Longer Treatment Duration Research Articles

Association of antihypertensives and Parkinson's disease in a primary care population matched for underlying diagnosis.

To examine the association of several antihypertensive medication classes with incidence of Parkinson's disease (PD), taking into account possible underlying conditions. In a case-control study based on a large primary care database and including 21,981 PD cases and 21,981 non-PD controls matched for age, sex, and possible treatment indications associations with different antihypertensive medication groups, including diuretics, betablockers, calcium channel blockers, angiotensin-converting enzyme inhibitors and angiotensin-II receptor-blockers and PD were examined. Antihypertensive medications overall were associated with a lower risk of subsequent diagnosis of PD (OR: 0.94, 95% CI 0.90-0.97), with the negative association most significant for medications acting on the renin-angiotensin-aldosterone system. A positive association with diagnosis of PD was only seen for betablockers and restricted to those with relatively young age and not in those with longer treatment duration. When taking into account underlying diagnoses, antihypertensive medications overall were associated with a reduced incidence of PD.

Glucagon-like peptide-1 receptor agonists modestly reduced blood pressure among patients with and without diabetes mellitus: A meta-analysis and meta-regression.

The cardiovascular benefits provided by glucagon-like peptide-1 receptor agonists (GLP-1RAs) extend beyond weight reduction and glycaemic control. One possible mechanism may relate to blood pressure (BP) reduction. We aim to quantify the BP-lowering effects of GLP1-RAs. A comprehensive database search for placebo-controlled randomized controlled trials on GLP-1RA treatment was conducted until December 2023. Data extraction and quality assessment were carried out, employing a robust statistical analysis using a random effects model to determine outcomes with a mean difference (MD) in mmHg and 95% confidence intervals (CIs). The primary endpoint was the mean difference in systolic BP (SBP) and diastolic BP. Subgroup analyses and meta-regressions were done to account for covariates. Compared with placebo, GLP-1RAs modestly reduced SBP [semaglutide: MD -3.40 (95% CI -4.22 to -2.59, p < .001); liraglutide: MD -2.61 (95% CI -3.48 to -1.74, p < .001); dulaglutide: MD -1.46 (95% CI -2.20 to -0.72, p < .001); and exenatide: MD -3.36 (95% CI -3.63 to -3.10, p < .001)]. This benefit consistently increased with longer treatment durations. Diastolic BP reduction was only significant in the exenatide group [MD -0.94 (95% CI -1.78 to -0.1), p = .03]. Among semaglutide cohorts, mean changes in glycated haemoglobin and mean changes in body mass index were directly associated with SBP reduction. Patients on GLP-1RA experienced modest SBP lowering compared with placebo. This observed effect was associated with weight/body mass index reduction and better glycaemic control, which suggests that BP-lowering is an indirect effect of GLP-1RA and unlikely to be responsible for the benefits.

Continuous Tralokinumab Treatment over 4 Years in Adults with Moderate-to-Severe Atopic Dermatitis Provides Long-Term Disease Control

Introduction: Tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, is approved for the treatment of moderate-to-severe AD in multiple countries. Clinical trials of up to 52-week duration showed tralokinumab was effective and well-tolerated as monotherapy and in combination with TCS. ECZTEND (NCT03587805) is an ongoing open-label, 5-yr extension trial investigating the long-term safety and efficacy of tralokinumab ± optional TCS. To assess the efficacy of long-term tralokinumab treatment, we conducted a post hoc interim subgroup analysis restricted to the largest, most homogenous patient population, with the longest treatment duration.&#x0D; Methods: Adult patients with moderate-to-severe AD who were continuously treated with tralokinumab ± optional TCS for 52 weeks in the phase 3 parents trials (PTs) ECZTRA 1 (NCT03131648) or ECZTRA 2 (NCT03160885) and for up to 152 weeks in ECZTEND as of data cutoff 04/30/2022 were included. Endpoints included proportion of patients achieving IGA 0/1, EASI-75 or EASI-90 relative to PT baseline, EASI ≤7, worst weekly pruritus (itch) NRS ≤4, and DLQI ≤5. Results are presented using observed data (AO). Sensitivity analyses on patients who completed Week152 in ECZTEND (or who withdrew, but were enrolled in the study ≥152 weeks prior to cutoff) were performed using mNRI with discontinuations due to AEs or lack of efficacy imputed as non-responders and a 2-step MI for other missing data.&#x0D; Results: 347 patients with mean age (SD) of 42.2 (14.5) years and mean EASI (SD) of 30.8 (13.7) at PT baseline were included. After 4 years of total tralokinumab treatment (at Week 152 in ECZTEND), IGA 0/1 [% (n/N)] was observed in 52.6% (92/175) of patients. EASI-75 {% (n/N) [95% CI]} was achieved in 84.5% (147/174) [78.4, 89.1] of patients AO, and 73.4% (254.8/347) [68.6, 78.3] using mNRI. EASI-90 was achieved in 64.4% (112/174) [57.0, 71.1] of patients AO, and 53.4% (185.2/347) [47.8, 59.0] using mNRI. EASI ≤7 was observed in 84.5% (147/174), itch NRS ≤4 in 68.0% (119/175), and DLQI ≤5 in 79.0% (128/162) of patients. The safety profile was favorable and consistent with earlier analyses, with no new safety signals arising with continued tralokinumab use.&#x0D; Conclusions: Continuous use of tralokinumab ± optional TCS provided long-term disease control over 4 years in adult patients with moderate-to-severe AD.&#x0D;

Adherence to Growth Hormone Treatment in Children During the COVID-19 Pandemic

Treatment adherence is crucial for the success of growth hormone (GH) therapy. Reported non-adherence rates in GH treatment have varied widely. Several factors may have an impact on adherence. Apart from these factors, the global impact of the Coronavirus disease-2019 (COVID-19) pandemic, including problems with hospital admission and routine follow-up of patients using GH treatment, may have additionally affected the adherence rate. The primary objective of this study was to investigate adherence to treatment in patients receiving GH. In addition, potential problems with GH treatment during the pandemic were investigated. This was a multicenter survey study that was sent to pediatric endocrinologists during the pandemic period (June-December 2021). Patient data, diagnosis, history of pituitary surgery, current GH doses, duration of GH therapy, the person administering therapy (either parent/patient), duration of missed doses, reasons for missed doses, as well as problems associated with GH therapy, missed dose data and the causes in the recent year (after the onset of the pandemic) were questioned. Treatment adherence was categorized based on missed dose rates over the past month (0 to 5%, full adherence; 5.1 to 10% moderate adherence; >10% non-adherence). The study cohort consisted of 427 cases (56.2% male) from thirteen centers. Median age of diagnosis was 8.13 (0.13-16) years. Treatment indications were isolated GH deficiency (61.4%), multiple pituitary hormone deficiency (14%), Turner syndrome (7.5%), idiopathic GH deficiency (7.5%), small for gestational age (2.8%), and “others“ (6.8%). GH therapy was administered by parents in 70% and by patients in 30%. Mean daily dose was 32.3 μg/kg, the annual growth rate was 1.15 standard deviation score (minimum -2.74, maximum 9.3). Overall GH adherence rate was good in 70.3%, moderate in 14.7%, and poor in 15% of the patients. The reasons for non-adherence were mainly due to forgetfulness, being tired, inability to access medication, and/or pen problems. It was noteworthy that there was a negative effect on adherence during the COVID-19 pandemic reported by 22% of patients and the main reasons given were problems obtaining an appointment, taking the medication, and anxiety about going to hospital. There was no difference between genders in the adherence rate. Non-adherence to GH treatment decreased significantly when the patient: administered the treatment; was older; had longer duration of treatment; and during the pandemic. There was a non-significant decrease in annual growth rate as non-adherence rate increased. During the COVID-19 pandemic, the poor adherence rate was 15%, and duration of GH therapy and older age were important factors. There was a negative effect on adherence during the pandemic period.

Comparative efficacy of cyclosporine 0.1%, rebamipide 2%, and carboxymethylcellulose-cyclosporine 0.05% combination eye drops in the management of dry eye disease among the Indian population

This comparative research study aims to evaluate and compare the results of three different eye drop formulations of Cyclosporine 0.1%, Rebamipide 2%, and a combination of Carboxymethylcellulose &amp; Cyclosporine 0.05%, in treating dry eye cases among the Indian population. This investigation employed a randomized controlled trial design to assess the efficacy of three distinct eye drop formulations. A total of 120 patients diagnosed with dry eye disease participated in this study. Participants were assigned to one of three treatment groups: Group C (cyclosporine 0.1%), Group R (rebamipide 2%), or Group CC (combination of carboxymethylcellulose and cyclosporine 0.05%). Patients take prescribed medication for six weeks. Patients were evaluated at baseline for tear production time (TFBUT) at two weeks, four weeks, and six weeks, tear production score using the Schirmer test, and dry eye symptoms were assessed with the Ocular Surface Disease Index (OSDI). The collected data were analyzed using appropriate tests to compare the effectiveness of three eye drop formulations in treating dry eye in the Indian population. : Disease improvement compared to baseline was seen in all groups based on scoring of Schirmer's score, OSDI score, and TBUT. : All three treatment groups demonstrated improvements in tear film stability, tear production, and a reduction in dry eye symptoms over the six-week treatment period. However, further research with larger sample sizes and longer treatment durations is needed to establish the long-term efficacy and compare the effectiveness of these treatments.

The prevalence, clinical reasoning and impact of non-standard anti-tuberculosis regimens at the initial prescription

Regarding clinically-concerning non-standard initial anti-tuberculous (TB) regimens, few studies have examined their prevalence, risk factors and impacts. We recruited patients with drug susceptible TB and non-standard initial anti-TB regimens (NSTB group) and matched them with patients with standard initial regimens (STB group) in a 1:1 ratio. The risk factors and outcomes were analyzed. During the 11-year study period, we analyzed 50 (3.7%) patients with NSTB from a total set of 1337 patients with drug-susceptible TB. Pyrazinamide (60%) was the drug most commonly not prescribed in the NSTB group, followed by ethambutol (34%). Multivariable logistic regression identified independent risk factors as underlying eye disease (adjusted odds ratio [aOR]: 8.869; 95% CI 2.542–30.949; p = 0.001), gout/hyperuricemia (aOR: 4.012 [1.196–13.425]; p = 0.024), and liver disease (aOR: 12.790 [3.981–41.089]; p < 0.001). The NSTB group had longer treatment durations (281 ± 121 vs. 223 ± 63 days; p = 0.003) and more occurrences of treatment interruption (26% vs. 8%; p = 0.021) than the STB group. In conclusion, NSTB occurs in around 3.7% of patients and is associated with longer treatment and more treatment interruption. The risk factors might include underlying liver and eye diseases, and gout. Further studies to improve non-standard initial regimens and prevent negative outcomes are warranted.

Long-term risk of neoplastic events after childhood growth hormone treatment: a population-based cohort study in Sweden.

Increased risk of neoplastic events after recombinant human growth hormone (rhGH) treatment in childhood has been an ongoing concern but long-term safety data are limited. A nationwide population-based cohort study in Sweden of patients treated with rhGH during childhood between 1985-2010, due to isolated growth hormone deficiency (GHD), small for gestational age (SGA) and idiopathic short stature (ISS). The comparison group consisted of 15 age-, sex-, and region-matched controls per patient, randomly selected from the general population. Data on neoplastic events and covariates, such as gestational age, birth weight, birth length, socioeconomic status, and height at study start, were collected through linkage with population-based registers. The cohort was followed for neoplastic events until the end of 2020. 53,444 individuals (3,408 patients; 50,036 controls) were followed for up to 35 years, with a median follow-up of 19.8 years and a total of 1,050,977 person-years. Patients showed a moderately increased hazard ratio (HR) for neoplastic events overall compared to controls (HR 1.28, 95% CI: 1.12-1.46), but only significant for males (HR 1.39, 95% CI: 1.17-1.66) and not females (HR 1.15, 95% CI: 0.94-1.41). Longer treatment duration was associated with an increased HR, but no association was found between neoplastic events and mean or cumulative dose. No increased risk of malignant neoplasms was observed for the patients compared to matched controls (HR 0.91 95% CI: 0.66-1.26). No association was found between rhGH treatment during childhood for GHD, SGA, or ISS and malignant neoplastic events in early to mid-adulthood. A moderate increase in overall neoplastic events was observed due to an increased number of events in male patients.

551 - Continuous tralokinumab treatment over 4 years in adults with moderate-to-severe atopic dermatitis provides long-term disease control

Abstract Introduction/Background There is a need for additional long-term treatment options for patients with moderate-to-severe atopic dermatitis (AD) that provide sustained disease control with a favorable safety profile. Tralokinumab, a monoclonal antibody that specifically neutralizes interleukin-13, is approved for the treatment of moderate-to-severe AD in multiple countries. Clinical trials of up to 52-wk duration showed that tralokinumab was effective and well tolerated as monotherapy and in combination with topical therapy. ECZTEND (NCT03587805) is an ongoing open-label, 5-yr extension trial investigating the long-term safety and efficacy of tralokinumab ± optional topical corticosteroids (TCS). Objectives To assess the efficacy of long-term tralokinumab treatment, we conducted a post hoc interim subgroup analysis restricted to the largest, most homogenous patient population, with the longest treatment duration. Methods Adult patients with moderate-to-severe AD who were continuously treated with tralokinumab ± optional TCS for 52 wks in the parent phase 3 trials ECZTRA 1 (NCT03131648) or ECZTRA 2 (NCT03160885) and for up to 152 wks in ECZTEND as of data cutoff April 30, 2022, were included. Endpoints included proportion of patients achieving Investigator’s Global Assessment (IGA) score of 0/1 (clear/almost clear skin), at least 75% or 90% improvement in Eczema Area and Severity Index (EASI) relative to parent trial baseline (EASI-75 or EASI-90), EASI ≤7, worst weekly pruritus Numeric Rating Scale (NRS) ≤4, and Dermatology Life Quality Index (DLQI) ≤5. Results are presented using observed data. Sensitivity analyses on patients who completed Wk 152 in ECZTEND (or who withdrew, but were enrolled in the study at least 152 wks prior to the study cutoff) were performed using modified non-responder imputation (mNRI) with discontinuations due to AEs or lack of efficacy imputed as non-responders and a 2-step multiple imputation (MI) for other missing data [Step 1: Missing data up to 1 year in ECZTEND were imputed using a standard regression-based MI method; Step 2: Missing data post 1 year imputed by carrying forward the within-subject area under the curve of days in-response]. Results 347 adult patients with a mean age (SD) of 42.2 (14.5) yrs and a mean EASI (SD) of 30.8 (13.7) at parent trial baseline were included in this analysis. After 4 yrs of total tralokinumab treatment (at Wk 152 in ECZTEND), IGA 0/1 [% (n/N)] was observed in 52.6% (92/175) of patients. EASI-75 {% (n/N) [95% CI]} was achieved in 84.5% (147/174) [78.4, 89.1] of patients as observed, and in 73.4% (254.8/347) [68.6, 78.3] using mNRI. EASI-90 was achieved in 64.4% (112/174) [57.0, 71.1] of patients as observed, and in 53.4% (185.2/347) [47.8, 59.0] using mNRI. Additionally, EASI ≤7 (mild disease) was observed in 84.5% (147/174) of patients, worst weekly pruritus NRS ≤4 (no to mild itch) in 68.0% (119/175), and DLQI ≤5 (no to small effect of AD on quality of life) in 79.0% (128/162) of patients. The safety profile was favorable and consistent with earlier analyses, with no new safety signals arising with continued tralokinumab use. Conclusions Continuous use of tralokinumab ± optional TCS provided long-term disease control over 4 yrs in adult patients with moderate-to-severe AD.

Differences in bone histomorphometry between White postmenopausal women with and without atypical femoral fracture after long-term bisphosphonate therapy.

Bone histomorphometric endpoints in transilial biopsies may be associated with an increased risk of atypical femoral fracture (AFF) in patients with osteoporosis who take antiresorptives, including bisphosphonates (BPs). One way to test this hypothesis is to evaluate bone histomorphometric endpoints in age-, gender-, and treatment time-matched patients who either had AFF or did not have AFF. In this study, we performed transiliac bone biopsies in 52 White postmenopausal women with (n= 20) and without (n= 32) AFFs, all of whom had been treated for osteoporosis continuously with alendronate for 4-17yr. Despite the matched range of treatment duration (4-17yr), AFF patients received alendronate for significantly longer time (10.7yr) than non-AFF patients (8.0yr) (P= .014). Bone histomorphometric endpoints reflecting microstructure and turnover were assessed in cancellous, intracortical, and endocortical envelopes from transilial biopsy specimens obtained from BP-treated patients 3-6mo after AFF and from non-AFF patients with similar age-, gender-, and range of BP treatment duration. However, in both cancellous and intracortical envelopes, AFF patients had significantly lower wall thickness (W.Th) and higher osteoclast surface (Oc.S/BS) than non-AFF patients. In addition, AFF patients had significantly higher eroded surface (ES/BS) only in the intracortical envelope. None of the dynamic variables related to bone formation and turnover differed significantly between the groups. In conclusion, in the ilium of BP-treated patients with osteoporosis, AFF patients have lower thickness of superficial bone (lower W.Th) of the cancellous and cortical envelopes than non-AFF patients. AFF and non-AFF patients have a similar bone turnover rate in the ilium. Furthermore, in this population, as in previous work, AFF is more likely to occur in BP-treated patients with longer treatment duration.

Semaglutide improves metabolic dysfunction-associated steatohepatitis: A 10-year retrospective study.

Semaglutide has been studied in patients with metabolic dysfunction-associated steatohepatitis (MASH) due to potential benefit from weight loss on liver inflammation. However, preclinical studies suggest that MASH improvement may be independent of weight loss. We aim to assess the impact of semaglutide on MASH in relation to weight loss. This retrospective study included 420 patients with diabetes on semaglutide for at least 12 months between 2011 and 2022. Exclusion criteria were liver disease other than MASH, decompensated cirrhosis, malignancy, and bariatric surgery. Primary endpoints were clinically significant improvements in AST or ALT (mean difference > 6.3 U/L and > 10.6 U/L respectively). Statistical analysis included Student's t-test/ANOVA, Wilcoxon signed-rank test/Friedman test as appropriate, and binary logistic regression. Median duration of semaglutide was 22.5 months and 80% of patients received 1 mg/week. BMI improved by a mean (SD) of 1.9 points (2.8), weight by 13.3 lbs. (19.1), AST by 4.1 U/L (11.5), and ALT by 5.3 U/L (14.2). In 28% and 22% of patients respectively, AST and ALT had a clinically significant improvement. MASH scores (NFS, FIB4, APRI) improved after semaglutide (p < 0.001). No statistically significant differences in AST or ALT improvement were found when patients were stratified by BMI prior to semaglutide or when stratified by percentage of weight loss. On logistic regression, the duration of semaglutide and pretreatment APRI score increased the odds of clinically significant improvements of AST and ALT. Semaglutide treatment was associated with improvement in transaminases and MASH scores. Higher odds of positive semaglutide effects were observed with longer treatment duration and were independent of weight loss.

Effect of Curcumin on Dysmenorrhea and Symptoms of Premenstrual Syndrome: A Systematic Review and Meta-Analysis.

Dysmenorrhea and premenstrual syndrome (PMS) are common periodic and frequent complications in women of reproductive age that can negatively affect health and quality of life. The present study examined the effects of curcumin on the severity of dysmenorrhea and PMS symptoms. A systematic review and meta-analysis of randomized controlled trials was conducted by searching databases such as the Cochrane Library, EMBASE, Scopus, PubMed, and Web of Science from inception to January 2023. Article screening was performed using Endnote ver. X8 (Clarivate). Review Manager (RevMan ver. 5.3; Cochrane) was used for the quality assessment and meta-analysis. A total of 147 studies were screened, of which five were finally selected for quantitative and qualitative analyses. The studies were conducted between 2015 and 2021, and a total of 379 participants with a mean age of 23.33±5.54 years had been recruited in these studies. The meta-analysis showed that curcumin consumption could significantly reduce the severity of dysmenorrhea (mean difference, -1.25; 95% confidence interval [CI], -1.52 to -0.98; three studies; I2=31%) and the overall score of PMS (standardized mean difference, -1.41; 95% CI, -1.81 to -1.02; two studies; I2=0%). The reduction in the severity of PMS and dysmenorrhea has been attributed to curcumin's anti-inflammatory and antidepressant activities. Although the findings suggest that curcumin may be an effective treatment for reducing the severity of PMS and dysmenorrhea, further research with a larger number of participants from various socioeconomic levels and a longer duration of treatment is needed to evaluate the effective dose of curcumin.

Situation Analysis of Early Implementation of Programmatic Management of Tuberculosis Preventive Treatment among Household Contacts of Pulmonary TB Patients in Delhi, India.

Tuberculosis Preventive Treatment (TPT) is a powerful tool for preventing the TB infection from developing into active TB disease, and has recently been expanded to all household contacts of TB cases in India. This study employs a mixed-methods approach to conduct a situational analysis of the initial phase of TPT implementation among household contacts of pulmonary TB patients in three districts of Delhi, India. It was completed using a checklist based assessments, care cascade data, and qualitative analysis. Our observations indicated that organizational structure and planning were established, but implementation of TPT was suboptimal with issues in drug availability and procurement, budget, human resources, and training. Awareness and motivation, and shorter regimen, telephonic assessment, and collaboration with NGOs emerged as enablers. Apprehension about taking TPT, erratic drug supply, long duration of treatment, side effects, overburden, large population, INH resistance, data entry issues, and private provider reluctance emerged as barriers. The study revealed potential solutions for optimizing TPT implementation. It is evident that, while progress has been made in TPT implementation, there is room for improvement and refinement across various domains.

Clinical Evaluation of Mahanarayana Taila Matra Basti in Anidra (Primary Insomnia)

Sleep is a naturally recurring state of mind and body. Insomnia disorder is defined as a subjective perception or complaint of inadequate or poor-quality sleep. Anidra has been described in detail by Acharyas in various contexts like Vata Nanatmaja Vikara, Vataja Jwara etc. Panchkarma therapies like Shirodhara, Shirobasti, Shiroabhyang, Shiropichu, Padaabhyang is very useful in treatment of Anidra. Insomnia is the most commonly encountered sleep disorder and occurs 10-50% of the population. Worldwide epidemiological studies assessed the prevalence of insomnia without restrictive criteria as 33% in general population. In Ayurveda, insomnia is described as Anidra and Nidranash under the heading of different disorders and conditions. Allopathic hypnotic drugs are useful for short term treatment in insomnia which is due to acute stage. Long term uses of certain classes of sedatives cause physical dependence, Ayurvedic approach in the disease is by pacifying the Doshas, paying special attention to Vata- Shamana, Santarpana and Srotoshodhak. Hence, with the aim of identifying and establishing an alternative, safer, effective and long-lasting treatment modality, the study entitled “Clinical Evaluation of Mahanarayana Taila Matra Basti in Anidra (Primary Insomnia)” was conducted in 56 patients. They were selected on the basis of standard inclusion and exclusion criteria and randomly allocated to two different treatment groups; Group- A (Mahanarayana Taila Matra Basti) and Group- B (Zolpidem). Total duration of the treatment was of 14 days along with a follow up period of 1 month. Both the interventions were almost equally effective, but in overall improvement of the patients “Group A” had better results than Group B. For better scientific validation, further research studies and clinical trials should be carried out with large sample size and longer duration of treatment.

Mycobacterial β-carbonic anhydrases: Molecular biology, role in the pathogenesis of tuberculosis and inhibition studies.

Mycobacterium tuberculosis (Mtb), which causes tuberculosis (TB), is still a major global health problem. According to the World Health Organization (WHO), TB still causes more deaths worldwide than any other infectious agent. Drug-sensitive TB is treatable using first-line drugs; treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB requires second- and third-line drugs. However, due to the long duration of treatment, the noncompliance of patients with different levels of resistance of Mtb to these drugs has worsened the situation. Previously developed anti-TB drugs targeted the replication machinery, protein synthesis, and cell wall biosynthesis pathways of Mtb. Therefore, novel drugs targeting alternate pathways crucial for the survival and pathogenesis of Mtb in the human host are needed. The genome of Mtb encodes three β-carbonic anhydrases (CAs) that are fundamental for pH homeostasis, hypoxia, survival, and pathogenesis. Recently, several studies have shown that the β-CAs of Mtb could be inhibited both in vitro and in vivo using small chemical molecules, suggesting that these enzymes could be novel targets for developing anti-TB compounds that are devoid of resistance by Mtb. In addition, homologs of β-CAs are absent in humans; therefore, drugs developed to target these enzymes might have minimal off-target effects. In this work, we describe the roles of β-CAs in Mtb and discuss bioinformatics and cheminformatics tools used in development and discovery of novel inhibitors of these enzymes. In addition, we summarize the in vitro and in vivo studies demonstrating that the β-CAs of Mtb are indeed druggable targets.

The protective role of chemokines 12 and chemokines 4 by mediating interleukin-6 in delayed diabetic foot wound healing

Refractory diabetic foot ulcer is commonly encountered in clinical practice and it is hardly cured with a long duration of treatment and a high expense, as such problem involves multiple disciplines. Therefore, in case of refractory wounds, it is necessary to first analyze the causes, general or local. Immunohistochemistry (IHC) was conducted to determine α-SMA, chemokines 12 (CXCL12) and chemokines 4 (CXCR4) levels in pancreatic tissues and distant normal pancreatic tissues. Cells were treated with recombinant human CXCL12 (rhCXCL12) or the CXCR4 antagonist AMD3100. After treatment, Western blot determined FAK-AKT and ERK1/2 expression in islet cells, whilst ELISA detected the content of IL-6 and IL-8. rhCXCL12 increased the expression and secretion of Interleukin-6 (IL-6) time- and dose-dependently. But the advent of CXCR4 antagonist abrogated the protective effect of rhCXCL12. rhCXCL12 exhibited a protective effect on apoptosis, but this effect was abrogated by down-regulation of IL-6 with AMD3100. In addition, rhCXCL12 increased the phosphorylation of FAK, ERK1/2, AKT, and P38 and inhibition of FAK inhibited IL-6 expression. FAK inhibition almost completely blocked CXCL12-induced activation. This study demonstrates that CXCL12/CXCR4 pathway mediates the expression of IL-6 to enhance healing of refractory diabetic foot wounds by down-regulating the FAK pathway.

Modeling Sex-Bias in Anxiety: Pros and Cons of a Larval Zebrafish Model

Anxiety disorders are the most prevalent psychiatric disorders, exhibiting strong female bias. Clinical studies implicate declining estradiol levels in the exacerbation of anxiety symptoms in the premenstrual phase of the menstrual cycle. This study aimed to simulate estradiol fluctuation-linked anxiety behavior in larval zebrafish, using an estradiol treatment withdrawal model. Contrary to model aims, estradiol treatment withdrawal decreased both basal activity and anxiety-like hyperlocomotion (ANOVA main effect of dose, P < 0.0001 and P < 0.01, respectively) in the light/dark transition test. The accuracy of the estradiol washout model was not improved by longer durations of treatment or withdrawal. Basal activity was slightly altered by supraphysiological concentrations of WAY-200070 in the absence of added estradiol. Estrogen receptor (ER) β expression was not upregulated in larvae exposed to physiologically relevant, low concentrations of estradiol. Longer exposure to low concentrations of estradiol increased antioxidant capacity (P < 0.01). In addition, acute exposure to low concentrations of estradiol increased basal activity. Data suggest that in the current models, estradiol-associated altered activity levels were linked to more favorable redox status, rather than reflecting altered anxiety levels. As such, it is recommended that zebrafish larval behavioral analysis be conducted in parallel with mechanistic studies such as redox indicators, for investigations focused on ER signaling.

Factors Affecting the Response and Patient Satisfaction of Topical Immunotherapy in Alopecia Areata: A Nationwide Study.

Contact immunotherapy using diphenylcyclopropenone (DPCP) is a recommended treatment for severe alopecia areata (AA); however, few clinical factors are known, and few standardized application methods affecting therapeutic efficacy have been devised. To confirm the therapeutic response of DPCP immunotherapy in AA, first we analyze the factors influencing its outcome and patient satisfaction levels, after which we standardize the DPCP treatment method for better outcomes. We utilized a nationwide questionnaire-based survey to assess patient satisfaction and undertook a medical record review involving 412 patients currently undergoing treatment for DPCP. The patients' mean age was 36.4 years, and 27% of the cases were diagnosed as AA in childhood. Treatment response was higher when DPCP was used to treat the entire scalp, including subclinical lesions, and longer treatment durations and longer intervals between treatments were associated with a better treatment response. Atopy (atopic dermatitis, allergic rhinitis and bronchial asthma), thyroid disorder, and extent of hair loss were all negatively correlated with the treatment response. However, there was no correlation between the treatment response and factors such as the age of onset, a family history of AA, nail changes, or AA duration, which are commonly known to be associated with a poor prognosis. DPCP immunotherapy is an effective treatment for AA, and the study demonstrated the factors affecting DPCP treatment response and patients' satisfaction and may contribute to standardizing the DPCP treatment method for better outcomes.

Exploring Drug Utilization Patterns and Adverse Drug Reactions in the Management of Osteoarthritis: A Prospective Study

Aim/Background Osteoarthritis (OA) is a degenerative joint disease characterized by pain and functional impairment, leading to significant healthcare challenges. Pharmacological management, including NSAIDs, analgesics, disease-modifying osteoarthritis drugs (DMOADs), and corticosteroids, is commonly used. However, limited data exist on drug utilization patterns and adverse drug reactions (ADRs) in OA treatment. This study aimed to evaluate these patterns and identify potential ADRs in patients with OA. Methods This prospective study included OA patients from diverse backgrounds. Baseline demographic data, disease severity, and treatment history were recorded. Drug utilization was monitored, focusing on NSAIDs, analgesics, DMOADs, corticosteroids, and alternative therapies. ADRs were identified through patient self-reports, clinician observations, and medical record reviews. Statistical analysis examined drug prescription trends, ADR frequency, severity, and associated risk factors. Results NSAIDs were the most frequently prescribed drugs (44.45%), followed by analgesics and DMOADs. Gastrointestinal discomfort was the most commonly reported ADR, particularly among NSAID users. Corticosteroids were linked to systemic side effects in a minority of patients. Advanced age, longer treatment duration, and existing gastrointestinal conditions were significant risk factors for ADRs. Conclusion The study underscores the widespread use of NSAIDs in OA treatment and highlights the need for careful monitoring due to potential ADRs, especially gastrointestinal issues. Identifying risk factors helps clinicians make informed prescribing decisions, improving patient outcomes and minimizing ADRs. Future research should focus on optimizing drug therapies to ensure better safety and efficacy in OA management.

The potential of several compounds in Peperomia pellucida as a solution to rifampicin resistance in tuberculosis disease

Background: Tuberculosis is a lung disease caused by Mycobacterium tuberculosis. In 2018, the incidence of tuberculosis in Indonesia was 1,017,290. The number of cases was accompanied by an increase in the number of resistances to first-line antibiotics (rifampicin) used due to patient non-compliance as well as the long duration of treatment. The increase in resistance around the world is always increasing every year by about 2%. Therefore, we need another alternative to existing plants in Indonesia that has the potential to be a solution to the problem and overcome resistance to these treatments.Objective: This review was conducted to find out the potential of Peperomia pellucida as an antituberculosis drug that can be a solution to rifampicin resistance in tuberculosis disease. Results: The results of the literature review showed that the Peperomia pellucida or suruhan plants have antibacterial potential against Mycobacterium tuberculosis because it contains a class of alkaloid compounds that function to inhibit deprenyl-phosphoryl-β-D-ribose-2 oxidase (an enzyme responsible for the biosynthesis of arabinogalactan in the cell walls of Mycobacterium tuberculosis), a flavonoid that has activity inhibition of fatty acid synthase II (FAS-II) enzymes, tannins that can precipitate proteins in Mycobacterium tuberculosis, and triterpenoids that have an activation mechanism of intracellular killing cascades in host cells during tuberculosis bacterial infection.Conclusion: Peperomia pellucida or suruhan plants have the potential to be further investigated as a solution to overcome rifampicin resistance in tuberculosis disease.Keywords: Mycobacterium tuberculosis, rifampicin resistance, Peperomia pellucida

Long- versus short-duration systemic corticosteroid regimens for acute exacerbations of COPD: A systematic review and meta-analysis of randomized trials and cohort studies.

While systemic corticosteroids quicken patient recovery during acute exacerbations of COPD, they also have many adverse effects. The optimal duration of corticosteroid administration remains uncertain. We performed a systematic review and meta-analysis to compare patient outcomes between short- (≤7 days) and long- (>7 days) corticosteroid regimens in adults with acute exacerbations of COPD. MEDLINE, EMBASE, CENTRAL, and hand searches were used to identify eligible studies. Risk of bias was assessed using the Cochrane RoB 2.0 tool and ROBINS-I. Data were summarized as ORs (odds ratios) or MDs (mean differences) whenever possible and qualitatively described otherwise. A total of 11532 participants from eight RCTs and three retrospective cohort studies were included, with 1296 from seven RCTs and two cohort studies eligible for meta-analyses. Heterogeneity was present in the methodology and settings of the studies. The OR (using short duration as the treatment arm) for mortality was 0.76 (95% CI = 0.40-1.44, n = 1055). The MD for hospital length-of-stay was -0.91 days (95% CI = -1.81--0.02 days, n = 421). The OR for re-exacerbations was 1.31 (95% CI = 0.90-1.90, n = 552). The OR for hyperglycemia was 0.90 (95% CI = 0.60-1.33, n = 423). The OR for infection incidence was 0.96 (95% CI = 0.59-1.156, n = 389). The MD for one-second forced expiratory volume change was -18.40 mL (95% CI = -111.80-75.01 mL, n = 161). The RCTs generally had low or unclear risks of bias, while the cohort studies had serious or moderate risks of bias. Our meta-analyses were affected by imprecision due to insufficient data. Some heterogeneity was present in the results, suggesting population, setting, and treatment details are potential prognostic factors. Our evidence suggests that short-duration treatments are not worse than long-duration treatments in moderate/severe exacerbations and may lead to considerably better outcomes in milder exacerbations. This supports the current GOLD guidelines. Trial registration: Our protocol is registered in PROSPERO: CRD42023374410.