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OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. METHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. RESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. INTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.

Abstract Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.

Genito-Pelvic Pain/Penetration Disorder is a common sexual disorder that affects an individual's sexual health and overall well-being. Education is a therapeutic resource that presents several advantages, and it can potentially generate improvements both in pain and sexual functioning-related outcomes in patients suffering from this affliction. The objective of this study was to assess if a therapeutic educational program produced improvements in the different domains of the Female Sexual Function Index in participants suffering from Genito-Pelvic Pain Penetration Disorder. Participants were randomized into a group that received a face-to-face therapeutic educational program, a group that received the same program but online, or a control group. The Female Sexual Function Index was assessed, and analysis of the change in the domains for every group was performed using multiple t-tests. Improvements were found in the face-to-face intervention group, but only the "Pain" domain showed significant improvements (-1.1 points, p < 0.05). Improvements were also found in the online group, but they were only significant in the "Pain" and "Satisfaction" domains (-0.8 points, p < 0.05 for both). A therapeutic educational program improves pain-related outcomes, and it shows a positive tendency to also improve sexual functioning-related outcomes in patients suffering from Genito-Pelvic Pain/Penetration Disorder. Registration: Clinical Trials (NCT05114473).

Abstract Background Despite the low-risk nature of participation in most clinical anesthesia trials, subject recruitment on the same day as surgery is often restricted due to the concerns of researchers and local research ethics boards that same-day consent may not afford adequate time and opportunity for patients to weigh and make decisions, as well as perceptions of patient vulnerability immediately prior to surgery that could impact the voluntary nature and the rigor of the informed consent process. However, specialties such as anesthesiology, critical care, interventional radiology, and emergency medicine have a varied pattern of practice and patient acquaintance that does not typically afford the luxury of time or, in many cases, advance consent for participation in research. Indeed, the initial encounter between anesthesiologists and patients undergoing elective procedures routinely occurs on the day of surgery. Concerns of coercion related to same-day consent for clinical anesthesia research trials have not been borne out in the literature, and represent a significant obstacle to clinical researchers, as well as to the patients who are denied opportunities for potential benefit through participation in research studies. Methods We describe the protocol for a prospective randomized controlled trial examining the voluntariness of patient consent, solicited either in advance of surgery or on the same day, to participate in an anesthesia research study at Women’s College Hospital. One hundred fourteen patients scheduled to undergo ambulatory anterior cruciate ligament repair facilitated by general anesthesia with an adductor canal block will be randomized for recruitment either (a) in the pre-operative assessment clinic before the day of surgery or (b) on the day of surgery, to be approached for consent to participate in a fabricated research study of adjunct medications in adductor canal blocks. Regardless of allocation, patients in both groups will receive the same routine standard of care and will complete a post-operative questionnaire to signal perceptions of undue influence in the process of providing informed consent for the fabricated trial. Discussion This study will inform trial design and practice guidelines surrounding the amount of time patients ought to be afforded in order to make durable decisions to participate (or not) in clinical research studies. This is expected to impact trial recruitment in a variety of clinical settings where researchers have only brief opportunities to interface with patients. Trial registration The trial was registered prospectively on the Open Science Framework (OSF), registration #46twc, on 2023-Mar-17.

Objective To evaluate the impact of coadministering statins with direct oral anticoagulants (DOACs) on the risk of major bleeding events in patients with venous thromboembolism (VTE).Design Observational cohort analysis based on a multicentre international registry.Setting Data were extracted from the Registro Informatizado de Enfermedad TromboEmbolica Registry, which involves 205 centres across 27 countries.Participants A total of 73 659 patients diagnosed with VTE were classified based on their anticoagulant therapy (DOACs) versus low-molecular-weight heparin (LMWH) or vitamin K antagonists (VKAs) and concurrent use of statins.Methods Multivariable Cox proportional hazards models adjusted for confounding variables to assess the risk of major bleeding events stratified by the type of anticoagulant use and statin use.Results From October 2013 to February 2023, 73 659 patients were recruited: 2573 were statin users on DOACs, 14 090 were statin users on LMWH or VKA therapy, 10 088 were non-statin users on DOACs and 46 908 were non-statin users on LMWH or VKA therapy. Statin users were 10 years older and more likely to have hypertension, diabetes, renal failure or prior artery disease. During anticoagulation (median, 187 days), 1917 patients (2.6%) suffered major bleeding. Rates of major bleeding per 100 patient-years were 2.33 (95% CI 1.72 to 3.09), 3.75 (95% CI 3.43 to 4.10), 1.39 (95% CI 1.13 to 1.69) and 3.10 (95% CI 2.93 to 3.27), respectively. On multivariable analysis, patients treated with DOACs had a significantly lower risk of major bleeding compared with those on LMWH or VKA therapy (adjusted HR 0.59; 95% CI 0.48 to 0.74). The adjusted HR in statin users versus non-users was 1.03 (95% CI 0.92 to 1.14), while in statin users on DOACs versus the rest of patients, it was 1.18 (95% CI 0.79 to 1.76).Conclusions In patients with VTE receiving statins, long-term anticoagulation with DOACs was associated with a reduced risk of major bleeding, regardless of the statin use. These findings support the safety profile of DOACs over VKAs or LMWH in the management of VTE in patients requiring statins.

Background: Current guidelines recommend quantitative neuromuscular block monitoring during neuromuscular blocking agent administration. Monitors using surface electromyography (EMG) determine compound motor action potential (cMAP) amplitude or area under the curve (AUC). Rigorous evaluation of the interchangeability of these methods is lacking but necessary for clinical and research assurance that EMG interpretations of the depth of neuromuscular block are not affected by the methodology. Methods: Digitised EMG waveforms were studied from 48 patients given rocuronium during two published studies. The EMG amplitudes and AUCs were calculated pairwise from all cMAPs classified as valid by visual inspection. Ratios of the first twitch (T1) to the control T1 before administration of rocuronium (T1c) and train-of-four ratios (TOFRs) were compared using repeated measures Bland–Altman analysis. Results: Among the 2419 paired T1/T1c differences where the average T1/T1c was ≤0.2, eight (0.33%) were outside prespecified clinical limits of agreement (−0.148 to 0.164). Among the 1781 paired TOFR differences where the average TOFR was ≥0.8, 70 (3.93%) were outside the prespecified clinical limits of agreement ((−0.109 to 0.134). Among all 7286 T1/T1c paired differences, the mean bias was 0.32 (95% confidence interval 0.202–0.043), and among all 5559 paired TOFR differences, the mean bias was 0.011 (95% confidence interval 0.0050–0.017). Among paired T1/T1c and TOFR differences, Lin's concordance correlation coefficients were 0.98 and 0.995, respectively. Repeatability coefficients for T1/T1c and TOFR were

Abstract Background Persistent pain is a common yet debilitating complication after breast cancer surgery. Given the pervasive effects of this pain disorder on the patient and healthcare system, post-mastectomy pain syndrome (PMPS) is becoming a larger population health problem, especially as the prognosis and survivorship of breast cancer increases. Interventions that prevent persistent pain after breast surgery are needed to improve the quality of life of breast cancer survivors. An intraoperative intravenous lidocaine infusion has emerged as a potential intervention to decrease the incidence of PMPS. We aim to determine the definitive effects of this intervention in patients undergoing breast cancer surgery. Methods PLAN will be a multicenter, parallel-group, blinded, 1:1 randomized, placebo-controlled trial of 1,602 patients undergoing breast cancer surgery. Adult patients scheduled for a lumpectomy or mastectomy will be randomized to receive an intravenous 2% lidocaine bolus of 1.5 mg/kg with induction of anesthesia, followed by a 2.0 mg/kg/h infusion until the end of surgery, or placebo solution (normal saline) at the same volume. The primary outcome will be the incidence of persistent pain at 3 months. Secondary outcomes include the incidence of pain and opioid consumption at 1 h, 1–3 days, and 12 months after surgery, as well as emotional, physical, and functional parameters, and cost-effectiveness. Discussion This trial aims to provide definitive evidence on an intervention that could potentially prevent persistent pain after breast cancer surgery. If this trial is successful, lidocaine infusion would be integrated as standard of care in breast cancer management. This inexpensive, widely available, and easily administered intervention has the potential to reduce pain and suffering in an already afflicted patient population, decrease the substantial costs of chronic pain management, potentially decrease opioid use, and improve the quality of life in patients. Trial registration This trial has been registered on clinicaltrials.gov (NCT04874038, Dr. James Khan. Date of registration: May 5, 2021).

Abstract Objective ACTN2, encoding alpha‐actinin‐2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2‐myopathy has also been proposed in a single series. Methods We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. Results We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. Interpretation This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult‐onset progressive muscle disease.

Collagen VI-related dystrophies (COL6-RDs) are a group of severe, congenital-onset muscular dystrophies for which there is no effective causative treatment. Dominant-negative mutations are common in COL6A1, COL6A2, and COL6A3 genes, encoding the collagen α1, α2, and α3 (VI) chains. They act by incorporating into the hierarchical assembly of the three α (VI) chains and consequently produce a dysfunctional collagen VI extracellular matrix, while haploinsufficiency for any of the COL6 genes is not associated with disease. Hence, allele-specific transcript inactivation is a valid therapeutic strategy, although selectively targeting a pathogenic single nucleotide variant is challenging. Here, we develop a small interfering RNA (siRNA) that robustly, and in an allele-specific manner, silences a common glycine substitution (G293R) caused by a single nucleotide change in COL6A1 gene. By intentionally introducing an additional mismatch into the siRNA design, we achieved enhanced specificity toward the mutant allele. Treatment of patient-derived fibroblasts effectively reduced the levels of mutant transcripts while maintaining unaltered wild-type transcript levels, rescuing the secretion and assembly of collagen VI matrix by reducing the dominant-negative effect of mutant chains. Our findings establish a promising treatment approach for patients with the recurrent dominantly negative acting G293R glycine substitution.

Abstract Ibogaine (IBO) is an atypical psychedelic with a complex mechanism of action. To date, the mechanisms that may underlie its anti-addictive effects are still not defined. This study aims to identify changes in gene expression induced by a single oral dose of IBO in the cortex of mice by means of a transcriptomic analysis for the first time. Our results showed significant alterations in gene expression in mouse frontal cortex samples 4 h after a single oral dose of IBO. Specifically, genes involved in hormonal pathways and synaptogenesis exhibited upregulation, while genes associated with apoptotic processes and endosomal transports showed downregulation. The findings were further corroborated through quantitative polymerase chain reaction (qPCR) analysis. However, the validation of gene expression related to hormonal pathways did not entirely align with the transcriptomic analysis results, possibly due to the brain region from which tissue was collected. Sex differences were observed, with female mice displaying more pronounced alterations in gene expression after IBO treatment. High variability was observed across individual animals. However, this study represents a significant advancement in comprehending IBO’s molecular actions. The findings highlight the influence of IBO on gene expression, particularly on hormonal pathways, synaptogenesis, apoptotic processes, and endosomal transports. The identification of sex differences underscores the importance of considering sex as a potential factor influencing IBO’s effects. Further research to assess different time points after IBO exposure is warranted.

Medicinal plants take a fundamental place in people's livelihoods. They seem to be a palliative therapeutic option for health problems. The knowledge of traditional uses of plants for healing held by indigenous people is an asset to the valorization of traditional medicine, which is increasingly solicited for the treatment of many diseases. The aim of this research is to improve know-how on plant species employed in the traditional pharmacopoeia practiced by the Baka people, recognized as great healers. Data were collected between 2018 and 2019 from 75 households distributed in five villages in the Mintom subdivision, Southern Region of Cameroon. The so-called popular ethnobotanical survey method was used. One thousand six hundred and thirty-five (1 635) citations and six hundred and five (605) recipes were recorded, involving 210 plant species, distributed in 183 genera and 75 families. A total of 69 health problems were identified and distinguished in 13 groups of diseases. Results reveal that for the same diseases, each village uses its own list of plants. The study area is highly diverse in terms both flora and uses. This paper can therefore be seen as a continuation of the research and development of plants-based medicines. It is also in the line with the import-substitution policy for valorization of Cameroonian.

The sedentarization of Pygmies in the Congo Basin has triggered a profound transformation in their traditional lifestyles, particularly affecting dietary habits and food consumption. We employed 24-hour dietary recalls in 10 sedentarized Baka Pygmy villages in southeastern Cameroon, gathering data on diet composition, diversity (Household Dietary Diversity Score, HDDS), and nutrient intake per adult male equivalent (AME) from 67 homes (28% of all households). Our findings revealed that 62% of consumed foods were agricultural produce, 29% were locally produced or purchased products, and the remaining 9% comprised items sourced or hunted from the wild. The average HDDS per village was low (4.1±1.56) and mean total energy intake was 1734.9±1,031.8 kcal/AME, with significant contributions from cultivated foods. There was a negative correlation between the consumption of cultivated and wild foods. Moreover, a considerable proportion of households (78.7%, ranging from 22.4% to 97%) exhibited nutrient consumption below the lower 95% uncertainty interval found in a Cameroonian nutrient supply study. Additionally, 78.3% of respondents fell below WHO/FAO recommendations for 21 nutrients, even after adjusting for the Baka’s shorter stature. This high prevalence of insufficient nutrient intake underscores the urgent need for targeted interventions to address nutritional deficiencies within this population. We show Baka households rely more on cultivated foods and are less dependent on wild sources. Understanding the profound transformation in dietary patterns and its repercussions on the health and overall well-being of the studied marginalized Indigenous communities is pivotal in devising strategies to enhance their survival. This shift in dietary profiles often stems from complex factors, including socioeconomic challenges, environmental changes, and cultural shifts. To address these issues effectively, a comprehensive approach that integrates cultural sensitivity, community engagement, and sustainable practices is imperative.

Background: Although total hip arthroplasty (THA) and total knee arthroplasty (TKA) offer significant cost savings to our health care system, the degree to which the burden of postoperative care has been transferred onto the informal caregiver is often overlooked. We performed a scoping review to identify the characteristics and factors that contribute to the burden of care experienced after outpatient THA and TKA. Methods: We systematically searched electronic literature databases according to scoping review guidelines from inception to June 2021 for articles reporting the experiences of informal caregivers providing care for patients having undergone outpatient THA or TKA. Our review included English-language studies that sought to elucidate the impact on caregivers in the acute postoperative period (up to 6 wk after surgery). Results: Our search yielded 1423 unique articles, which were screened for inclusion. We removed 310 duplicate records and excluded another 1099 articles because they did not meet the inclusion criteria for full-text screening with relevancy. We thus assessed 14 articles for full-text review, and none were found to meet our inclusion criteria. Conclusion: We found no published data pertaining to the burden borne by informal caregivers who provide perioperative care to patients who have undergone ambulatory THA or TKA. Further research is needed to identify, quantify and determine the modifability of the various characteristics and factors that contribute to caregiver burden in the outpatient setting. Contexte : L'arthroplastie totale de la hanche (ATH) et l'arthroplastie totale du genou (ATG) realisees en contexte ambulatoire entrainent des economies considerables pour le systeme de sante, mais la part du fardeau des soins postoperatoires qui est transferee aux aidants naturels est souvent ignoree. Nous avons effectue un examen de la portee pour cerner les caracteristiques et les facteurs contribuant au fardeau des soins apres une ATH ou une ATG ambulatoire. Methodes : Nous avons procede, en suivant la methodologie de l'examen de la portee, a une interrogation systematique des bases de donnees electroniques, de leur mise en service a juin 2021, pour recenser des articles sur les experiences des aidants naturels qui offrent des soins aux patients ambulatoires ayant subi une ATH ou une ATG. Notre examen comprenait des etudes publiees en anglais tentant de mieux comprendre les repercussions sur les aidants naturels durant la periode postoperatoire aigue (jusqu'a 6 semaines apres l'intervention). Resultats : Nos recherches ont repere 1423 articles distincts, ensuite passes en revue pour inclusion. Nous avons retire 310 doublons et exclu 1099 autres articles ne repondant pas aux criteres d'inclusion d'un examen complet du texte pour en evaluer la pertinence. En fin de compte, 14 articles ont ete soumis a l'examen complet du texte et aucun n'a repondu aux criteres d'inclusion. Conclusion : Nous n'avons trouve aucune donnee publiee sur le fardeau assume par les aidants naturels offrant des soins perioperatoires aux patients ayant subi une ATH ou une ATG ambulatoire. D'autres recherches seront necessaires pour cerner, quantifer et determiner la variation des caracteristiques et facteurs contribuant au fardeau assume par l'aidant en contexte ambulatoire., Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are 2 of the most common and successful surgical procedures performed worldwide, with more than 120 000 primary total joint arthroplasty [...]

Background: International guidelines recommend quantitative neuromuscular monitoring when administering neuromuscular blocking agents. The train-of-four count is important for determining the depth of block and appropriate reversal agents and doses. However, identifying valid compound motor action potentials (cMAPs) during surgery can be challenging because of low-amplitude signals and an inability to observe motor responses. A convolutional neural network (CNN) to classify cMAPs as valid or not might improve the accuracy of such determinations. Methods: We modified a high-accuracy CNN originally developed to identify handwritten numbers. For training, we used digitised electromyograph waveforms (TetraGraph) from a previous study of 29 patients and tuned the model parameters using leave-one-out cross-validation. External validation used a dataset of 19 patients from another study with the same neuromuscular block monitor but with different patient, surgical, and protocol characteristics. All patients underwent ulnar nerve stimulation at the wrist and the surface electromyogram was recorded from the adductor pollicis muscle. Results: The tuned CNN performed highly on the validation dataset, with an accuracy of 0.9997 (99% confidence interval 0.9994–0.9999) and F1 score=0.9998. Performance was equally good for classifying the four individual responses in the train-of-four sequence. The calibration plot showed excellent agreement between the predicted probabilities and the actual prevalence of valid cMAPs. Ten-fold cross-validation using all data showed similar high performance. Conclusions: The CNN distinguished valid cMAPs from artifacts after ulnar nerve stimulation at the wrist with >99.5% accuracy. Incorporation of such a process within quantitative electromyographic neuromuscular block monitors is feasible.