Frequency Of Adverse Events Research Articles

Cutaneous adverse events to systemic anticancer therapies : Hand-foot syndrome and nail changes

Hand-foot syndrome (HFS) and nail changes are frequent adverse events of anticancer therapies. To provide areview of current evidence in HFS and nail disorders associated with medical tumor treatment. Basis is the current German S3guideline "Supportive therapy in oncologic patients" and literature on this topic published since the guideline was finalized. Two variants of HFS are distinguished: achemotherapy-associated and akinase-inhibitor-associated variant. In the first form, painful erythema, blisters and ulceration can occur, also in other areas with ahigh number of sweat glands such as axillary and inguinal regions. Thus, the secretion of toxic substances through sweat glands is aproposed pathogenetic mechanism. For the second form, which results in callus-like painful thickening of the horny layer on areas of mechanic pressure, avascular mechanism is proposed. For prophylaxis of HFS, avoidance of mechanical stress, regular cleaning of predisposed areas, and also urea- and diclofenac-containing ointments are recommended; in case of infusions (taxanes, doxorubicine), cooling of hands and feet during infusion is recommended. In case of manifest HFS, dose reduction or prolongation of intervals of the associated treatment are recommended. Nail changes often develop under therapy with chemotherapeutic agents but also under treatment with agents such as checkpoint inhibitors or under targeted therapy. Different components of the nail unit may be involved such as the nail matrix, nail bed, nail plate, hyponychium, lunula and proximal and lateral nail folds. This work gives insight into the pathophysiology of HFS and nail disorders that develop under systemic oncologic treatments and gives recommendations for prophylaxis and treatment.

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. Pirfenidone (PFD) and nintedanib (NDN) were both conditionally recommended in the clinical practice guideline published in 2015. Safety and tolerability are related to the risk of treatment discontinuation. Therefore, this study evaluated and compared the adverse events (AEs) of PFD and NDN in a large real-world population by analyzing data from the FDA Adverse Event Reporting System (FAERS) to provide a reference for their rational and safe use. The AEs of PFD and NDN were extracted from the FAERS database. The pharmacovigilance online analysis tool OpenVigil 2.1 was used to retrieve data from the FAERS database from the first quarter of 2012 to the second quarter of 2022. The reporting odds ratio (ROR) and proportional reporting ratio were used to detect the risk signals. The database included 26,728 and 11,720 reports for PFD and NDN, respectively. The most frequent AEs of PFD and NDN were gastrointestinal disorders. The RORs for these drugs were 5.874 and 5.899, respectively. "Cardiac disorders" was the most statistically significant system order class for NDN with an ROR of 9.382 (95% confidence interval = 8.308-10.594). Furthermore, the numbers of designated medical events of PFD and NDN were 552 and 656, respectively. Notably, liver injury was reported more frequently for NDN (11.096%) than for PFD (6.076%). This study revealed differences in the reporting of AEs between PFD and NDN. The findings provide reference for physicians in clinical practice. Attention should be paid to the risks of cardiac disorders and liver injury associated with NDN.

Effect of Avenciguat on Albuminuria in Patients with CKD: Two Randomized Placebo-Controlled Trials.

Avenciguat is a novel, potent soluble guanylate cyclase activator in development for CKD. Two trials investigated avenciguat in diabetic (NCT04750577) and non-diabetic (NCT04736628) CKD. A prespecified pooled analysis of two randomized, double-blind, placebo-controlled trials of identical design. Adults with CKD (eGFR ≥20 and <90 mL/min/1.73 m 2 , urine albumin-to-creatinine ratio [UACR] ≥200 and <3500 mg/g) were randomized to 20 weeks of placebo or avenciguat 1, 2, or 3 mg three times daily (TID; adjunctive to angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker. Primary endpoint: change from baseline in UACR in 10-hour urine at week 20, analyzed per protocol. Secondary endpoint: UACR change from baseline in first morning void urine at week 20. Safety was monitored throughout. Overall 500 patients (mean age 62 years [SD 13]; mean eGFR 44 mL/min/1.73 m 2 [SD 18] and median 10-hour UACR 719 [interquartile range 379-1285] mg/g ) received placebo (n=122) or avenciguat 1 mg (n=125), 2 mg (n=126), or 3 mg (n=127) TID. All 243 patients in study one and 27/261 patients in study two had diabetes. Avenciguat 1, 2, and 3 mg TID reduced UACR in 10-hour and first morning void urine versus placebo throughout the treatment period. At week 20, placebo-corrected geometric mean changes (95% confidence interval) from baseline in UACR in 10-hour urine with avenciguat 1, 2, and 3 mg TID were -15.5% (-26.4, -3.0), -13.2% (-24.6, -0.1), and -21.5% (-31.7, -9.8), respectively, analyzed per protocol. Corresponding changes in first morning void urine were -19.4% (-30.0, -7.3), -15.5% (-26.9, -2.5), and -23.4% (-33.5, -11.8), respectively. Avenciguat was well tolerated, overall frequency of adverse events was low and similar to placebo. The number of patients who discontinued study drug due to adverse events with avenciguat 1, 2, and 3 mg TID were 5 (4%), 11 (9%), and 11 (9%), respectively, compared with 4 (3%) in the placebo group. Avenciguat lowered albuminuria, and was well tolerated in patients with CKD.

A multicenter, retrospective archive study of radiological and clinical features of ALK-positive non-small cell lung cancer patients and crizotinib efficacy.

To evaluate radiological and clinical features in metastatic anaplastic lymphoma kinase+ non-small cell lung cancer patients and crizotinib efficacy in different lines. This national, non-interventional, multicenter, retrospective archive screening study evaluated demographic, clinical, and radiological imaging features, and treatment approaches in patients treated between 2013-2017. Totally 367 patients (54.8% males, median age at diagnosis 54 years) were included. Of them, 45.4% were smokers, and 8.7% had a family history of lung cancer. On radiological findings, 55.9% of the tumors were located peripherally, 7.7% of the patients had cavitary lesions, and 42.9% presented with pleural effusion. Pleural effusion was higher in nonsmokers than in smokers (37.3% vs. 25.3%, P = .018). About 47.4% of cases developed distant metastases during treatment, most frequently to the brain (26.2%). Chemotherapy was the first line treatment in 55.0%. Objective response rate was 61.9% (complete response: 7.6%; partial response: 54.2%). The highest complete and partial response rates were observed in patients who received crizotinib as the 2nd line treatment. The median progression-free survival was 14 months (standard error: 1.4, 95% confidence interval: 11.2-16.8 months). Crizotinib treatment lines yielded similar progression-free survival (P = .078). The most frequent treatment-related adverse event was fatigue (14.7%). Adrenal gland metastasis was significantly higher in males and smokers, and pleural involvement and effusion were significantly higher in nonsmokers-a novel finding that has not been reported previously. The radiological and histological characteristics were consistent with the literature data, but several differences in clinical characteristics might be related to population characteristics.

Effect of Nuts on Anthropometric and Glycemic Indexes and Blood Pressure in Secondary Cardiovascular Prevention: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Nut-enriched diets have a positive impact on cardiovascular risk factors, such as body mass, blood pressure, and fasting blood glucose. However, studies in individuals undergoing secondary cardiovascular prevention show controversial results. This systematic review with meta-analysis assessed the effect of nut supplementation on anthropometric, glycemic, and blood pressure indices in patients with atherosclerotic cardiovascular disease, as well as the frequency of adverse events. Six databases were used for the search-PubMed, Cochrane Library, EMBASE, BVS (Biblioteca Virtual da Saude), Web of Science, and ClinicalTrials.gov-until February 2023, with no language restrictions. The Cochrane Handbook for Systematic Reviews of Interventions methodology and the PICOS (Population, Intervention, Comparison, Outcome, Setting/design) strategy were used. Seven independent reviewers were involved in data extraction and resolution of disagreements. Certainty of the evidence was evaluated using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. From 5187 records identified, 6 publications containing data referring to 5 randomized clinical trials (n = 436) were included in the final analyses. The nuts evaluated were almonds, pecans, Brazil nuts, and mixed nuts, with portions that varied between 5 g and 85 g (median: 30 g/day). The intervention period varied between 6 and 12 weeks. The nuts had no effect on fasting glucose and anthropometric indices, although the certainty of the evidence for most of these outcomes was low or very low. They also had no effect on systolic (mean difference [MD]: -1.16 mmHg [95% CI, -5.68 to 3.35], I2 = 0%-moderate certainty of evidence) or diastolic (MD: 0.10 mmHg [95% CI, -2.30 to 2.51], I2 = 0%-high certainty of evidence) blood pressure. It was not possible to aggregate data on adverse events. Nut supplementation had no effect on blood pressure, fasting glucose, or anthropometric profile in the context of atherosclerotic cardiovascular disease. PROSPERO registration no. CRD42020163456.

#2084 Biologic effect evaluation of de novo long-term release tacrolimus on metabolizer phenotype and T cell composition after kidney transplantation

Abstract Background and Aims Kidney transplantation (KTX) is the current treatment of choice in patients with kidney failure. Since immunosuppressive medication to prevent acute rejection is still needed in high doses with frequent adverse events, new strategies to achieve risk-appropriate personalization of immunosuppression are needed. Calcineurin inhibitors are the cornerstone of T cell suppression, currently available in different release formulations including once daily long-term release tacrolimus (LCPT) and regular twice daily immediate release tacrolimus (IRT). Little is known about the temporal evolution of tacrolimus metabolism potentially influencing T cell composition and clinical endpoints between different tacrolimus formulations after KTX. Method To evaluate the influence of de novo LCPT on clinical endpoints, metabolizer phenotype and immune cell composition after KTX, subgroup analysis of a single-center, prospective, observational cohort study including 32 patients started on LCPT (0.1 mg/kg) and 55 patients started on IRT (0.1 mg/kg) was conducted. Peripheral blood mononuclear cells were isolated from whole blood samples drawn before KTX, 2 months and 12 months after KTX for flow cytometry analysis. Study visits were simultaneously conducted to obtain tacrolimus dosing, plasma levels, acute rejection and infection incidence. Statistical analysis was done using GraphPad Prism (v10), accepting significance for p &amp;lt; 0.05, and flow cytometry analysis was done using FlowJo (v10) software. Results The cohort represented KTX recipients with a median age of 60 years and similar distributions of gender, HLA-mismatches and induction therapy. Clinical outcome data showed a trend towards lower acute rejection rate, lower serum-creatinine values and increased incidence of BK-viremia in LCPT treated patients. Rejection rate was associated with a fast-metabolizer phenotype (HR 3.9; 1.1-6.8, p &amp;lt; 0.01) and HLA mismatch &amp;gt; 3 (HR 4.0; 1.2-7.3, p &amp;lt; 0.01) while this effect was blunted in the LCPT group (HR 1.9; 0.7-3.2, p = 0.67 and HR 0.9; 0.3-1.4, p = 0.38 respectively) in a multivariate Cox-regression model. Cluster exploration and tSNE analysis of flow cytometry data revealed diminution of activated-proliferative effector and regulatory T cell trajectories, with significant reduction in cell counts of CD4+CD15s+/CD45RA-Ki67+Foxp3+ Treg and in CD4+CD147high/CD45RA-LAP+HLADR+FcRL3+ effector T cells in LCPT treated patients after KTX. Conclusion Induction with de novo LCPT was associated with a blunted influence of metabolizer phenotype and HLA-mismatch on acute rejection in our cohort. Major changes were detected in peripheral T cell composition after transplantation, with signs of a stronger immunosuppressive effect of LCPT on circulating activated T cells. Therefore, LCPT may be considered for KTX recipients with higher HLA-mismatch (i.e. “old-for-old”) or fast-metabolizer phenotype. Inclusion of changes in T cell composition as biologic effect measures may be worthwhile in future studies evaluating biomarkers to guide immunosuppression and predict complications after KTX.

Distribution of COVID-19 related deaths in municipalities from Sonora, Mexico, 2020

Introduction: The COVID-19 pandemic has challenged societies, not only because of its magnitude and impact, but also because it has deepened health inequalities and inequities. Socially disadvantaged groups show a higher frequency of adverse health events due to COVID-19, particularly in Latin America. With that in mind, we describe the distribution of deaths in COVID-19 patients stratified by sociodemographic characteristics and medical comorbidities, and explore perceptions related to disease-care, in selected rural and urban localities from Sonora, Mexico. Methods: We conducted a cross-sectional study on 160 deaths attributed to COVID-19, from the period April 1st and July 31st 2020, using death certificates as a data source. Furthermore, to explore the variables of interest, a verbal autopsy was applied to a relative caregiver for the patient’s health. Data collected was analyzed by descriptive statistics and qualitative technique. Results: We did not find significant differences in sociodemographic conditions among the COVID-19 deaths. Interestingly, 85.6% of the deceased had a chronic medical condition and 74.4% of all deaths took place in an urban locality. Caregivers frequently consigned deficiencies from medical services over the disease-care process of COVID-19 deaths.

#1431 Risk factors of adverse cardiovascular events in the early postoperative period in kidney transplant recipients

Abstract Background and Aims Kidney transplantation improves quality of life and increases life expectancy in patients with Stage 5 Chronic Kidney Disease. However, the frequency of adverse cardiovascular events in the postoperative period remains high and reduces the effectiveness of transplantation. The aim was to study the incidence of cardiovascular risk factors in the preoperative period in kidney transplant recipients with adverse cardiovascular events in the early postoperative period. Method The study included 51 kidney transplant recipients whose age was 46.1 ± 4.6 years. 12 (23.5%) recipients had adverse cardiovascular events (acute myocardial infarction, unstable angina, rhythm disturbance, complicated hypertensive crisis) in the early postoperative period. 39 (76.5%) recipients with uncomplicated postoperative period formed the comparison group. The study groups were comparable by gender and age. Results Traditional cardiovascular risk factors were assessed. The study groups had comparable rates of arterial hypertension, obesity, hyperglycemia, dyslipidemia and smoking in the preoperative period and graft function in the postoperative period. The study groups didn't have significant differences in the incidence of anemia and hemoglobin blood concentration. But the erythropoietin blood level in the preoperative period in recipients with adverse cardiovascular events was higher—38.5 (23.5-155.0) mU/mL versus 16.0 (10.0-32.0) mU/mL, p &amp;lt; 0.01, and hypererythropoietinemia was diagnosed more often—58.3% (n = 7) versus 25.6% (n = 10), p &amp;lt; 0.05, than in patients without cardiovascular events. The incidence of elevated interleukin-6 blood level in the preoperative period was higher in recipients with adverse cardiovascular events—25.0% (n = 3) versus 5.1% (n = 2), p &amp;lt; 0.05. At the same time C-reactive protein levels and white blood cell counts were not significantly different. Recipients with adverse cardiovascular events had a lower left ventricular ejection fraction—59.5 ± 10.6% versus 65.6 ± 7.1%, p &amp;lt; 0.05, and a higher incidence of left ventricular diastolic dysfunction in the preoperative period—75.0% (n = 9) versus 35.9% (n = 14), p &amp;lt; 0.05, than in recipients without cardiovascular complications. Conclusion Kidney transplant recipients with adverse cardiovascular events in the early postoperative period had a higher incidence of left ventricular diastolic dysfunction, increased blood levels of erythropoietin and interleukin-6 and a lower left ventricular ejection fraction before transplantation than recipients with an uncomplicated postoperative period.

Phase I Study of Tivozanib Eye Drops in Healthy Volunteers and Patients with Neovascular Age-Related Macular Degeneration

PurposeTo evaluate the safety, pharmacokinetics, and exploratory efficacy of tivozanib eye drops in healthy volunteers and patients with neovascular age-related macular degeneration (nAMD). DesignThis multicenter, group-sequential dose escalation phase 1 study consisted of a placebo-controlled, double-masked study of healthy volunteers (Cohorts 1 and 2) and an open-label study of nAMD patients (Cohort 3). ParticipantsHealthy volunteers: Japanese or White men aged 20 to <50 years. Patients with nAMD with central subfield thickness ≥300 μm and best-corrected visual acuity score ≥23 letters in the study eye. MethodsIn the single-dose cohort of healthy men (Cohort 1: Steps 1–5), 1 or 2 tivozanib eye drops (30 μL/drop, 5-minute interval; 0.5, 1.0, and 2.0 w/v%) or placebo were administered in 1 eye once. In the multiple-dose cohort of healthy men (Cohort 2: Steps 1–6), 1 or 2 tivozanib eye drops (0.5, 1.0, and 2.0 w/v%) or placebo were administered 3 times daily (TID) in 1 eye for 21 days. In the multiple-dose cohort of nAMD patients (Cohort 3, Steps 1–3), 1 or 2 tivozanib eye drops (0.5 and 1.0 w/v%) were administered TID in 1 affected eye for 21 days. Main Outcome MeasuresThe safety outcome measures included adverse events (AEs). The pharmacokinetic outcome was serum tivozanib concentration. Among the exploratory efficacy outcomes, central subfield thickness (CST) was evaluated. ResultsIn total, 40, 48, and 28 participants were enrolled in Cohorts 1, 2, and 3, respectively. Serious AEs did not occur in Cohorts 1–3. The most frequent AE in multiple-dose cohorts was reversible punctate keratitis: placebo arm, 8.3% (healthy men, 1/12); tivozanib arm, 47.2% (healthy men, 17/36) and 14.3% (nAMD, 4/28). Serum tivozanib exposure increased dose-dependently and was similar in healthy men and patients with nAMD. In patients with nAMD, mean CST changes from baseline to Day 22 were −27.6 ± 54.88 (0.5 w/v%; 1 drop, TID), −35.6 ± 49.64 (1.0 w/v%; 1 drop, TID), and −43.7 ± 55.19 μm (1.0 w/v%; 2 drops, TID). ConclusionsTivozanib eye drops showed a favorable safety profile in healthy Japanese and White men and Japanese patients with nAMD.

Evaluation of the efficacy and safety of nivolumab in the second- or later-line treatment of patients with locally advanced/metastatic non-small cell lung cancer in Türkiye: a retrospective multicenter non-interventional registry study

Objective To evaluate the efficacy and safety of nivolumab in the second-line (2L) or later-line (LL) treatment of patients with locally advanced/metastatic non-small cell lung cancer (NSCLC) in real-life setting in Türkiye. Methods This study was designed as a national, multi-center, retrospective study. The study population was evaluated in two groups for the line of nivolumab therapy: those receiving nivolumab in the 2L (Group 2L) and third-line (3L) or LL (Group 3L/LL). Efficacy was evaluated based on one-year overall survival (OS) and progression-free survival (PFS). Safety was evaluated based on treatment-related adverse events (AEs) and nivolumab discontinuation rate. Results Of 244 patients, 52.9% were in Group 2L and 47.1% were in Group 3L/LL. Demographic and clinical characteristics did not differ between the groups. In Group 2L and Group 3L/LL, one-year OS and PFS rates were 60.8% and 61.4% (p = 0.592) and 31.2% and 21.3% (p = 0.078), respectively. The objective response rate (ORR) was 34.7% in Group 2L and 27.3% in Group 3L/LL (p = 0.262). The percentage of patients reporting at least one AE in Groups 2L and 3L/LL was 34.9% and 43.5%, respectively (p = 0.169). Fatigue was the most common (16.4%) treatment-related AE in each group. The groups were comparable regarding the AE frequency. Nivolumab was discontinued in 61 patients in Group 2L and 53 patients in Group 3L/LL, with the most common reason being disease progression (57.4% and 66.0%, respectively). Conclusion Nivolumab is safe and effective in the 2L or 3L/LL treatment of locally advanced/metastatic NSCLC and associated with acceptable AEs in real-life setting.

Antibiotic treatment for patients with exacerbation of chronic obstructive pulmonary disease: A systematic review and meta-analysis

BackgroundAlthough respiratory tract infection is a significant factor that triggers exacerbation of chronic obstructive pulmonary disease (COPD), the benefit of antibiotics for patients with COPD exacerbation remains controversial. It is necessary to evaluate the efficacy and safety of antibiotics versus placebo in such patients. MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials of antibiotics versus placebo for the treatment of COPD exacerbation, and compared the frequencies of treatment failure, mortality, and adverse events between patients treated with antibiotics and those treated with placebo. ResultsA total of six studies were included in this meta-analysis. The frequency of treatment failure was significantly lower in the antibiotic-treated patients compared to the placebo-treated patients (odds ratios [OR] 0.50, 95% confidence intervals [CI] 0.35–0.71, p = 0.0001). There was no significant difference between the two groups in mortality (OR 0.44, 95% CI 0.05–3.76, p = 0.45) or frequency of adverse events (OR 1.05, 95% CI 0.75–1.48, p = 0.78). ConclusionIn the current systematic review and meta-analysis, we found that antibiotics were superior to placebo in patients with exacerbated COPD, as shown by the lower treatment failure rate.

Safe Continuation of Glucagon-like Peptide 1 Receptor Agonists at Endoscopy: A Case Series of 57 Adults Undergoing Endoscopic Sleeve Gastroplasty.

Glucagon-like receptor agonists (GLP1-RAs) have raised peri-procedural concerns due to their potential to delay gastric emptying. The American Association of Anesthesiologists has advised pausing a single dose before elective endoscopy. However, a subsequent directive from multiple gastroenterology societies underscored the need for further assessment to substantiate this practice. We aimed to evaluate the frequency of serious adverse events and retained gastric products during endoscopic sleeve gastroplasty (ESG) with uninterrupted GLP1-RA use. We conducted a retrospective evaluation of all patients undergoing ESG while on GLP1-RAs at three centers from August 2022 to February 2024. Per standard protocol, all patients had refrained from solid foods for at least 24h and maintained nil per os for 12h preceding their ESG. Records were reviewed for patient characteristics and medication type and doses. Primary outcomes included serious adverse events and retained gastric products based on patient records, procedure reports, and procedural videos. Fifty-seven consecutive adults (89.5% women, mean age of 44 ± 9years, mean BMI of 40.1 ± 8.1kg/m2, 35.1% with T2DM, and 26.3% with pre-T2DM) underwent ESG without stopping GLP1-RAs, which included semaglutide (45.6%), liraglutide (19.3%), dulaglutide (22.8%), and tirzepatide (12.3%). During intubation, endoscopy, and recovery, there were no instances of retained gastric solids, pulmonary aspiration, gastroesophageal regurgitation, or hypoxia. A ≥ 24-h pre-endoscopy liquid-only diet with ≥ 12-h pre-endoscopy fast may negate the need for GLP1-RA interruption for routine upper endoscopy in adults with native gastric anatomy.

Therapeutic plasma exchange in critically ill children: A single center experience.

Therapeutic plasma exchange (TPE) is used in a wide spectrum of diseases in critically ill pediatric patients. We aim to review the indications, complications, safety, and outcomes of critically ill children who received TPE. All of the TPE procedures performed in a pediatric intensive care unit providing tertiary care during 19 years (January 2013-January 2023) were evaluated retrospectively. A total of 154 patients underwent 486 TPE sessions. Median age was 6 years (2-12.5) and 35 children had a body weight of <10 kg (22.7%). Number of organ failure was 4 (2-6). Liver diseases were the most common indication for TPE (31.2%) followed by sepsis with multiorgan dysfunction syndrome (27.3%). Overall survival rate was 72.7%. The highest mortality was observed in hemophagocytic lymphohistiocytosis group. Non-survivors had significantly higher number of organ failure (p < 0.001), higher PRISM score (p < 0.001), and higher PELOD score on admission (p < 0.001). Adverse events were observed in 68 (13.9%) sessions. Hypotension (7.8%) and hypocalcemia (5.1%) were the most frequent adverse events. TPE is safe for critically ill pediatric patients with experienced staff. Survival rate may vary depending on the underlying disease. Survival decreases with the increase in the number of failed organs.

Efficacy of extracorporeal shockwave therapy, compared to corticosteroid injections, on pain, plantar fascia thickness and foot function in patients with plantar fasciitis: A systematic review and meta-analysis

Objective To compare the efficacy of extracorporeal shock waves versus corticosteroids injections on pain, thickness of plantar fascia and foot function in patients with plantar fasciitis. Secondarily, to assess the efficacy of radial and focused extracorporeal shock waves and the most appropriated intensity (high, medium or low). Data sources PubMed, SCOPUS, CINAHL and PEDro, until April 2024, according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Review methods Randomized controlled trials comparing the efficacy of extracorporeal shock waves versus corticosteroids injections on pain intensity and sensitivity, thickness of plantar fascia and foot function in patients with plantar fasciitis. Methodological quality and risk of bias were assessed using PEDro Scale and Cochrane Risk of Bias Tool. Pooled effect was calculated using the standardized mean difference (SMD) and its 95% confidence interval (95%CI). Results Sixteen studies involving 1121 patients, showing a mean of 6 points in PEDro scale, were included. At three months, extracorporeal shock waves were better than corticosteroids injections in reducing pain (SMD −0.6; 95%CI −1.1 to −0.11) and thickness of the plantar fascia (SMD −0.4; 95%CI −0.8 to −0.01) and increasing foot function (SMD 0.27; 95%CI 0.12–0.44). At six months, extracorporeal shock waves are more effective in reducing pain (SMD −0.81; 95%CI −1.6 to −0.06) and increasing foot function (SMD 0.67; 95%CI 0.45–0.89). Local pain and slight erythema were the most frequent adverse events. Conclusions Extracorporeal shock waves are a safe therapy, presenting more efficacy than corticosteroids injections in improving pain, thickness of plantar fascia and foot function at mid-term.

Real-Time Use of SGLT2i Verified in Pre-dialysis: The RSVP Cross-sectional Study.

The use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in nephrology practice is increasingly becoming standard of care in patients with diabetes or those with proteinuria. The primary outcome was to identify the proportion of pre-dialysis patients with chronic kidney disease (CKD) G3a, G3b, or G4 prescribed an SGLT2i and describe their characteristics. This was a retrospective, multicentric, cross-sectional study of patients with CKD followed at 4 pre-dialysis clinics in the province of Quebec, Canada. We collected data of multiple covariates associated with prescribing SGLT2i in patients over 18 years of age with CKD G3a, G3b, or G4. We then performed a multivariate logistic regression to assess their associations. Of the 874 patients included, 22.7% were prescribed an SGLT2i. Factors most strongly associated included male sex (odds ratio [OR] = 4.88, 95% CI = 2.38-10.03), being prescribed metformin (OR = 4.30, 95% CI = 2.23-8.31), having type 2 diabetes (OR = 4.00, 95% CI = 1.86-8.62), or having an albumin-to-creatinine ratio greater than 300 mg/g (OR = 1.84, 95% CI = 1.08-3.14). The majority of patients (60.4%) had their SGLT2i initiated by the pre-dialysis clinic and the most frequent adverse event was an initial increase in serum creatinine 1 week after starting treatment (33.9%). An increasing number of patients with CKD are being prescribed SGLT2i. Nonetheless, significant disparities in sex, severity of disease, and comorbidities remain. We suggest that specific strategies be put in place to promote prescribing of SGLT2i in women and other at-risk populations, in particular among nephrology teams, to improve patient care.

Rationale, completeness and quality of evidence for the use of ursodeoxycholic acid in neonatal hyperbilirubinemia

Background. Systematic reviews are considered the highest evidence of the effectiveness and safety of treatment methods used in clinical practice. The veracity of a results and conclusions of systematic reviews is directly related to their quality. The aim of the study is an assessment of the currency, completeness and methodological quality of published systematic reviews on the evaluation of the effectiveness of ursodeoxycholic acid (UDCA) for the treatment of neonatal hyperbilirubinemia. Materials and methods. A meta-epidemiological methodological study was conducted. The search for evidence sources was performed in November 2023 in the specialized databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), LILACS, CNKI, LENS.ORG, еLibrary.Ru, in registers ClinicalTrials.gov, ICTRP, ISRCTN, PROSPERO, as well as in the Google Academy and Google search engines. Additionally, the lists of references and citations of selected publications have been reviewed. Only systematic reviews and randomized clinical trials are included in the study. The search was carried out to assess the currency and completeness of systematic reviews. A systematic review is considered currency if the most recent studies are included in its analysis. A systematic review is considered complete if its analysis includes all identified studies that meet the inclusion criteria set by the review authors and are published no later than the date of the last search conducted by the review authors. The methodological quality of the systematic reviews was assessed using the AMSTAR-2 tool. Results. As a result of the search, 4 systematic reviews and 23 randomized trials were identified. All reviews evaluated the effect of UDCA in combination with phototherapy on the level of total serum bilirubin, the duration of phototherapy and the frequency of adverse events (for example, loose stools, vomiting, rash) compared with phototherapy alone and/or placebo. All systematic reviews have been published over the past two years, but have already lost their currency. There are missing studies and/or outcomes in each review. The methodological quality of the reviews was found to be extremely low. Conclusion. Given the listed shortcomings of systematic reviews, their results and conclusions should be treated with caution. In order to obtain the most accurate and reliable evidence, a new systematic review is needed.

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

Capmatinib plus nivolumab in pretreated patients with EGFR wild-type advanced non–small cell lung cancer

IntroductionDysregulated MET is an established oncogenic driver in non–small cell lung cancer (NSCLC). MET signaling may also suppress anticancer immune responses. Concomitant MET inhibition with capmatinib (a MET inhibitor) synergistically enhanced the efficacy of immunotherapies in murine cancer models, regardless of tumor dependency to MET signaling. Here, we report results of a multicenter, open-label, phase 2 study of capmatinib plus nivolumab (a PD-1 inhibitor) in patients with EGFR wild-type advanced NSCLC, previously treated with platinum-based chemotherapy. MethodsPatients were allocated into high-MET or low-MET groups according to MET expression determined by immunohistochemistry, MET gene copy number as assessed by fluorescence in-situ hybridization, and presence of MET exon 14 skipping mutation, then received capmatinib 400 mg, oral, twice daily in combination with nivolumab 3 mg/kg intravenously every 2 weeks. The primary endpoint was investigator-assessed 6-month progression-free survival (PFS) rate per RECIST v1.1. ResultsThe primary endpoint was met in both the high-MET (N = 16) and low-MET (N = 30) groups. In the high-MET and low-MET groups, respectively, the estimated mean 6-month PFS rate (95 % credible interval) by Bayesian analysis was 68.9 % (48.5–85.7) and 50.9 % (35.6–66.4). The Kaplan-Meier median PFS (95 % CI) was 6.2 months (3.5–19.2) and 4.2 months (1.8–7.4). The overall response rate (95 % CI) was 25.0 % (7.3–52.4) and 16.7 % (5.6–34.7). Most frequent treatment-related adverse events (≥30 % any grade, N = 46) were nausea (52.2 %), peripheral edema (34.8 %), and increased blood creatinine (30.4 %). ConclusionsCapmatinib plus nivolumab showed clinical activity and manageable safety in pretreated patients with advanced EGFR wild-type NSCLC, independent of MET status. Trial RegistrationClinicalTrials.gov NCT02323126.

Metformin as adjunctive therapy in combination with multidrug treatment for multibacillary leprosy: A protocol for a randomized double-blind, controlled Phase 2 trial in Indonesia (MetLep Trial).

The clinical management of leprosy is complicated by leprosy reactions (LR) causing irreversible nerve damage and disabilities. LR often require long-term use of corticosteroids causing serious side effects. Adjunct host-directed therapy (HDT) is a potentially attractive strategy in leprosy to prevent LR and associated immunopathology, modulate immunological memory that protects against recurrence, and thereby reduce nerve damage, disability and corticosteroid-associated morbidities. Metformin, a well-tolerated, safe and cheap anti-hyperglycaemic drug, is repurposed as HDT in auto-immune and infectious diseases, like tuberculosis (TB). Metformin use in people with diabetes is associated with reduced risks of TB-infection, progression to active TB, treatment failure and TB-mortality. Given the similarities both mycobacteria share, we hypothesize that among persons with multibacillary (MB) leprosy, adjunctive metformin may prevent/mitigate LR. We will perform a double-blind controlled proof-of-concept trial in which people with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin hydrochloride 1000mg extended release once daily versus placebo for 24 weeks in addition to standard-of-care WHO MB multidrug therapy (MDT) during 48 weeks. We aim to enrol 166 participants aged between 18 and 65 years, across five clinical sites in two leprosy endemic areas in Indonesia. Primary outcomes are the proportion of participants experiencing a LR and the frequency of (serious) adverse events. Secondary outcomes are the severity and time to first LR, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks. LR signify the most important cause of irreversible nerve damage leading to anatomical deformities and disabilities, imposing a social and financial burden on those affected. Our study aims to evaluate the efficacy, tolerability and safety of adjunct metformin added to MDT in persons with multibacillary leprosy, and explore its effects on clinical and immunological outcomes. NCT05243654 (17/02/2022).

JAKinhibs in Psoriatic Disease: Analysis of the Efficacy/Safety Profile in Daily Clinical Practice.

Psoriatic disease (PsD) affects multiple clinical domains and causes a significant inflammatory burden in patients, requiring comprehensive evaluation and treatment. In recent years, new molecules such as JAK inhibitors (JAKinhibs) have been developed. These have very clear advantages: they act quickly, have a beneficial effect on pain, are well tolerated and the administration route is oral. Despite all this, there is still little scientific evidence in daily clinical practice. This observational, retrospective, single-center study was carried out in patients diagnosed with PsA in the last two years, who started treatment with Tofacitinib or Upadacitinib due to failure of a DMARD. The data of 32 patients were analyzed, and the majority of them (75%) started treatment with Tofacitinib. Most had moderate arthritis activity and mild psoriasis involvement according to activity indices. Both Tofacitinib and Upadacitinib demonstrated significant efficacy, with rapid and statistically significant improvement in joint and skin activity indices, C-reactive protein reduction, and objective measures of disease activity such as the number of painful and inflamed joints. Although there was some difference in the baseline characteristics of the cohort, treatment responses were comparable or even superior to those in the pivotal clinical trials. In addition, there was a low frequency of mild adverse events leading to treatment discontinuation and no serious adverse events. These findings emphasize the strong efficacy and tolerability of JAKinhibs in daily clinical practice, supporting their role as effective therapeutic options for patients with PsD.