Drug Discov Today. 2024 Mar 1:103938. doi: 10.1016/j.drudis.2024.103938. Online ahead of print.

ABSTRACT

Drug-induced renal injury (DIRI) causes >1.5 million adverse events annually in the USA alone. Although standard biomarkers exist for DIRI, they lack the sensitivity or specificity to detect nephrotoxicity before the significant loss of renal function. In this study, we describe the creation of DIRIL - a list of drugs associated with DIRI and nephrotoxicity - from two literature datasets with DIRI annotation, confirmed using FDA drug labeling. DIRIL comprises 317 orally administered drugs covering all 14 anatomical, therapeutic and chemical (ATC) classification categories. Of the 317 drugs, 171 were DIRI-positive and 146 were DIRI-negative. DIRIL will be a relevant and invaluable resource for discovery of new approach methods (NAMs) to predict the occurrence and possible severity of DIRI earlier in drug development.

PMID:38432353 | DOI:10.1016/j.drudis.2024.103938

Reg Anesth Pain Med. 2024 Mar 1:rapm-2024-105387. doi: 10.1136/rapm-2024-105387. Online ahead of print.

NO ABSTRACT

PMID:38431307 | DOI:10.1136/rapm-2024-105387

Eur J Immunol. 2024 Mar 2:e2350580. doi: 10.1002/eji.202350580. Online ahead of print.

ABSTRACT

Recombinant human IL-2 has been used to treat inflammatory diseases and cancer; however, side effects like skin rashes limit the use of this therapeutic. To identify key molecules and cells inducing this side effect, we characterized IL-2-induced cutaneous immune reactions and investigated the relevance of CD25 (IL-2 receptor α) in the process. We injected IL-2 intradermally into WT mice and observed increases in immune cell subsets in the skin with preferential increases in frequencies of IL-4- and IL-13-producing group 2 innate lymphoid cells and IL-17-producing dermal γδ T cells. This overall led to a shift toward type 2/type 17 immune responses. In addition, using a novel topical genetic deletion approach, we reduced CD25 on skin, specifically on all cutaneous cells, and found that IL-2-dependent effects were reduced, hinting that CD25 - at least partly - induces this skin inflammation. Reduction of CD25 specifically on skin Tregs further augmented IL-2-induced immune cell infiltration, hinting that CD25 on skin Tregs is crucial to restrain IL-2-induced inflammation. Overall, our data support that innate lymphoid immune cells are key cells inducing side effects during IL-2 therapy and underline the significance of CD25 in this process.

PMID:38430129 | DOI:10.1002/eji.202350580

PLoS One. 2024 Mar 1;19(3):e0298609. doi: 10.1371/journal.pone.0298609. eCollection 2024.

ABSTRACT

Risdiplam is a new drug for treating spinal muscular atrophy (SMA). However, pharmacovigilance analyses are necessary to objectively evaluate its safety-a crucial step in preventing severe adverse events (AEs). Accordingly, the primary objective of the current study was to examine the AEs associated with risdiplam use based on real-world data obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. More specifically, we examined incidents reported between the third quarter of 2020 and the second quarter of 2023. The imbalance of risdiplam-related AEs was evaluated by computing the reporting odds ratio. A total of 5,406,334 reports were thoroughly reviewed. By removing duplicate reports, we identified 1588 reports in which risdiplam was the main suspected drug whose use was accompanied by 3470 associated AEs. Among the included AEs, 703 were categorized as serious and 885 as non-serious. Risdiplam use induced AEs across 18 organ systems, resulting in 130 positive signals. Notably, we detected new AE signals, including cardiac arrest, nephrolithiasis, tachycardia, loss of libido, and elevated hepatic enzyme activities; however, no ophthalmologic toxicity was reported. Although these new adverse reaction signals associated with risdiplam have been defined, long-term clinical studies are needed to confirm these findings. Nevertheless, our findings provide a valuable reference for improving the clinical management of SMA.

PMID:38427665 | PMC:PMC10906863 | DOI:10.1371/journal.pone.0298609

Cochrane Database Syst Rev. 2024 Mar 1;3(3):CD013880. doi: 10.1002/14651858.CD013880.pub2.

ABSTRACT

BACKGROUND: The number of older people is increasing worldwide and public expenditure on residential aged care facilities (ACFs) is expected to at least double, and possibly triple, by 2050. Co-ordinated and timely care in residential ACFs that reduces unnecessary hospital transfers may improve residents' health outcomes and increase satisfaction with care among ACF residents, their families and staff. These benefits may outweigh the resources needed to sustain the changes in care delivery and potentially lead to cost savings. Our systematic review comprehensively and systematically presents the available evidence of the effectiveness, safety and cost-effectiveness of alternative models of providing health care to ACF residents.

OBJECTIVES: Main objective To assess the effectiveness and safety of alternative models of delivering primary or secondary health care (or both) to older adults living in ACFs. Secondary objective To assess the cost-effectiveness of the alternative models.

SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, five other databases and two trials registers (WHO ICTRP, ClinicalTrials.gov) on 26 October 2022, together with reference checking, citation searching and contact with study authors to identify additional studies.

SELECTION CRITERIA: We included individual and cluster-randomised trials, and cost/cost-effectiveness data collected alongside eligible effectiveness studies. Eligible study participants included older people who reside in an ACF as their place of permanent abode and healthcare professionals delivering or co-ordinating the delivery of healthcare at ACFs. Eligible interventions focused on either ways of delivering primary or secondary health care (or both) or ways of co-ordinating the delivery of this care. Eligible comparators included usual care or another model of care. Primary outcomes were emergency department visits, unplanned hospital admissions and adverse effects (defined as infections, falls and pressure ulcers). Secondary outcomes included adherence to clinical guideline-recommended care, health-related quality of life of residents, mortality, resource use, access to primary or specialist healthcare services, any hospital admissions, length of hospital stay, satisfaction with the health care by residents and their families, work-related satisfaction and work-related stress of ACF staff.

DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data, and assessed risk of bias and certainty of evidence using GRADE. The primary comparison was any alternative model of care versus usual care.

MAIN RESULTS: We included 40 randomised trials (21,787 participants; three studies only reported number of beds) in this review. Included trials evaluated alternative models of care aimed at either all residents of the ACF (i.e. no specific health condition; 11 studies), ACF residents with mental health conditions or behavioural problems (12 studies), ACF residents with a specific condition (e.g. residents with pressure ulcers, 13 studies) or residents requiring a specific type of care (e.g. residents after hospital discharge, four studies). Most alternative models of care focused on 'co-ordination of care' (n = 31). Three alternative models of care focused on 'who provides care' and two focused on 'where care is provided' (i.e. care provided within ACF versus outside of ACF). Four models focused on the use of information and communication technology. Usual care, the comparator in all studies, was highly heterogeneous across studies and, in most cases, was poorly reported. Most of the included trials were susceptible to some form of bias; in particular, performance (89%), reporting (66%) and detection (42%) bias. Compared to usual care, alternative models of care may make little or no difference to the proportion of residents with at least one emergency department visit (risk ratio (RR) 1.01, 95% confidence interval (CI) 0.84 to 1.20; 7 trials, 1276 participants; low-certainty evidence), but may reduce the proportion of residents with at least one unplanned hospital admission (RR 0.74, 95% CI 0.56 to 0.99, I2 = 53%; 8 trials, 1263 participants; low-certainty evidence). We are uncertain of the effect of alternative models of care on adverse events (proportion of residents with a fall: RR 1.15, 95% CI 0.83 to 1.60, I² = 74%; 3 trials, 1061 participants; very low-certainty evidence) and adherence to guideline-recommended care (proportion of residents receiving adequate antidepressant medication: RR 5.29, 95% CI 1.08 to 26.00; 1 study, 65 participants) as the certainty of the evidence is very low. Compared to usual care, alternative models of care may have little or no effect on the health-related quality of life of ACF residents (MD -0.016, 95% CI -0.036 to 0.004; I² = 23%; 12 studies, 4016 participants; low-certainty evidence) and probably make little or no difference to the number of deaths in residents of ACFs (RR 1.03, 95% CI 0.92 to 1.16, 24 trials, 3881 participants, moderate-certainty evidence). We did not pool the cost-effectiveness or cost data as the specific costs associated with the various alternative models of care were incomparable, both across models of care as well as across settings. Based on the findings of five economic evaluations (all interventions focused on co-ordination of care), we are uncertain of the cost-effectiveness of alternative models of care compared to usual care as the certainty of the evidence is very low.

AUTHORS' CONCLUSIONS: Compared to usual care, alternative models of care may make little or no difference to the number of emergency department visits but may reduce unplanned hospital admissions. We are uncertain of the effect of alternative care models on adverse events (i.e. falls, pressure ulcers, infections) and adherence to guidelines compared to usual care, as the certainty of the evidence is very low. Alternative models of care may have little or no effect on health-related quality of life and probably have no effect on mortality of ACF residents compared to usual care. Importantly, we are uncertain of the cost-effectiveness of alternative models of care due to the limited, disparate data available.

PMID:38426600 | PMC:PMC10905654 | DOI:10.1002/14651858.CD013880.pub2

Invest Radiol. 2024 Mar 1. doi: 10.1097/RLI.0000000000001072. Online ahead of print.

ABSTRACT

BACKGROUND: The macrocyclic gadolinium-based contrast agent gadobutrol was introduced to the market in February 1998. Over the last 25 years, gadobutrol has been administered more than 100 million times worldwide providing a wealth of data related to safety.

OBJECTIVE: The aim of this study was to perform a thorough review and status update on gadobutrol's safety.

MATERIALS AND METHODS: Safety data from the clinical phase II-IV program and postmarketing surveillance were descriptively analyzed from February 1998 until December 31, 2022. Literature on special at-risk populations and specific safety aspects was critically summarized.

RESULTS: Forty-five clinical phase II-IV studies recruited 7856 patients receiving gadobutrol. Drug-related adverse events (AEs) were reported in 3.4% and serious AEs in <0.1% of patients. Nausea (0.7%) and dysgeusia (0.4%) were the most reported AEs. All other drug-related AEs occurred ≤0.3%. After more than 100 million gadobutrol administrations, overall adverse drug reactions (ADRs) from postmarketing surveillance (including clinical trials) were rare with an overall reporting rate of 0.0356%, hypersensitivity reactions (0.0147%), nausea (0.0032%), vomiting (0.0025%), and dyspnea (0.0010%). All other ADRs were <0.001%. No trend for higher rates of AEs was found in patients with reduced renal or liver function. Seven clinical studies reported safety findings in 7292 children ≤18 years, thereof 112 newborns/toddlers younger than 2 years. Overall, 61 ADRs (0.84%) were reported, including 3 serious ones. Adverse events in patients ≥65 years of age ("elderly") were significantly less frequent than in younger patients. A total of 4 reports diagnostic of or consistent with nephrogenic systemic fibrosis have been received. No causal relationship has been established between clinical signs and symptoms and the presence of small amounts of gadolinium in the body in patients with normal renal function after use of gadobutrol.

CONCLUSIONS: More than 100 million administrations worldwide have shown gadobutrol's well-established benefit-risk profile in any approved indication and populations.

PMID:38426761 | DOI:10.1097/RLI.0000000000001072

Lancet Oncol. 2024 Mar;25(3):388-399. doi: 10.1016/S1470-2045(23)00674-5.

ABSTRACT

BACKGROUND: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia.

METHODS: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3 + 3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513.

FINDINGS: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29).

INTERPRETATION: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia.

FUNDING: ImmunoGen.

PMID:38423051 | DOI:10.1016/S1470-2045(23)00674-5

Future Cardiol. 2024 Feb 29. doi: 10.2217/fca-2023-0136. Online ahead of print.

ABSTRACT

Aim: To evaluate the safety and efficacy of lomitapide in real-world clinical practice in Japan. Patients & methods: Interim analysis of 39 patients with homozygous familial hypercholesterolemia from an all-case surveillance study. Results: Median lomitapide dose (across 42 months) was 9.8 mg/day. 74 drug-related adverse events (AEs) were reported in 24 (61.5%) patients, including 14 (35.9%) with liver-related AEs, 19 (48.7%) with gastrointestinal disorders and 1 (2.6%) bleeding disorder. Lomitapide dose was reduced for 39.2% of drug-related AEs, withdrawn temporarily for 12.2%, and discontinued for 1 event (1.4%). Mean ± SD blood LDL-C level decreased from 225.9 ± 172.0 mg/dl (5.8 ± 4.5 mmol/l) predose to 159.4 ± 93.0 mg/dl (4.1 ± 2.4 mmol/l) at 12 months (p = 0.0245). Conclusion: This interim analysis suggests lomitapide is safe and effective in real-world clinical practice in Japan.

PMID:38420884 | DOI:10.2217/fca-2023-0136

Pharmacoepidemiol Drug Saf. 2024 Mar;33(3):e5768. doi: 10.1002/pds.5768.

ABSTRACT

BACKGROUND: A series of signal detection methods have been developed to detect adverse drug reaction (ADR) signals in spontaneous reporting system. However, different signal detection methods yield quite different signal detection results, and we do not know which method has the best detection performance. How to choose the most suitable signal detection method is an urgent problem to be solved. In this study, we systematically reviewed the characteristics and application scopes of current signal detection methods, with the goal of providing references for the optimization selection of signal detection methods in spontaneous reporting system.

METHODS: We searched six databases from inception to January 2023. The search strategy targeted literatures regarding signal detection methods in spontaneous reporting system. We used thematic analysis approach to summarize the advantages, disadvantages, and application scope of each signal detection method.

RESULTS: A total of 93 literatures were included, including 27 reviews and 66 methodological studies. Moreover, 31 signal detection methods were identified in these literatures. Each signal detection method has its inherent advantages and disadvantages, resulting in different application scopes of these methods.

CONCLUSION: Our systematic review finds that there are variabilities in the advantages, disadvantages, and application scopes of different signal detection methods. This finding indicates that the most suitable signal detection method varies across different drug safety scenarios. Moreover, when selecting signal detection method in a particular drug safety scenario, the following factors need to be considered: purpose of research, database size, drug characteristics, adverse event characteristics, and characteristics of the relations between drugs and adverse events.

PMID:38419132 | DOI:10.1002/pds.5768

In Vivo. 2024 Mar-Apr;38(2):923-927. doi: 10.21873/invivo.13520.

ABSTRACT

BACKGROUND/AIM: Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER).

PATIENTS AND METHODS: A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start.

RESULTS: CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days.

CONCLUSION: JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment.

PMID:38418128 | DOI:10.21873/invivo.13520

In Vivo. 2024 Mar-Apr;38(2):917-922. doi: 10.21873/invivo.13519.

ABSTRACT

BACKGROUND/AIM: Hypothyroidism induced by roxadustat, a hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor, was recently reported; however, information regarding roxadustat-associated hypothyroidism is still lacking. We explored the risk and time to onset of hypothyroidism associated with HIF-PH inhibitors using the Japanese Adverse Drug Event Report (JADER), a pharmacovigilance database.

PATIENTS AND METHODS: The participants of this study were registered in the JADER database between April 2004 and March 2023. The association between HIF-PH inhibitors and hypothyroidism was evaluated using the reporting odds ratio (ROR) and information component (IC). We also calculated the period from the start of drug administration to the onset of hypothyroidism and determined the onset pattern using Weibull distribution.

RESULTS: Roxadustat had positive signals for hypothyroidism among the HIF-PH inhibitors based on the ROR [31.03, 95% confidence interval (CI)=27.81-34.62] and IC (4.51, 95%CI=4.36-4.67) values, and a strong relationship was confirmed. In addition, the median time to roxadustat-associated hypothyroidism onset was 92 days, and over 50% of cases occurred within 100 days of starting treatment. Furthermore, the onset pattern was an early failure type.

CONCLUSION: There is a possible association between roxadustat and hypothyroidism. Therefore, enhanced thyroid function testing within 100 days of treatment initiation may help detect roxadustat-associated hypothyroidism. However, further research is required to confirm these findings, considering study limitations using databases of spontaneous adverse event reports.

PMID:38418113 | DOI:10.21873/invivo.13519

JAMA Netw Open. 2024 Feb 5;7(2):e240572. doi: 10.1001/jamanetworkopen.2024.0572.

NO ABSTRACT

PMID:38416493 | DOI:10.1001/jamanetworkopen.2024.0572

Cochrane Database Syst Rev. 2024 Feb 28;2:CD007837. doi: 10.1002/14651858.CD007837.pub3.

ABSTRACT

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a pathology that changes the three-dimensional shape of the spine and trunk. While AIS can progress during growth and cause cosmetic issues, it is usually asymptomatic. However, a final spinal curvature above the critical threshold of 30° increases the risk of health problems and curve progression in adulthood. The use of therapeutic exercises (TEs) to reduce the progression of AIS and delay or avoid other, more invasive treatments is still controversial.

OBJECTIVES: To evaluate the effectiveness of TE, including generic therapeutic exercises (GTE) and physiotherapeutic scoliosis-specific exercises (PSSE) in treating AIS, compared to no treatment, other non-surgical treatments, or between treatments.

SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases, and two clinical trials registers to 17 November 2022. We also screened reference lists of articles.

SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing TE with no treatment, other non-surgical treatments (braces, electrical stimulation, manual therapy), and different types of exercises. In the previous version of the review, we also included observational studies. We did not include observational studies in this update since we found sufficient RCTs to address our study aims.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Our major outcomes were progression of scoliosis (measured by Cobb angle, trunk rotation, progression, bracing, surgery), cosmetic issues (measured by surface measurements and perception), and quality of life (QoL). Our minor outcomes were back pain, mental health, and adverse effects.

MAIN RESULTS: We included 13 RCTs (583 participants). The percentage of females ranged from 50% to 100%; mean age ranged from 12 to 15 years. Studies included participants with Cobb angles from low to severe. We judged 61% of the studies at low risk for random sequence generation and 46% at low risk for allocation concealment. None of the studies could blind participants and personnel. We judged the subjective outcomes at high risk of performance and detection bias, and the objective outcomes at high risk of detection bias in six studies and at low risk of bias in the other six studies. One study did not assess any objective outcomes. Comparing TE versus no treatment, we are very uncertain whether TE reduces the Cobb angle (mean difference (MD) -3.6°, 95% confidence interval (CI) -5.6 to -1.7; 2 studies, 52 participants). Low-certainty evidence indicates PSSE makes little or no difference in the angle of trunk rotation (ATR) (MD -0.8°, 95% CI -3.8 to 2.1; 1 study, 45 participants), may reduce the waist asymmetry slightly (MD -0.5 cm, 95% CI -0.8 to -0.3; 1 study, 45 participants), and may result in little to no difference in the score of cosmetic issues measured by the Spinal Appearance Questionnaire (SAQ) General (MD 0.7 points, 95% CI -0.1 to 1.4; 1 study, 16 participants). PSSE may result in little to no difference in self-image measured by the Scoliosis Research Society - 22 Patient Questionnaire (SRS-22) (MD 0.3 points, 95% CI -0.3 to 0.9; 1 study, 16 participants) and improve QoL slightly measured by SRS-22 Total score (MD 0.3 points, 95% CI 0.1 to 0.4; 2 studies, 61 participants). Only Cobb angle results were clinically meaningful. Comparing PSSE plus bracing versus bracing, low-certainty evidence indicates PSSE plus bracing may reduce Cobb angle (-2.2°, 95% CI -3.8 to -0.7; 2 studies, 84 participants). Comparing GTE plus other non-surgical interventions versus other non-surgical interventions, low-certainty evidence indicates GTE plus other non-surgical interventions may reduce Cobb angle (MD -8.0°, 95% CI -11.5 to -4.5; 1 study, 80 participants). We are uncertain whether PSSE plus other non-surgical interventions versus other non-surgical interventions reduces Cobb angle (MD -7.8°, 95% CI -12.5 to -3.1; 1 study, 18 participants) and ATR (MD -8.0°, 95% CI -12.7 to -3.3; 1 study, 18 participants). PSSE plus bracing versus bracing alone may make little to no difference in subjective measurement of cosmetic issues as measured by SAQ General (-0.2 points, 95% CI -0.9 to 0.5; 1 study, 34 participants), self-image score as measured by SRS-22 Self-Image (MD 0.1 points, 95% CI -0.3 to 0.5; 1 study, 34 participants), and QoL measured by SRS-22 Total score (MD 0.2 points, 95% CI -0.1 to 0.5; 1 study, 34 participants). None of these results were clinically meaningful. Comparing TE versus bracing, we are very uncertain whether PSSE allows progression of Cobb angle (MD 2.7°, 95% CI 0.3 to 5.0; 1 study, 60 participants), changes self-image measured by SRS-22 Self-Image (MD 0.1 points, 95% CI -1.0 to 1.1; 1 study, 60 participants), and QoL measured by SRS-22 Total score (MD 3.2 points, 95% CI 2.1 to 4.2; 1 study, 60 participants). None of these results were clinically meaningful. Comparing PSSE with GTE, we are uncertain whether PSSE makes little or no difference in Cobb angle (MD -3.0°, 95% CI -8.2 to 2.1; 4 studies, 192 participants; very low-certainty evidence). PSSE probably reduces ATR (clinically meaningful) (-MD 3.0°, 95% CI -3.4 to -2.5; 2 studies, 138 participants). We are uncertain about the effect of PSSE on QoL measured by SRS-22 Total score (MD 0.26 points, 95% CI 0.11 to 0.62; 3 studies, 168 participants) and on self-image measured by SRS-22 Self-Image and Walter Reed Visual Assessment Scale (standardised mean difference (SMD) 0.77, 95% CI -0.61 to 2.14; 3 studies, 168 participants). Further, low-certainty evidence indicates that 38/100 people receiving GTE may progress more than 5° Cobb versus 7/100 receiving PSSE (risk ratio (RR) 0.19, 95% CI 0.67 to 0.52; 1 study, 110 participants). None of the included studies assessed adverse effects.

AUTHORS' CONCLUSIONS: The evidence on the efficacy of TE is currently sparse due to heterogeneity, small sample size, and many different comparisons. We found only one study following participants to the end of growth showing the efficacy of PSSE over TE. This result was weakened by adding studies with short-term results and unclear preparation of treating physiotherapists. More RCTs are needed to strengthen the current evidence and study other highly clinically relevant outcomes such as QoL, psychological and cosmetic issues, and back pain.

PMID:38415871 | DOI:10.1002/14651858.CD007837.pub3

Cochrane Database Syst Rev. 2024 Feb 28;2:CD007156. doi: 10.1002/14651858.CD007156.pub3.

ABSTRACT

BACKGROUND: Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity that causes progressive constriction of the cheeks and mouth accompanied by severe pain and reduced mouth opening. OSF has a significant impact on eating and swallowing, affecting quality of life. There is an increased risk of oral malignancy in people with OSF. The main risk factor for OSF is areca nut chewing, and the mainstay of treatment has been behavioural interventions to support habit cessation. This review is an update of a version last published in 2008.

OBJECTIVES: To evaluate the benefits and harms of interventions for the management of oral submucous fibrosis.

SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 5 September 2022.

SELECTION CRITERIA: We considered randomised controlled trials (RCTs) of adults with a biopsy-confirmed diagnosis of OSF treated with systemic, locally delivered or topical drugs at any dosage, duration or delivery method compared against placebo or each other. We considered surgical procedures compared against other treatments or no active intervention. We also considered other interventions such as physiotherapy, ultrasound or alternative therapies.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. participant-reported resumption of normal eating, chewing and speech; 2. change or improvement in maximal mouth opening (interincisal distance); 3. improvement in range of jaw movement; 4. change in severity of oral/mucosal burning pain/sensation; 5.

ADVERSE EFFECTS: Our secondary outcomes were 6. quality of life; 7. postoperative discomfort or pain as a result of the intervention; 8. participant satisfaction; 9. hospital admission; 10. direct costs of medication, hospital bed days and any associated inpatient costs for the surgical interventions. We used GRADE to assess certainty of evidence for each outcome.

MAIN RESULTS: We included 30 RCTs (2176 participants) in this updated review. We assessed one study at low risk of bias, five studies at unclear risk of bias and 24 studies at high risk of bias. We found diverse interventions, which we categorised according to putative mechanism of action. We present below our main findings for the comparison 'any intervention compared with placebo or no active treatment' (though most trials included habit cessation for all participants). Results for head-to-head comparisons of active interventions are presented in full in the main review. Any intervention versus placebo or no active treatment Participant-reported resumption of normal eating, chewing and speech No studies reported this outcome. Interincisal distance Antioxidants may increase mouth opening (indicated by interincisal distance (mm)) when measured at less than three months (mean difference (MD) 3.11 mm, 95% confidence interval (CI) 0.46 to 5.77; 2 studies, 520 participants; low-certainty evidence), and probably increase mouth opening slightly at three to six months (MD 8.83 mm, 95% CI 8.22 to 9.45; 3 studies, 620 participants; moderate-certainty evidence). Antioxidants may make no difference to interincisal distance at six-month follow-up or greater (MD -1.41 mm, 95% CI -5.74 to 2.92; 1 study, 90 participants; low-certainty evidence). Pentoxifylline may increase mouth opening slightly (MD 1.80 mm, 95% CI 1.02 to 2.58; 1 study, 106 participants; low-certainty evidence). However, it should be noted that these results are all less than 10 mm, which could be considered the minimal change that is meaningful to someone with oral submucous fibrosis. The evidence was very uncertain for all other interventions compared to placebo or no active treatment (intralesional dexamethasone injections, pentoxifylline, hydrocortisone plus hyaluronidase, physiotherapy). Burning sensation Antioxidants probably reduce burning sensation visual analogue scale (VAS) scores at less than three months (MD -30.92 mm, 95% CI -31.57 to -30.27; 1 study, 400 participants; moderate-certainty evidence), at three to six months (MD -70.82 mm, 95% CI -94.39 to -47.25; 2 studies, 500 participants; moderate-certainty evidence) and at more than six months (MD -27.60 mm, 95% CI -36.21 to -18.99; 1 study, 90 participants; moderate-certainty evidence). The evidence was very uncertain for the other interventions that were compared to placebo and measured burning sensation (intralesional dexamethasone, vasodilators). Adverse effects Fifteen studies reported adverse effects as an outcome. Six of these studies found no adverse effects. One study evaluating abdominal dermal fat graft reported serious adverse effects resulting in prolonged hospital stay for 3/30 participants. There were mild and transient general adverse effects to systemic drugs, such as dyspepsia, abdominal pain and bloating, gastritis and nausea, in studies evaluating vasodilators and antioxidants in particular.

AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that antioxidants administered systemically probably improve mouth opening slightly at three to six months and improve burning sensation VAS scores up to and beyond six months. We found only low/very low-certainty evidence for all other comparisons and outcomes. There was insufficient evidence to make an informed judgement about potential adverse effects associated with any of these treatments. There was insufficient evidence to support or refute the effectiveness of the other interventions tested. High-quality, adequately powered intervention trials with a low risk of bias that compare biologically plausible treatments for OSF are needed. It is important that relevant participant-reported outcomes are evaluated.

PMID:38415846 | DOI:10.1002/14651858.CD007156.pub3

Clin Epigenetics. 2024 Feb 28;16(1):36. doi: 10.1186/s13148-024-01648-4.

ABSTRACT

BACKGROUND: Metabolic side effects of psychotropic medications are a major drawback to patients' successful treatment. Using an epigenome-wide approach, we aimed to investigate DNA methylation changes occurring secondary to psychotropic treatment and evaluate associations between 1-month metabolic changes and both baseline and 1-month changes in DNA methylation levels. Seventy-nine patients starting a weight gain inducing psychotropic treatment were selected from the PsyMetab study cohort. Epigenome-wide DNA methylation was measured at baseline and after 1 month of treatment, using the Illumina Methylation EPIC BeadChip.

RESULTS: A global methylation increase was noted after the first month of treatment, which was more pronounced (p < 2.2 × 10-16) in patients whose weight remained stable (< 2.5% weight increase). Epigenome-wide significant methylation changes (p < 9 × 10-8) were observed at 52 loci in the whole cohort. When restricting the analysis to patients who underwent important early weight gain (≥ 5% weight increase), one locus (cg12209987) showed a significant increase in methylation levels (p = 3.8 × 10-8), which was also associated with increased weight gain in the whole cohort (p = 0.004). Epigenome-wide association analyses failed to identify a significant link between metabolic changes and methylation data. Nevertheless, among the strongest associations, a potential causal effect of the baseline methylation level of cg11622362 on glycemia was revealed by a two-sample Mendelian randomization analysis (n = 3841 for instrument-exposure association; n = 314,916 for instrument-outcome association).

CONCLUSION: These findings provide new insights into the mechanisms of psychotropic drug-induced weight gain, revealing important epigenetic alterations upon treatment, some of which may play a mediatory role.

PMID:38419113 | DOI:10.1186/s13148-024-01648-4

Drug Ther Bull. 2024 Feb 28:dtb-2024-000013. doi: 10.1136/dtb.2024.000013. Online ahead of print.

NO ABSTRACT

PMID:38417949 | DOI:10.1136/dtb.2024.000013

Sci Rep. 2024 Feb 27;14(1):4819. doi: 10.1038/s41598-024-55664-8.

ABSTRACT

One of the significant worldwide health problems associated with pharmacovigilance is the under-reporting of adverse drug reactions (ADRs). Reporting suspected ADRs is essential to ensure patient safety, medicine safety, and healthcare quality. The new policy in Saudi Arabia emphasizes pharmacists taking a new clinical role, which may facilitate and improve the documentation of ADRs. Therefore, this study aimed to assess the knowledge and perception of community pharmacists towards the ADRs and their reporting practice in Saudi Arabia. A cross-sectional study using a structured self-administered questionnaire was administered to community pharmacists working in Saudi Arabia. Data were analyzed using descriptive and inferential statistics to identify the association between perceptions and ADR reporting practices. A P value < of 0.05 was considered statistically significant. A response rate of 43% (n = 163) was achieved, of whom 55.2% demonstrated knowledge of PV. Only 16% of community pharmacists were aware of the responsible center for monitoring and collecting ADRs in Saudi Arabia. The key facilitator was offering incentives to pharmacists, and the lack of time was found to be a key barrier among reporter community pharmacists. Positive attitudes toward pharmacovigilance and ADR reporting were expressed by community pharmacists. The findings of this study emphasize the further need for education and training programs and simplifying the ADR reporting process used in Saudi Arabia to enhance the reporting practice.

PMID:38413787 | PMC:PMC10899240 | DOI:10.1038/s41598-024-55664-8

Sci Rep. 2024 Feb 27;14(1):4785. doi: 10.1038/s41598-024-54886-0.

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has been a major challenge worldwide for the past years with high morbidity and mortality rates. While vaccination was the cornerstone to control the pandemic and disease spread, concerns regarding safety and adverse events (AEs) have been raised lately. A cross-sectional study was conducted between January 1st and January 22nd, 2022, in six Arabic countries namely Saudi Arabia, Egypt, Syria, Libya, Iraq, and Algeria. We utilized a self-administered questionnaire validated in Arabic which encompassed two main parts. The first was regarding sociodemographic data while the second was about COVID-19 vaccination history, types, doses, and experienced AEs. A multistage sampling was employed in each country, involving the random selection of three governorates from each country, followed by the selection of one urban area and one rural area from each governorate. We included the responses of 1564 participants. The most common AEs after the first and second doses were local AEs (67.9% and 46.6%, respectively) followed by bone pain and myalgia (37.6% and 31.8%, respectively). After the third dose, the most common AEs were local AEs (45.7%) and fever (32.4%). Johnson and Johnson, Sputnik Light, and Moderna vaccines showed the highest frequency of AEs. Factors associated with AEs after the first dose included an increase in age (aOR of 61-75 years compared to the 12-18 years group: 2.60, 95% CI: 1.59-4.25, p = 0.001) and male gender (OR: 0.72, 95% CI: 0.63-0.82, p < 0.001). The cumulative post-vaccination COVID-19 disease was reported with Sinovac (16.1%), Sinopharm (15.8%), and Johnson and Johnson (14.9) vaccines. History of pre-vaccination SARS-CoV-2 infection significantly increases the risk of post-vaccination COVID-19 after the first, second, and booster doses (OR: 3.09, CI: 1.9-5.07, p < 0.0001; OR: 2.56, CI: 1.89-3.47, p < 0.0001; and OR: 2.94, CI: 1.6-5.39, p = 0.0005 respectively). In conclusion, AEs were common among our participants, especially local AEs. Further extensive studies are needed to generate more generalizable data regarding the safety of different vaccines.

PMID:38413637 | PMC:PMC10899622 | DOI:10.1038/s41598-024-54886-0

Front Immunol. 2024 Feb 12;15:1292122. doi: 10.3389/fimmu.2024.1292122. eCollection 2024.

ABSTRACT

Immunotherapy has revolutionized the cancer treatment landscape by opening up novel avenues for intervention. As the use of immune checkpoint inhibitors (ICIs) has exponentially increased, so have immune-related adverse events (irAEs). The mechanism of irAEs may involve the direct damage caused by monoclonal antibodies and a sequence of immune responses triggered by T cell activation. Common side effects include dermatologic toxicity, endocrine toxicity, gastrointestinal toxicity, and hepatic toxicity. While relatively rare, neurotoxicity, cardiotoxicity, and pulmonary toxicity can be fatal. These toxicities pose a clinical dilemma regarding treatment discontinuation since they can result in severe complications and necessitate frequent hospitalization. Vigilant monitoring of irAEs is vital in clinical practice, and the principal therapeutic strategy entails the administration of oral or intravenous glucocorticoids (GSCs). It may be necessary to temporarily or permanently discontinue the use of ICIs in severe cases. Given that irAEs can impact multiple organs and require diverse treatment approaches, the involvement of a multidisciplinary team of experts is imperative. This review aims to comprehensively examine the pathogenesis, clinical manifestations, incidence, and treatment options for various irAEs.

PMID:38410506 | PMC:PMC10895024 | DOI:10.3389/fimmu.2024.1292122

Reg Anesth Pain Med. 2024 Feb 27:rapm-2023-105261. doi: 10.1136/rapm-2023-105261. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Perioperative psychological stress and pharmacological anxiolysis can negatively affect the quality of recovery after total knee arthroplasty. We aimed to assess whether hypnosis combined with virtual reality could reduce intraoperative pharmacological sedation and improve quality of recovery after total knee arthroplasty surgery.

METHODS: In this prospective randomized clinical trial, 60 patients scheduled for total knee arthroplasty with spinal anesthesia were randomly divided into 2 groups of 30 patients each. Intraoperatively, intermittent boluses of midazolam 1 mg were administered at 5 min intervals at the patient's request, with a maximum driven by the clinical assessment of sedation depth. During surgery, patients received standard care (group control) or virtual reality hypnosis (group VRH). An unblinded observer recorded the total dose of midazolam administered during surgery, and changes in the Quality-of-Recovery 15-item score, comfort, fatigue, pain and anxiety before and 1, 3 and 7 days after surgery.

RESULTS: Patients in the VRH group required a lower dose of midazolam (mg; median (range)) intraoperatively (group VRH: 0 (0-4) and group control: 2 (0-9), p<0.001). Quality-of-Recovery 15-item, anxiety, and pain were similar between groups.

CONCLUSIONS: In total knee arthroplasty with spinal anesthesia, VRH reduces the requirement for intraoperative pharmacological sedation, without a change in the quality of recovery.

TRIAL REGISTRATION NUMBER: NCT05707234.

PMID:38413184 | DOI:10.1136/rapm-2023-105261