survival outcomes. METHODS: The authors compared the survival outcomes of patients ≥60 years of age treated on the phase 2 clinical trial of venetoclax (Ven) added to cladribine (CLAD) and low dose cytarabine (LDAC) alternating with azacitidine (CLAD/LDAC/Ven arm) (NCT03586609) who underwent allogeneic SCT in first remission to a retrospective cohort of patients ≥60 years of age who underwent SCT after intensive chemotherapy. Intensive chemotherapy was defined as the use of cytarabine >1 g/m2 and anthracyclines during induction/consolidation. RESULTS: Thirty-five patients at median age of 68 years in the CLAD/LDAC/Ven arm were compared to 42 patients at a median age of 62 years in the intensive therapy arm. The 2-year relapse-free survival was superior with CLAD/LDAC/Ven versus intensive chemotherapy (88% vs. 65%; p = .03) whereas the 2-year overall survival (OS) was comparable (84% vs. 70%; p = .14). On a competing event analysis, the 2-year cumulative incidence of relapse (CIR) was significantly lower with CLAD/LDAC/Ven versus intensive chemotherapy (2.9% vs. 17.2%, Gray's p = .049) whereas nonrelapse mortality was comparable (16.2% vs. 17.1%; p = .486). CONCLUSION: In conclusion, treatment with CLAD/LDAC/Ven was associated with favorable outcomes in older patients who underwent subsequent allogeneic SCT. The OS was comparable to that with intensive chemotherapy followed by allogeneic SCT, but the CIR rate was significantly lower.

Principal component analysis of phenotypic and breeding value data for semen traits in Egyptian buffalo bulls.

Buffalo bull semen traits are economically important traits that influence farm fertility and profitability. Genetic improvement of semen characteristics is an important detail of the genetic improvement. This study was conducted to assess the relationship between the breeding values as well as the phenotypic values for semen traits (VOL, MM, LS, AS and CONC) of the Egyptian buffalo bulls. A total of 7761 normal semen ejaculates were collected and characterized at ILMTC laboratory from 26 bulls from 2009 to 2019. For VOL, MM, LS, AS, and CONC, the actual means were 3.89 mL, 62.37%, 60.64%, 3.94%, and 0.67 × 109 sperm/mL, respectively. The prediction of breeding values for semen traits was estimated using a Bayesian procedure. The estimated standardized EBVs and phenotypic values were used in the principal component analysis (PCA). Of five PCs, one PC (PC1) had > 1 eigenvalues that was responsible for 87.19% of the total variation of SEBV, and two PCs had > 1 eigenvalues that were responsible for 59.61% and 21.35% of the total variation of the phenotypic values. Together, PC1 and PC2 accounted for 97.97% of the total variance of SEBV and 80.96% of the total variance of phenotypic values. A graphs of the first two components showed the traits separated into two different directions by group. This indicates each group was under similar genetic influence. Therefore, selection can be done separately for each group without influencing the other. Principal component analysis reduced variables to describe the key information in buffalo semen data.

Case report of substantial reconstruction of second ray segment by osteo-tendo-cutaneous pedicled radial forearm flap.

Introduction and importance: The hand is one of the most vital organ that the surgeon aims to preserve its function and natural appearance. Gunshot injuries are common, especially in a war zone, and unfortunately, they create complex wounds that are hard to reconstruct and infection is very common. In this article, we report rebuilding segment of index finger with a pedicled osteo-tendo-cutaneous radial forearm flap. Case presentation: A 50-year-old man-African with no past medical comorbidities, sustained trauma to his left index finger by high-velocity injury that led to composite tissue loss including metacarpal and proximal phalanx. After applying the initial irrigation and dressing to the wound, his hand was supported by a volar cast then he was referred to the hospital. The hand was examined at the operation room and the index finger was found to be hanged with a medial skin pedicle with necrotic and exposed bone and tendon. He underwent a session of debridement followed by reconstruction using a pedicled osteo-cutaneous radial forearm flap accompanied with metacarpophalangeal joint arthrodesis. Clinical discussion: A significant number of war-related hand injuries resulted in amputations because there were not enough facilities or doctors. While they are alternatives to free flap, abdominal and regional flaps won't yield the same outcomes. The second ray of the hand is reshaped using a radial flap, producing an acceptable result. Conclusion: The Radial forearm flap was used to reconstruct segment of index finger and fulfill our requirements, which include bone, tendon, and skin cover. Additionally, this is a simple and single stage procedure and micro-surgical equipment is not necessary.

Dysfunction of Thyroid Hormones Following Acute Coronary Syndrome in a Tertiary Care Hospital in Dhaka City.

In cardiovascular homeostasis thyroid hormone plays an important role. We planned to study the changes in thyroid hormone profile in acute coronary syndrome patients admitted in the coronary care unit and compare them between two groups: unstable angina/non-ST elevated Myocardial infarction (UA/NSTEMI) and ST elevated Myocardial infarction (STEMI). This study was a hospital based descriptive cross sectional study which was conducted from 01 March 2018 to 01 February 2019 in Coronary Care Unit of Bangladesh Medical College Hospital and laboratory tests were done in Microbiology Department of Bangladesh Medical College, Dhaka, Bangladesh. Eighty three cases of acute coronary syndromes were taken for the study. Troponin-I was measured as cardiac marker, Electrocardiogram, Complete blood count, blood glucose level, Blood urea, serum creatinine, serum electrolytes, Fasting lipid profile, Thyroid profile, Echocardiography 2D were done. Most of the respondents were distributed in age group 46-60 years where 34(64.15%) male and 19(35.85%) female. Out of 83 Acute Coronary Syndrome (ACS) patients, 27(32.53%) hypertensive, 22(26.50%) diabetic and 16(19.27%) were Chronic kidney disease (CKD). Abnormal lipid profile was present in 30(43.47%) patients. Among total 52 male and 31 female 9(17.30%) male and 6(19.35%) female had abnormal thyroid function. We further elaborated abnormal thyroid function tests in STEMI group and UA/Non STEMI group of ACS patients. We found 10 patients in STEMI group and 5 patients in UA/Non STEMI group with abnormal thyroid function 29.41% and 10.20% respectively which was not statistically significant (p=0.025). This study depicts abnormality in thyroid hormone profile in 18.07% patients of ACS. Abnormal thyroid function increases risk of coronary artery disease. TSH level of ACS patients on hospital admission could be helpful to evaluate further prognosis of the disease.

Evaluation of Antimicrobial Efficacy and Clinical Outcomes of Triphala and 2.5% Sodium Hypochlorite as Intraradicular Irrigants in Pulpectomy of Primary Teeth.

A natural irrigation solution with a broad spectrum of antimicrobial coverage, triphala was selected for the pulpectomy procedure. Because of its natural ingredients, it is well-known for promoting tissue healing. It also supposedly has certain additional qualities as compared to usual irrigation solutions that are made chemically. Although 2.5% NaOCl is thought to be perfect since it meets most of the requirements for an irrigation solution but it cannot be optimized for pulpectomy procedure. Primary teeth that were recommended for pulpectomy underwent this randomized controlled experiment. Two groups of eighty-four primary teeth were randomly assigned to receive irrigations: triphala in Group A; 2.5% Sodium hypochlorite in Group B. Sample were taken from infected primary root canals. A sterile test tube with bhi broth as the transport media was used to collect pre- and post-irrigation samples using sterile absorbent paper tips. On agar media, microorganisms were cultivated and their mean colony count was assessed. Following the procedure, the patient's follow-up visits at one, two and three months were used to evaluate the clinical result. The post-microbial colony count was dramatically reduced (p<0.001) by both irrigation treatments. Triphala in Group A is demonstrating desirable efficacy. Clinical success was found satisfactory in both the groups studied (p<0.001). But statistically significant difference was not found (p=0.175). Considering undesirable properties of sodium hypochlorite triphala can be a better alternative as a root canal irrigants in pulpectomy of primary teeth.

Novel RP-HPLC method for estimation of a newly developed combination of tizanidine and etoricoxib in rat plasma: Eight criteria for greens evaluation.

A novel environmentally friendly reversed-phase high-performance liquid chromatography (RP-HPLC) method has been effectively validated for simultaneously measuring a prospective conjunction of tizanidine (TIZ) and etoricoxib (ETC), the combined medicine, in rat plasma. The technique employs diclofenac potassium as the internal standard, guaranteeing dependable and precise outcomes. This study aimed to assess the impact of the suggested combination therapy on treating inflammation resulting from rheumatoid arthritis (RA) in a rat model. The procedure was performed using an Agilent series 1200 model HPLC apparatus. The chromatographic conditions consist of isocratic elution mode, C18 column with dimensions of 150 mm × 4.6 mm × 5 µm, flow rate of 1.5 mL/min, wavelength of 230 nm, temperature of 50°C, and injection volume of 10 µL. The elution was performed using a mobile phase consisting of a phosphate buffer with a pH of 3.5 and acetonitrile in a ratio of 80:20 v/v. Calibration curves were conducted for TIZ and ETC within the 1-50 µg/mL range, demonstrating linear trends with R2 values over 0.999. The effectiveness and eco-friendliness of the proposed method were evaluated using eight separate environmentally conscious metrics. The addition of TIZ and ETC to arthritic rodents amplified these effects significantly. Furthermore, TIZ and ETC significantly reduced serum levels in arthritic rodents, and safety investigations revealed normal complete blood count, liver, and renal functions. TIZ and ETC appear to have antiarthritic, anti-inflammatory, and safe combinations, making them viable future treatment options for RA that are also safe and efficacious. Following validation by United States Food and Drug Administration (US-FDA) rules, all goods met the criteria.

Vegetation-edaphic correlation and importance value index in himalayan 'ecotone' temperate conifer forest using the multivariate technique.

Himalayan 'Ecotone' temperate conifer forest is the cradle of life for human survival and wildlife existence. In spite of the importance of these areas, they have not been studied in depth. This study aimed to quantify the floristic structure, important value index (IVI), topographic and edaphic variables between 2019 and 2020 utilizing circular quadrant method (10 m x 10 m). The upper-storey layer consisted of 17 tree species belongs to 12 families and 9 orders. Middle-storey shrubs comprised of 23 species representing 14 families and 12 orders. A total of 43 species of herbs, grasses, and ferns were identified from the ground-storey layer, representing 25 families and 21 orders. Upper-storey vegetation structure was dominated by Pinus roxburghii (22.45 %) and middle-storey by Dodonaea viscosa (7.69 %). However, the ground layer vegetation was diverse in species composition (43 species) and distribution. The floral vegetation structure was encompassing of three floral communities which were diverse in IVI, such as, in Piro-Aial (Group 2), Pinus roxburghii (54.46 x 15.94) had the highest IVI value, followed by Pinus wallichiana (45.21 x 14.85) in Piwa-Quin (Group 3) and Ailanthus altissima (22.84 x 19.25) in Aial-Qugal (Group 1). However, the IVI values for Aesculus indica, Celtis australis, and Quercus incana in Aial-Qugal (Group 1) were not determined due to low detection rate. Nevertheless, eleven of these species showed 0 IVI values in Piro-Aial (Group 2) and Piwa-Quin (Group 3). CCA ordination biplot illustrated the significant differences among floral communities and its distribution, which impacted by temperature, rainfall, soil pH, altitude, and topographic features. Ward's agglomerative clustering finding reflected 'Ecotone' temperate conifer forest is rich and diverse floristic structure.

Pavement ant extract is a chemotaxis repellent for C. elegans.

Ant behavior relies on a collection of natural products, from following trail pheromones during foraging to warding off potential predators. How nervous systems sense these compounds to initiate a behavioral response remains unclear. Here, we used Caenorhabditis elegans chemotaxis assays to investigate how ant compounds are detected by heterospecific nervous systems. We found that C. elegans avoid extracts of the pavement ant ( Tetramorium immigrans ) and either osm-9 or tax-4 ion channels are required for this response. These experiments were conducted in an undergraduate laboratory course, demonstrating that new insights into interspecies interactions can be generated through genuine research experiences in a classroom setting.

Formulation and evaluation of azithromycin-loaded silver nanoparticles for the treatment of infected wounds.

Infected wounds pose a significant challenge in healthcare, requiring innovative therapeutic strategies. Therefore, there is a critical need for innovative pharmaceutical materials to improve wound healing and combat bacterial growth. This study examined the efficacy of azithromycin-loaded silver nanoparticles (AZM-AgNPs) in treating infected wounds. AgNPs synthesized using a green method with Quinoa seed extract were loaded with AZM. Characterization techniques, including X-ray Powder Diffraction (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), and Uv-Vis analysis were utilized. The agar diffusion assay and determination of the MIC were used to assess the initial antibacterial impact of the formulations on both MRSA and E. coli. In addition, the antimicrobial, wound-healing effects and histological changes following treatment with the AZM-AgNPs were assessed using an infected rat model. The nanoparticles had size of 24.9 ± 15.2 nm for AgNPs and 34.7 ± 9.7 nm for AZM-AgNPs. The Langmuir model accurately characterized the adsorption of AZM onto the AgNP surface, indicating a maximum loading capacity of 162.73 mg/g. AZM-AgNPs exhibited superior antibacterial properties in vivo and in vitro compared to controls. Using the agar diffusion technique, AZM-AgNPs showed enhanced zones of inhibition against E. coli and MRSA, which was coupled with decreased MIC levels. In addition, in vivo studies showed that AZM-AgNP treated rats had the best outcome characterized by improved healing process, lower bacterial counts and superior epithelialization, compared to the control group. In conclusion, AZM-AgNPs can be synthesized using a green method with Quinoa seed with successful loading of azithromycin onto silver nanoparticles. In vitro and in vivo studies suggest the promising use of AZM-AgNPs as an effective therapeutic agent for infected wounds.

Tiny Guides, Big Impact: Focus on the Opportunities and Challenges of miR-Based Treatments for ARDS.

Acute Respiratory Distress Syndrome (ARDS) is characterized by lung inflammation and increased membrane permeability, which represents the leading cause of mortality in ICUs. Mechanical ventilation strategies are at the forefront of supportive approaches for ARDS. Recently, an increasing understanding of RNA biology, function, and regulation, as well as the success of RNA vaccines, has spurred enthusiasm for the emergence of novel RNA-based therapeutics. The most common types of RNA seen in development are silencing (si)RNAs, antisense oligonucleotide therapy (ASO), and messenger (m)RNAs that collectively account for 80% of the RNA therapeutics pipeline. These three RNA platforms are the most mature, with approved products and demonstrated commercial success. Most recently, miRNAs have emerged as pivotal regulators of gene expression. Their dysregulation in various clinical conditions offers insights into ARDS pathogenesis and offers the innovative possibility of using microRNAs as targeted therapy. This review synthesizes the current state of the literature to contextualize the therapeutic potential of miRNA modulation. It considers the potential for miR-based therapeutics as a nuanced approach that incorporates the complexity of ARDS pathophysiology and the multifaceted nature of miRNA interactions.

Learning to stand with sensorimotor delays generalizes across directions and from hand to leg effectors.

Humans receive sensory information from the past, requiring the brain to overcome delays to perform daily motor skills such as standing upright. Because delays vary throughout the body and change over a lifetime, it would be advantageous to generalize learned control policies of balancing with delays across contexts. However, not all forms of learning generalize. Here, we use a robotic simulator to impose delays into human balance. When delays are imposed in one direction of standing, participants are initially unstable but relearn to balance by reducing the variability of their motor actions and transfer balance improvements to untrained directions. Upon returning to normal standing, aftereffects from learning are observed as small oscillations in control, yet they do not destabilize balance. Remarkably, when participants train to balance with delays using their hand, learning transfers to standing with the legs. Our findings establish that humans use experience to broadly update their neural control to balance with delays.

Consensus-Based Overarching Principles and Recommendations on the Use of Biosimilars in the Treatment of Inflammatory Arthritis in the Gulf Region.

BACKGROUND: Though biologic agents have significantly improved the treatment of inflammatory arthritis (rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis), high costs, stringent regulations, strict reimbursement criteria, and existing patents have limited patient access to treatments. While being highly similar in quality, safety, and efficacy to biologic reference products, biosimilars can reduce the financial burden and prevent underutilization of medication. OBJECTIVE: The objective of this initiative was to develop an evidence-based consensus of overarching principles and recommendations aimed at standardizing the use of biosimilars in treating inflammatory arthritis in the Gulf region. METHODS: A task force of practicing rheumatologists, a clinical pharmacist, a health economist, patients, regulators, and payors from across the Gulf region developed recommendations and overarching principles based on the outputs of a systematic literature review conducted to address Patient-Intervention-Comparison-Outcome (PICO) questions specific to key challenges regarding the use of biosimilars for the treatment of inflammatory arthritis in the region. As the data before 2017 have been previously reviewed in another publication, the current review focused on data published between January 2017 and August 2022 (PROSPERO ID CRD42022364002). Consensus on each statement required a level of agreement of 70% or greater. RESULTS: Consensus was reached for five overarching principles and nine recommendations by the task force. The principles emphasize the importance of improving the awareness, understanding, and perception of biosimilars, as well as the need for regulated regional real-world data generation and protocols to make biosimilars a viable and affordable treatment option for all patients. The consensus recommendations advocate the need for shared treatment decisions between rheumatologists and patients when considering biosimilars. They further recommend that confirmation of a biosimilar's efficacy and safety in a single indication is sufficient for extrapolation to other diseases for which the reference product has been approved. Finally, there is a need for pharmacovigilance and national health policies governing the adoption and prescription of biosimilars in clinical practice across the region. CONCLUSIONS: These are the first consensus recommendations for the Gulf region based on a systematic literature review and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines, integrating clinical evidence with clinical expertise to optimize decision making for the use of biosimilars in patients with inflammatory arthritis. They were formulated based on predominantly international data because of the limited regional data and therefore can be generalized to serve as recommendations for healthcare professionals in other parts of the world.