Assessing the therapeutic and toxicological profile of novel GLP-1 receptor agonists for type 2 diabetes.

INTRODUCTION: GLP-1 receptor agonists provide multiple benefits for patients with type 2 diabetes. Nonetheless, there are also several significant adverse effects associated with these agents. A thorough understanding of both therapeutic and toxicological profiles of GLP-1 receptor agonists is crucial for appropriate utilization of this medication class. A literature search of PubMed and ClinicalTrials.gov was carried out to inform discussion on the topic. AREAS COVERED: This review article discusses the key advantages and disadvantages derived from the use of GLP-1 receptor agonists in the treatment of type 2 diabetes. Landmark trials which helped characterize the cardiovascular and renal benefits of GLP-1 receptor agonists are highlighted. We also discuss key studies still in progress and new formulations under investigation. EXPERT OPINION: GLP-1 receptor agonists provide glycemic and complication-risk reduction benefits for individuals with type 2 diabetes. Current data suggests there is a lot of potential for further applications, even outside of type 2 diabetes management. It would be of particular interest to see the range of benefits conferred from GLP-1 receptor agonists in individuals without type 2 diabetes. Broader application of these medications could be expected given the ongoing development of new oral formulations and combination agents.

Bestrophin-like protein 4 is involved in photosynthetic acclimation to light fluctuations in Chlamydomonas.

In many eukaryotic algae, CO2 fixation by Rubisco is enhanced by a CO2-concentrating mechanism, which utilizes a Rubisco-rich organelle called the pyrenoid. The pyrenoid is traversed by a network of thylakoid membranes called pyrenoid tubules, which are proposed to deliver CO2. In the model alga Chlamydomonas (Chlamydomonas reinhardtii), the pyrenoid tubules have been proposed to be tethered to the Rubisco matrix by a bestrophin-like transmembrane protein, BST4. Here, we show that BST4 forms a complex that localizes to the pyrenoid tubules. A Chlamydomonas mutant impaired in the accumulation of BST4 (bst4) formed normal pyrenoid tubules, and heterologous expression of BST4 in Arabidopsis (Arabidopsis thaliana) did not lead to the incorporation of thylakoids into a reconstituted Rubisco condensate. Chlamydomonas bst4 mutants did not show impaired growth under continuous light at air level CO2 but were impaired in their growth under fluctuating light. By quantifying the non-photochemical quenching (NPQ) of chlorophyll fluorescence, we propose that bst4 has a transiently lower thylakoid lumenal pH during dark-to-light transition compared to control strains. We conclude that BST4 is not a tethering protein but is most likely a pyrenoid tubule ion channel involved in the ion homeostasis of the lumen with particular importance during light fluctuations.

Exploring chemical space, scaffold diversity, and activity landscape of spleen tyrosine kinase active inhibitors.

This study aims to comprehensively characterize 576 inhibitors targeting Spleen Tyrosine Kinase (SYK), a non-receptor tyrosine kinase primarily found in haematopoietic cells, with significant relevance to B-cell receptor function. The objective is to gain insights into the structural requirements essential for potent activity, with implications for various therapeutic applications. Through chemoinformatic analyses, we focus on exploring the chemical space, scaffold diversity, and structure-activity relationships (SAR). By leveraging ECFP4 and MACCS fingerprints, we elucidate the relationship between chemical compounds and visualize the network using RDKit and NetworkX platforms. Additionally, compound clustering and visualization of the associated chemical space aid in understanding overall diversity. The outcomes include identifying consensus diversity patterns to assess global chemical space diversity. Furthermore, incorporating pairwise activity differences enhances the activity landscape visualization, revealing heterogeneous SAR patterns. The dataset analysed in this work has three activity cliff generators, CHEMBL3415598, CHEMBL4780257, and CHEMBL3265037, compounds with high affinity to SYK are very similar to compounds analogues with reasonable potency differences. Overall, this study provides a critical analysis of SYK inhibitors, uncovering potential scaffolds and chemical moieties crucial for their activity, thereby advancing the understanding of their therapeutic potential.

Exploring the antimicrobial and cytotoxic potential of novel chloroquine analogues.

Aim: To synthesize novel chloroquine analogues and evaluate them for antimicrobial and cytotoxic potential. Methods: Novel analogues were synthesized from chloroquine by nucleophilic substitution reaction at the 4-amino position. Results: Analogue CS1 showed maximum antimicrobial potential (30.3 ± 0.15 mm zone) against Pseudomonas aeruginosa and produced a 19.2 ± 0.21 mm zone against Candida albicans, while CS0 produced no zone at the same concentration. Analogue CS9 has excellent cytotoxic potential (HeLa cell line), showing 100% inhibition (IC50 = 8.9 ± 1.2 µg/ml), compared with CS0 (61.9% inhibition at 30 µg/ml). Conclusion: These synthesized chloroquine analogues have excellent activity against different microbial strains and cervical cancer cell lines (HeLa) compared with their parent molecule.

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Unveiling the Latest Advancements in Vanadium Carbide MXene based Supercapacitors and their Future Trends.

Vanadium-carbide-based MXenes have bewitched the scientific community due to their distinctive characteristics, which make them potential candidates for several technological applications, such as supercapacitors (SCs), batteries, gas separation, biological sensors, and desalination. This article provides an overview of recent developments in the synthesis and applications of vanadium-carbide MXene in SCs. Vanadium carbide is one of the most difficult MXenes to synthesize, and various synthesis techniques, including electrochemical exfoliation and chemical etching, have been utilized to fabricate this material. Additionally, the review article also emphasizes the potential use of vanadium carbide MXene as SCs. Finally, the paper concludes with the challenges faced in the synthesis process and the prospects of vanadium carbide MXene-based material fabrication. Overall, this review article provides in-depth and detailed information on recent research on vanadium carbide MXene and its possible uses.

Encephalopathy of Autoimmune Origin: Steroid-Responsive Encephalopathy With Associated Thyroiditis.

Background/Objective: Our objective is to highlight the importance of identifying symptoms of steroid-responsive encephalopathy with associated thyroiditis (SREAT), especially in the setting of intermittent cognitive dysfunction, and to inform that SREAT can develop even in patients with a history of partial thyroidectomies. Case Report: We present a case of a 51-year-old woman with a long-standing history of hypothyroidism presenting with acute onset myoclonus, involuntary tremors, fatigue, malaise, and palpitations for two weeks, with intermittent lapses in cognitive function. The patient's workup is completely within normal limits, including her cognition, except for elevated thyroid stimulating hormone levels and markedly elevated levels of antithyroid peroxidase antibodies, despite the fact that she previously had a partial thyroidectomy. Discussion: SREAT is an autoimmune condition characterized by cognitive dysfunction, elevated thyroid autoantibodies, and therapeutic response to corticosteroids. SREAT is primarily considered a diagnosis of exclusion. A crucial feature is the hallmark of significant improvement in symptoms when glucocorticoids are administered. There is a significant correlation between patients with elevated antithyroid peroxidase antibodies and new-onset SREAT. Although total thyroidectomy has been reported as a definitive treatment of SREAT, response to corticosteroids is the "sine qua non" in diagnosing this condition. Conclusion: Hashimoto's thyroiditis can lead to a rare complication called SREAT, presenting with various neurologic symptoms. Prompt glucocorticoid treatment is vital, and a positive response confirms the diagnosis. Total thyroidectomy may be necessary for definitive SREAT treatment. More research is needed for alternate treatments and an understanding of the pathophysiology of SREAT.

Unilateral Thyroid Lobe Involvement of Graves Disease.

A 30-year-old man presented with 3-year history of Graves disease. He was initially diagnosed after he developed unilateral proptosis and was initiated on methimazole 5 mg, on which he was currently euthyroid. Visible right-sided thyromegaly and trouble swallowing developed 2 months after presentation to our practice. Biochemical evaluation revealed suppressed TSH, normal free T4 and total T3, and elevated thyroid stimulating immunoglobulin with normal thyroid receptor antibody. An ultrasound of the thyroid demonstrated left-sided small nodules with right-sided thyromegaly. A nuclear medicine uptake scan revealed significantly greater uptake in the right thyroid lobe, with overall minimal uptake in the left lobe. The need for definitive therapy that would not exacerbate orbitopathy was discussed, and the patient elected for a right-sided hemithyroidectomy. Postoperative biochemical evaluation demonstrated biochemical euthyroidism despite continued elevation in thyroid stimulating immunoglobulin and newly elevated thyroid receptor antibody while remaining off methimazole. Graves disease can rarely involve a single thyroid lobe. Given the rarity, further investigation is needed to determine the natural course of this form of Graves disease.

The role of BST4 in the pyrenoid of Chlamydomonas reinhardtii.

In many eukaryotic algae, CO2 fixation by Rubisco is enhanced by a CO2-concentrating mechanism, which utilizes a Rubisco-rich organelle called the pyrenoid. The pyrenoid is traversed by a network of thylakoid-membranes called pyrenoid tubules, proposed to deliver CO2. In the model alga Chlamydomonas reinhardtii (Chlamydomonas), the pyrenoid tubules have been proposed to be tethered to the Rubisco matrix by a bestrophin-like transmembrane protein, BST4. Here, we show that BST4 forms a complex that localizes to the pyrenoid tubules. A Chlamydomonas mutant impaired in the accumulation of BST4 (bst4) formed normal pyrenoid tubules and heterologous expression of BST4 in Arabidopsis thaliana did not lead to the incorporation of thylakoids into a reconstituted Rubisco condensate. Chlamydomonas bst4 mutant did not show impaired growth at air level CO2. By quantifying the non-photochemical quenching (NPQ) of chlorophyll fluorescence, we show that bst4 displays a transiently lower thylakoid lumenal pH during dark to light transition compared to control strains. When acclimated to high light, bst4 had sustained higher NPQ and elevated levels of light-induced H2O2 production. We conclude that BST4 is not a tethering protein, but rather is an ion channel involved in lumenal pH regulation possibly by mediating bicarbonate transport across the pyrenoid tubules.

Glucagon-Like Peptide 1 Analogues as Adjunctive Therapy for Patients With Type 1 Diabetes: An Updated Systematic Review and Meta-analysis.

CONTEXT: Concomitant obesity is common among patients with type 1 diabetes mellitus (T1DM), yet adjunctive therapy options are scarce. OBJECTIVE: We assess the efficacy and adverse outcomes of glucagon-like peptide 1 (GLP-1) analogues when used as adjunctive therapy for T1DM. METHOD: PubMed, EMBASE, Cochrane Central, and Scopus databases were searched for randomized controlled trials up to December 2022. Efficacy outcomes were A1c level, body weight, and total daily insulin (TDI) after ≥12 weeks of GLP-1 therapy. We also assessed 12 different adverse outcomes. Subgroup analysis was done for newly diagnosed or C-peptide positive (C-pos) patients. We report the certainty of evidence based on the GRADE assessment tool. RESULTS: A total of 24 studies using 4 different GLP-1 analogues with a total of 3377 patients were included. Liraglutide had the most substantial evidence with effect sizes on A1c (-0.09%/mg), weight (-2.2 kg/mg), and TDI (-4.32 IU/mg). Liraglutide dose was the greatest predictor of greater average weight loss and TDI decrease but was associated with higher odds of nausea (OR 6.5; 95% CI, 5.0-8.4) and ketosis (OR 1.8; 95% CI, 1.1-2.8). Odds of severe (OR 0.67; 95% CI, 0.43-1.04) or symptomatic hypoglycemia (OR 0.89; 95% CI, 0.53-1.51) were not significantly elevated. Among C-pos patients, greater A1c decrease (-0.51% vs -0.28%) but similar weight loss and TDI were seen. Effect sizes for exenatide were similar, but studies had higher risk of bias and safety data were sparse. CONCLUSION: Our meta-analysis supports therapeutic benefits of liraglutide for patients with T1DM mainly for weight loss and insulin dose reduction. Newly diagnosed or C-pos patients do not appear to experience greater weight loss benefits.

Efficacy of recurrent transcutaneous magnetic stimulation in the treatment of diabetic peripheral neuropathy: Multicenter randomized trial.

AIMS: Transcutaneous magnetic stimulation (TCMS) is successful in decreasing pain in several neurologic conditions. This multicenter parallel double-blind phase II clinical trial is a follow-up to a pilot study that demonstrated pain relief in patients with diabetic peripheral neuropathy (DPN) treated with TCMS. METHODS: Thirty-four participants with confirmed DPN and baseline pain score ≥ 5 were randomized to treatment at two sites. Participants were treated with either TCMS (n = 18) or sham (n = 16) applied to each foot once a week for four weeks. Pain scores using the Numeric Pain Rating Scale after 10 steps on a hard floor surface and answers to Patient-Reported Outcomes Measurement Information System pain questions were recorded by participants daily for 28 days. RESULTS: Thirty-one participants completed the study and were analyzed. Average pain scores decreased from baseline in both the groups. The difference in pain scores between TCMS and sham treatments was -0.55 for morning, -0.13 for evening, and -0.34 overall, below the pre-determined clinically relevant difference of -2. Moderate adverse events that resolved spontaneously were experienced in both treatment arms. CONCLUSION: In this two-arm trial, TCMS failed to demonstrate a significant benefit over sham in patient reported pain suggesting a substantial placebo effect in our previous pilot study. TRIAL REGISTRATION: TCMS for the Treatment of Foot Pain Caused By Diabetic Neuropathy, https://clinicaltrials.gov/ct2/show/NCT03596203, ID-NCT03596203.

Association between bisphosphonate use and stroke risk: a meta-analysis.

Previous studies have suggested that bisphosphonates may reduce stroke risk. This meta-analysis, which included 21 studies with 741,274 participants, revealed that bisphosphonates might be associated with lower stroke risk. However, evidence derived from randomized controlled trials identified no statistically significant association. Future high-quality studies are still required to determine causality. PURPOSE: Whether bisphosphonates may reduce the risk of stroke remains inconclusive. We conducted a systematic review and meta-analysis to evaluate the association between bisphosphonate use and the risk of stroke based on up-to-date evidence. METHODS: We searched for studies evaluating the effects of bisphosphonate on the risk of stroke from inception until January 3, 2022, on PubMed, Embase, Scopus, and Cochrane libraries and updated our search until August 22, 2022, using PubMed to identify any new potential published studies. Two or more reviewers independently screened articles, extracted data, and assessed the study quality. We retrieved the data to synthesize the pooled relative risk (RR) of stroke associated with bisphosphonate use compared with controls; random-effects models were used for meta-analysis. RESULTS: A total of 21 studies (7 randomized controlled trials [RCTs] and 14 observational studies) involving 741,274 participants were included in our meta-analysis. Overall, bisphosphonate use was associated with a lower risk of stroke, but the result was only borderline significant (pooled RR = 0.87, 95% confidence interval [CI]: 0.76-0.99, p = 0.048), and high between-study heterogeneity was found (I2 = 83.7%). Subgroup analyses showed that the evidence derived from RCTs suggested no significant association between bisphosphonate use and stroke risk (pooled RR = 0.93, 95% CI: 0.76-1.13, p = 0.462; I2 = 13.4%). CONCLUSION: Our results suggest that bisphosphonate use is associated with a lower risk of stroke. However, the current evidence does not lead to a definite conclusion due to the borderline statistical significance and high between-study heterogeneity. Future studies, especially RCTs, are necessary to assess causality.

Risk of serious hypoglycaemia in patients with atrial fibrillation and diabetes concurrently taking antidiabetic drugs and oral anticoagulants: a nationwide cohort study.

AIMS: Evidence regarding the risks of serious hypoglycaemia for patients with atrial fibrillation (AF) and diabetes mellitus (DM) taking antidiabetic medications with concurrent non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin is limited. This study aimed to investigate this knowledge gap. METHODS AND RESULTS: This retrospective cohort study used nationwide data from Taiwan's National Health Insurance Research Database and included a total of 56 774 adult patients treated with antidiabetic medications and oral anticoagulants between 1 January 2012 and 31 December 2020. The incidence rate ratios (IRRs) of serious hypoglycaemia were estimated for patients taking antidiabetic drugs with NOACs vs. warfarin. Poisson regression models with generalized estimating equations accounting for intra-individual correlation across follow-up periods were used. Stabilized inverse probability of treatment weighting was used to create treatment groups with balanced characteristics for comparisons. Compared to concurrent use of antidiabetic drugs with warfarin, those with NOACs showed a significantly lower risk of serious hypoglycaemia (IRR = 0.73, 95% CI: 0.63-0.85, P < 0.001). In the analyses of each NOAC, patients taking dabigatran (IRR = 0.76, 95% CI: 0.63-0.91, P = 0.002), rivaroxaban (IRR = 0.72, 95% CI: 0.61-0.86, P < 0.001), and apixaban (IRR = 0.71, 95% CI: 0.57-0.89, P = 0.003) showed a significantly lower risk of serious hypoglycaemia than those taking warfarin. CONCLUSION: In patients with AF and DM taking antidiabetic drugs, concurrent use of NOACs was associated with a lower risk of serious hypoglycaemia than concurrent use of warfarin.

Eliciting Low-Risk Thyroid Cancer Treatment Preferences Using Clinical Vignettes: A Pilot Study.

OBJECTIVE: While surgical resection has been the traditional standard treatment for small (≤1 cm), differentiated thyroid cancers, active surveillance (AS) and radiofrequency ablation (RFA) are increasingly considered. The aim of this study was to explore patient preferences in thyroid cancer treatment using a series of clinical vignettes. METHODS: Thyroid cancer survivors and general population volunteers were recruited to rank experience-driven clinical vignettes in order of preference. Rankings were compared using Wilcoxon signed rank. Formative qualitative methods were used to develop and refine clinical vignettes that captured 4 treatments-thyroid lobectomy (TL), total thyroidectomy (TT), AS, and RFA-along with 6 treatment complications. Content was validated via interviews with 5 academic subspecialists. RESULTS: Nineteen volunteers participated (10 survivors, 9 general population). Treatment complications were ranked lower than uncomplicated counterparts in 99.0% of cases, indicating excellent comprehension. Counter to our hypothesis, among uncomplicated vignettes, median rankings were 1 for AS, 2 for RFA, 3.5 for TL, and 5 for TT. Trends were consistent between thyroid cancer survivors and the general population. AS was significantly preferred over RFA (P = .02) and TT (P < .01). Among surgical options, TL was significantly preferred over TT (P < .01). CONCLUSION: When treatments for low-risk thyroid cancer are described clearly and accurately through clinical vignettes, patients may be more likely to choose less invasive treatment options over traditional surgical resection.

Incidence and molecular characterization of extended-spectrum beta-lactamase (ESBL)-producing Salmonella enterica and Escherichia coli of avifauna origin in Pakistan.

Members of Enterobacteriaceae are known to produce extended-spectrum beta-lactamases (ESBL) which hydrolyze the beta-lactam group of antibiotics. The existence of ESBL-producing Salmonella enterica (S. enterica) and Escherichia coli (E. coli) harbored by urban avifauna was investigated in this study. Dropping samples (n= 180) were collected from six different bird species in the district Jhang, Punjab province, Pakistan. Isolation and identification of ESBL isolates were made by using cefotaxime- (4 mg/L) supplemented MacConkey agar and double disc synergy test (DDST). Polymerase chain reaction (PCR) was performed for the detection of four different ESBL genes including blaCTX-M, blaTEM, blaSHV and blaOXA. A total of 42.69% isolates were confirmed as ESBL via DDST including 30.64% S. enterica and 49.54% E. coli. The incidence of ESBL S. enterica and ESBL E. coli was found highest in egret (Ardea alba) and pigeon (Columba livia) as 64.28% and 78.95%, respectively. The blaCTX-M gene was detected in 57.89% and 64.81% of isolates of S. enterica and E. coli, respectively. Among other genes in S. enterica and E. coli, blaTEM (21.05%, 20.4%); blaSHV (15.78%, 9.26%), and blaOXA (5.26%, 5.56%) were detected, respectively. All of the tested isolates were found resistant to at least one of the thirteen antimicrobial agents except meropenem. To the best of our knowledge, this is the first study reporting the incidence and genetic diversity of ESBL bacteria associated with urban avifauna in Pakistan. The urban avifauna can serve as a potential subject of bio-surveillance to monitor the emergence of antimicrobial-resistant bacteria.

Type 1 diabetes: key drug targets and how they could influence future therapeutics.

INTRODUCTION: Despite significant strides made in the management of T1DM, standard management is still insulin analog therapy. Some non-insulin therapies traditionally reserved for the treatment of T2DM have been explored in caring for patients with T1DM, and pancreas transplant is an option for few. However, T1DM remains a challenging disease to manage, encouraging development of novel pharmacologic agents. AREAS COVERED: We retrieved PubMed, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov records to identify studies and articles focused on new pharmacologic advances to treat T1DM. EXPERT OPINION: Recent research has focused on new targets of pharmacologic treatment of T1DM. Beta-cell preservation through immunomodulation or inhibiting inflammation hopes to delay or halt the progression of the disease. Beta cell regeneration through islet cell transplant or modification in transcription pathways aim to reverse the disease effects. Multiple other new targets such as glucagon antagonism and glucokinase activation are also in development as a potential adjunctive therapy. These new therapeutic targets offer the hope of reducing the daily burden of diabetes management with eventual insulin discontinuation for many individuals with T1DM.

Risk of heart failure in elderly patients with atrial fibrillation and diabetes taking different oral anticoagulants: a nationwide cohort study.

BACKGROUND: Heart failure (HF) is a critical complication in elderly patients with atrial fibrillation (AF) and diabetes mellitus (DM). Recent preclinical studies suggested that non-vitamin K antagonist oral anticoagulants (NOACs) can potentially suppress the progression of cardiac fibrosis and ischemic cardiomyopathy. Whether different oral anticoagulants influence the risk of HF in older adults with AF and DM is unknown. This study aimed to evaluate the risk of HF in elderly patients with AF and DM who were administered NOACs or warfarin. METHODS: A nationwide retrospective cohort study was conducted based on claims data from the entire Taiwanese population. Target trial emulation design was applied to strengthen causal inference using observational data. Patients aged ≥ 65 years with AF and DM on NOAC or warfarin treatment between 2012 and 2019 were included and followed up until 2020. The primary outcome was newly diagnosed HF. Propensity score-based fine stratification weightings were used to balance patient characteristics between NOAC and warfarin groups. Hazard ratios (HRs) were estimated using Cox proportional hazard models. RESULTS: The study included a total of 24,835 individuals (19,710 NOAC and 5,125 warfarin users). Patients taking NOACs had a significantly lower risk of HF than those taking warfarin (HR = 0.80, 95% CI 0.74-0.86, p < 0.001). Subgroup analyses for individual NOACs suggested that dabigatran (HR = 0.86, 95% CI 0.80-0.93, p < 0.001), rivaroxaban (HR = 0.80, 95% CI 0.74-0.86, p < 0.001), apixaban (HR = 0.78, 95% CI 0.68-0.90, p < 0.001), and edoxaban (HR = 0.72, 95% CI 0.60-0.86, p < 0.001) were associated with lower risks of HF than warfarin. The findings were consistent regardless of age and sex subgroups and were more prominent in those with high medication possession ratios. Several sensitivity analyses further supported the robustness of our findings. CONCLUSIONS: This nationwide cohort study demonstrated that elderly patients with AF and DM taking NOACs had a lower risk of incident HF than those taking warfarin. Our findings suggested that NOACs may be the preferred oral anticoagulant treatment when considering the prevention of heart failure in this vulnerable population. Future research is warranted to elucidate causation and investigate the underlying mechanisms.

Emerging drugs for the treatment of diabetic nephropathy.

INTRODUCTION: Diabetic nephropathy remains a significant economic and social burden on both the individual patient and health-care systems as the prevalence of diabetes increases in the general population. The complex pathophysiology of diabetic kidney disease poses a challenge in the development of effective medical treatments for the disease. However, the multiple facets of diabetic nephropathy also offer a variety of potential strategies to manage this condition. AREAS COVERED: We retrieved PubMed, Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov records to identify studies and articles focused on new pharmacologic advances to treat diabetic nephropathy. EXPERT OPINION: RAAS blockers have remained the mainstay of therapy for DM nephropathy for many years, with only recent advancements with SGLT2 inhibitors and nonsteroidal MRAs. Better understanding of the long-term renal effects of ambient hyperglycemia, ranging from hemodynamic changes to increased production of oxidative and pro-inflammatory substances, has evolved our approach to the treatment of diabetic nephropathy. With continuing research for new therapeutics as well as combination therapy, the medical community may be able to better ease the burden of diabetic kidney disease.

Voriconazole-Induced Diffuse Periostitis.

Background/Objective: Voriconazole treatment has been associated with diffuse periostitis, especially in immunocompromised patients who have had transplants or are on immunosuppressants. Here, we present a case of diffuse periostitis induced by prophylactic low-dose voriconazole for pulmonary aspergillosis. Case Report: A 66-year-old woman presented with 1 year of progressive, diffuse bone pain most prominent over the left shoulder and bilateral hips. She had a history of sarcoidosis requiring a single orthotopic lung transplant. Left phalangeal soft tissue swelling and painful nodules without clubbing were noted on examination. Prophylactic voriconazole 200 mg twice a day for pulmonary aspergillosis was prescribed for over 7 years. Elevated levels of alkaline phosphatase (469 units/L [reference range, 38-126]), bone-specific alkaline phosphatase (125 µg/L [0-20]), and parathyroid hormone (137 pg/mL [8-54]) and normal c-telopeptide level (842 pg/mL [34-1037]) were noted. Radiographs showed "multifocal periostitis" in both hip joints and bilateral proximal femurs, findings suggestive of voriconazole-induced periostitis deformans. Voriconazole was discontinued, and the patient improved symptomatically, despite persistent bone deformities on imaging. Discussion: Diffuse bone pain can be due to various pathologies, including metabolic or inflammatory diseases and bone tumors. Voriconazole-induced periostitis is caused by skeletal fluorosis, which can result in diffuse bone pain. It is a clinical diagnosis that is supported with radiologic findings, including focal, nodular, dense, and irregular periosteal reactions. Biochemical evaluation may reveal elevated alkaline phosphatase levels, but it is usually related to normal voriconazole trough levels. Periostitis is a benign condition, and discontinuation of the drug usually leads to clinical improvement. Conclusion: Voriconazole-induced periostitis should be considered as a diagnosis in elderly, immunosuppressed patients with diffuse bone pain on antifungal treatment. Early recognition of voriconazole-induced periostitis may result in both improved patient clinical outcomes and avoidance of unnecessary diagnostic testing.

Molecular detection and therapeutic study of Trypanosoma brucei evansi from naturally infected horses in Punjab, Pakistan.

Trypanosomiasis is one of the severe pathogenic infections, caused by several Trypanosoma species, affecting both animals and humans, causing substantial economic losses and severe illness. The objective of this study was to determine the molecular diagnosis and the risk factors associated with trypanosomiasis in District Jhang, Punjab, Pakistan. For this purpose, blood samples were randomly collected from 200 horses. A predesigned questionnaire was used to collect data on risk factors before the sample collection. The microscopy examination through Giemsa staining, formol gel test and PCR techniques were used to find the prevalence. The prevalence was recorded as 22.5% with microscopy examination, 21% through formol gel test and 15.5% with PCR based results. Analysis of risk factors associated with Trypanosoma brucei evansi occurrence was carried out using Chi-square test. It showed the prevalence of Trypanosoma brucei evansi was significantly (p⟨0.05) associated with sex, age, rearing purpose and body condition whereas non-significantly (p⟩0.05) with insects control practices. This study supports the idea that PCR is a sensitive, robust and more reliable technique to diagnose trypanosomiasis. It was concluded that Trypanosoma brucei evansi is widely prevalent in Jhang (Pakistan), highlighting a dire need to develop control strategies and education programmes to control this disease in developing countries.