Association of peri-operative prescription of non-steroidal anti-inflammatory drugs with continued prescription of opioids after total knee arthroplasty: a retrospective claims-based cohort study.

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the mainstays of multimodal pain management. While effective for acute pain control, recent pre-clinical evidence has raised concerns regarding an association between NSAIDs and chronic pain and potential opioid use. Our objective was to explore the association between peri-operative use of prescription NSAIDs and the need for continued opioid prescriptions lasting 90-180 days in previously opioid-naïve patients undergoing total knee arthroplasty. A database of health claims in the USA was used to identify all opioid-naïve adult patients who underwent primary knee arthroplasty between January 2010 and October 2021. We evaluated the magnitude of association between peri-operative prescription NSAID claims and claims for opioids at 90 days postoperatively using multivariable logistic regression models. Secondary outcomes included: the magnitude of association between peri-operative NSAID prescription and claims for opioids at 180 days postoperatively; and identifying other potential factors associated with opioid claims at 90 days postoperatively. After risk adjustment using multivariable logistic regression models in the 789,736-patient cohort, the adjusted odds ratio (95%CI) for a continuous claim of opioids at 90 and 180 days postoperatively among patients with a peri-operative NSAID prescription within 30 days was 1.32 (1.30-1.35), p < 0.001; and 1.12 (1.10-1.15), p < 0.001, respectively. This estimate of effect remained robust at 90 days after accounting for known potential confounders, including pre-existing knee pain and acute postoperative pain severity. Similar analysis of other pain medications (e.g. paracetamol) did not detect such an association. This population-based cohort study suggests that peri-operative prescription NSAID use may be associated with continued opioid prescription claims at 90 and 180 days after knee arthroplasty, even after adjusting for other observed covariates for continuous opioid claims. These novel findings can inform clinical decision-making for post-surgical pain management, risk-benefit discussions with patients and future research.

Network meta-analysis of the analgesic effectiveness of regional anaesthesia techniques for anterior cruciate ligament reconstruction.

Anterior cruciate ligament reconstruction can cause moderate to severe acute postoperative pain. Despite advances in our understanding of knee innervation, consensus regarding the most effective regional anaesthesia techniques for this surgical population is lacking. This network meta-analysis compared effectiveness of regional anaesthesia techniques used to provide analgesia for anterior cruciate ligament reconstruction. Randomised trials examining regional anaesthesia techniques for analgesia following anterior cruciate ligament reconstruction were sought. The primary outcome was opioid consumption during the first 24 h postoperatively. Secondary outcomes were: rest pain at 0, 6, 12 and 24 h; area under the curve of pain over 24 h; and opioid-related adverse effects and functional recovery. Network meta-analysis was conducted using a frequentist approach. A total of 57 trials (4069 patients) investigating femoral nerve block, sciatic nerve block, adductor canal block, local anaesthetic infiltration, graft-donor site infiltration and systemic analgesia alone (control) were included. For opioid consumption, all regional anaesthesia techniques were superior to systemic analgesia alone, but differences between regional techniques were not significant. Single-injection femoral nerve block combined with sciatic nerve block had the highest p value probability for reducing postoperative opioid consumption and area under the curve for pain severity over 24 h (78% and 90%, respectively). Continuous femoral nerve block had the highest probability (87%) of reducing opioid-related adverse effects, while local infiltration analgesia had the highest probability (88%) of optimising functional recovery. In contrast, systemic analgesia, local infiltration analgesia and adductor canal block were each poor performers across all analgesic outcomes. Regional anaesthesia techniques that target both the femoral and sciatic nerve distributions, namely a combination of single-injection nerve blocks, provide the most consistent analgesic benefits for anterior cruciate ligament reconstruction compared with all other techniques but will most likely impair postoperative function. Importantly, adductor canal block, local infiltration analgesia and systemic analgesia alone each perform poorly for acute pain management following anterior cruciate ligament reconstruction.

Ion Channels in Gliomas-From Molecular Basis to Treatment.

Ion channels provide the basis for the nervous system's intrinsic electrical activity. Neuronal excitability is a characteristic property of neurons and is critical for all functions of the nervous system. Glia cells fulfill essential supportive roles, but unlike neurons, they also retain the ability to divide. This can lead to uncontrolled growth and the formation of gliomas. Ion channels are involved in the unique biology of gliomas pertaining to peritumoral pathology and seizures, diffuse invasion, and treatment resistance. The emerging picture shows ion channels in the brain at the crossroads of neurophysiology and fundamental pathophysiological processes of specific cancer behaviors as reflected by uncontrolled proliferation, infiltration, resistance to apoptosis, metabolism, and angiogenesis. Ion channels are highly druggable, making them an enticing therapeutic target. Targeting ion channels in difficult-to-treat brain tumors such as gliomas requires an understanding of their extremely heterogenous tumor microenvironment and highly diverse molecular profiles, both representing major causes of recurrence and treatment resistance. In this review, we survey the current knowledge on ion channels with oncogenic behavior within the heterogeneous group of gliomas, review ion channel gene expression as genomic biomarkers for glioma prognosis and provide an update on therapeutic perspectives for repurposed and novel ion channel inhibitors and electrotherapy.

Evaluation of immunogenicity and reactogenicity of COVID-19 vaccines in pregnant women.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is associated with increased risk of adverse maternal and perinatal outcomes. Vaccines are highly effective at preventing severe coronavirus disease 2019 (COVID-19), but there are limited data on COVID-19 vaccines in pregnancy. This study aimed to investigate the reactogenicity and immunogenicity of COVID-19 vaccines in pregnant women when administered according to the 12-week-interval dosing schedule recommended in the UK. METHODS: This was a cohort study of pregnant women receiving COVID-19 vaccination between April and September 2021. The outcomes were immunogenicity and reactogenicity after COVID-19 vaccination. Pregnant women were recruited by phone, e-mail and/or text and were vaccinated according to vaccine availability at their local vaccination center. For immunogenicity assessment, blood samples were taken at specific timepoints after each dose to evaluate nucleocapsid protein (N) and spike protein (S) antibody titers. The comparator group comprised non-pregnant female healthcare workers in the same age group who were vaccinated as part of the national immunization program in a contemporaneous longitudinal cohort study. Longitudinal changes in serum antibody titers and association with pregnancy status were assessed using a two-step regression approach. Reactogenicity assessment in pregnant women was undertaken using an online questionnaire. The comparator group comprised non-pregnant women aged 18-49 years who had received two vaccine doses in primary care. The association of pregnancy status with reactogenicity was assessed using logistic regression analysis. RESULTS: Overall, 67 pregnant women, of whom 66 had received a mRNA vaccine, and 79 non-pregnant women, of whom 50 had received a mRNA vaccine, were included in the immunogenicity study. Most (61.2%) pregnant women received their first vaccine dose in the third trimester, while 3.0% received it in the first trimester and 35.8% in the second trimester. SARS-CoV-2 S-antibody geometric mean concentrations after mRNA vaccination were not significantly different at 2-6 weeks after the first dose but were significantly lower at 2-6 weeks after the second dose in infection-naïve pregnant compared with non-pregnant women. In pregnant women, prior infection was associated with higher antibody levels at 2-6 weeks after the second vaccine dose. Reactogenicity analysis included 108 pregnant women and 116 non-pregnant women. After the first dose, tiredness and chills were reported less commonly in pregnant compared with non-pregnant women (P = 0.043 and P = 0.029, respectively). After the second dose, feeling generally unwell was reported less commonly (P = 0.046) in pregnant compared with non-pregnant women. CONCLUSIONS: Using an extended 12-week interval between vaccine doses, antibody responses after two doses of mRNA COVID-19 vaccine were found to be lower in pregnant compared with non-pregnant women. Strong antibody responses were achieved after one dose in previously infected women, regardless of pregnancy status. Pregnant women reported fewer adverse events after both the first and second dose of vaccine. These findings should now be addressed in larger controlled studies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Prevalence of extended-spectrum ß-lactamase-producing Enterobacterales in retail sheep meat from Zagazig city, Egypt.

BACKGROUND: The goal of this study was to investigate the prevalence of extended-spectrum ß-lactamase production in Enterobacterales isolated from retail sheep meat in Zagazig, Egypt. METHODS: One hundred random samples of sheep meat were collected from different retail butcher shops (n = 5) in the city of Zagazig, Egypt. Bacterial isolates were identified by MALDI-TOF MS and screened for antibiotic susceptibility by disk diffusion; further genotypic characterization of ß-lactamase-encoding genes was performed with Real-Time PCR. E. coli strains were phylotyped with the Clermont triplex PCR method. RESULTS: Of the total of 101 bacterial isolates recovered from retail sheep meat samples, 93 were E. coli, six were Enterobacter cloacae and two were Proteus mirabilis. As many as 17% of these 100 samples showed ESBL phenotypes, all were E. coli. The blaCTX-M genes were detected in seven isolates (six were blaCTX-M-15 and one was blaCTX-M-14), three isolates harboured blaTEM (all were blaTEM-one), and two carried genes of the blaSHV family (both were blaSHV-12). Eight E. coli isolates expressed ESBL phenotype but no blaTEM, blaSHV or blaCTX-M genes were detected by PCR. ESBL- positive E. coli isolates were nearly equally distributed over the commensal groups A/B1 and the virulent group D. CONCLUSION: Nearly one in five sheep meat samples was contaminated with ESBL-E. coli. This further corroborates the potential role played by contaminated meat in the increasing resistance rates that have been reported worldwide.

Analgesic benefits of the quadratus lumborum block in total hip arthroplasty: a systematic review and meta-analysis.

The quadratus lumborum block (QLB) is reported to reduce pain and improve function following total hip arthroplasty; however, randomised controlled trials evaluating the benefits of adding this block to general or spinal anaesthesia in this population are conflicting. We performed a systematic review seeking randomised controlled trials investigating QLB benefits for total hip arthroplasty, stratifying comparisons regarding the addition of QLB to either general or spinal anaesthesia. The primary outcome was 24-h area under the curve (AUC) pain score. Pain scores were interpreted in the context of a population-specific minimal clinically important difference of 1.86 cm on a 10-cm visual analogue scale, or an AUC pain score of 5.58 cm.h. Secondary outcomes included analgesic consumption, functional recovery and opioid-related side-effects. In all, 18 trials (1318 patients) were included. Adding QLB to general or spinal anaesthesia improved 24-h AUC rest pain scores by a mean difference (95%CI) of -3.56 cm.h (-6.70 to -0.42; p = 0.034) and - 4.19 cm.h (-7.20 to -1.18; p = 0.014), respectively. These improvements failed to reach the pre-determined minimal clinically important difference, as did the reduction in analgesic consumption. Quadratus lumborum block improved functional recovery for general, but not spinal, anaesthesia. Opioid-related side-effects were reduced with QLB regardless of anaesthetic modality. Low-to-moderate quality evidence suggests that the extent to which adding QLB to either general or spinal anaesthesia reduces postoperative pain and opioid consumption after total hip arthroplasty is statistically significant but may be clinically unimportant for most patients. However, adding QLB to general anaesthesia might enhance functional recovery. Taken together, our findings do not support the routine use of QLB as part of multimodal analgesic regimens for total hip arthroplasty.

Quality of recovery scores in deep serratus anterior plane block vs. sham block in ambulatory breast cancer surgery: a randomised controlled trial.

Deep serratus anterior plane block has been widely adopted as an analgesic adjunct for patients undergoing breast surgery, but robust supporting evidence of efficacy is lacking. We randomly allocated 40 patients undergoing simple or partial mastectomy with sentinel node biopsy to receive either a pre-operative deep serratus anterior plane block (serratus group) or a placebo injection (sham group), in addition to systemic analgesia. The primary outcome measure was the quality of recovery score at discharge, as assessed by the quality of recovery-15 questionnaire at various time-points. Secondary analgesic outcomes included: pain severity; postoperative opioid consumption; opioid-related side-effects; patient satisfaction up to 7 days postoperatively; and persistent postoperative pain up to 3 months after surgery. All patients who were recruited completed the study. There were no differences in the quality of recovery-15 scores between patients in the serratus and control groups, with mean (SD) scores of 96 (14) and 102 (20) for the control and serratus groups, respectively. We were also unable to detect differences in any of the secondary analgesic outcomes examined. The addition of a deep serratus anterior plane block to systemic analgesia does not enhance quality of recovery in patients undergoing ambulatory breast cancer surgery.

Intra-articular infiltration analgesia for arthroscopic shoulder surgery: a systematic review and meta-analysis.

Phrenic-sparing analgesic techniques for shoulder surgery are desirable. Intra-articular infiltration analgesia is one promising phrenic-sparing modality, but its role remains unclear because of conflicting evidence of analgesic efficacy and theoretical concerns regarding chondrotoxicity. This systematic review and meta-analysis evaluated the benefits and risks of intra-articular infiltration in arthroscopic shoulder surgery compared with systemic analgesia or interscalene brachial plexus block. We sought randomised controlled trials comparing intra-articular infiltration with interscalene brachial plexus block or systemic analgesia (control). Cumulative 24-h postoperative oral morphine equivalent consumption was designated as the primary outcome. Secondary outcomes included visual analogue scale pain scores during the first 24 h postoperatively; time-to-first analgesic request; patient satisfaction; opioid-related side-effects; block-related adverse events; and any indicators of chondrotoxicity. Fifteen trials (863 patients) were included. Compared with control, intra-articular infiltration reduced 24-h postoperative analgesic consumption by a weighted mean difference (95%CI) of -30.9 ([-38.9 to -22.9]; p < 0.001). Intra-articular infiltration also reduced the weighted mean difference (95%CI) pain scores up to 12 h postoperatively, with the greatest reduction at 4 h (-2.2 cm [(-4.4 to -0.04]); p < 0.05). Compared with interscalene brachial plexus block, there was no difference in opioid consumption, but patients receiving interscalene brachial plexus block had better pain scores at 2, 4 and 24 h postoperatively. There was no difference in opioid- or block-related adverse events, and none of the trials reported chondrotoxic effects. Compared with systemic analgesia, intra-articular infiltration provides superior pain control, reduces opioid consumption and enhances patient satisfaction, but it may be inferior to interscalene brachial plexus block patients having arthroscopic shoulder surgery.

Perineural and intravenous dexamethasone and dexmedetomidine: network meta-analysis of adjunctive effects on supraclavicular brachial plexus block.

Both perineural and intravenous dexamethasone and dexmedetomidine are used as local anaesthetic adjuncts to enhance peripheral nerve block characteristics. However, the effects of dexamethasone and dexmedetomidine based on their administration routes have not been directly compared, and the relative extent to which each adjunct prolongs sensory blockade remains unclear. This network meta-analysis sought to compare and rank the effects of perineural and intravenous dexamethasone and dexmedetomidine as supraclavicular block adjuncts. We sought randomised trials investigating the effects of adding perineural and intravenous dexamethasone or dexmedetomidine to long-acting local anaesthetics on supraclavicular block characteristics, including time to block onset and durations of sensory, motor and analgesic blockade. Data were compared and ranked according to relative effectiveness for each outcome. Our primary outcome was sensory block duration, with a 2-h difference considered clinically important. We performed a frequentist analysis, using the GRADE framework to appraise evidence. One-hundred trials (5728 patients) were included. Expressed as mean (95%CI), the control group (local anaesthetic alone) had a duration of sensory block of 401 (366-435) min, motor block duration of 369 (330-408) min and analgesic duration of 435 (386-483) min. Compared with control, sensory block was prolonged most by intravenous dexamethasone [mean difference (95%CI) 477 (160-795) min], followed by perineural dexamethasone [411 (343-480) min] and perineural dexmedetomidine [284 (235-333) min]. Motor block was prolonged most by perineural dexamethasone [mean difference (95%CI) 294 (236-352) min], followed by intravenous dexamethasone [289 (129-448)min] and perineural dexmedetomidine [258 (212-304)min]. Analgesic duration was prolonged most by perineural dexamethasone [mean difference (95%CI) 518 (448-589) min], followed by intravenous dexamethasone [478 (277-679) min] and perineural dexmedetomidine [318 (266-371) min]. Intravenous dexmedetomidine did not prolong sensory, motor or analgesic block durations. No major network inconsistencies were found. The quality of evidence for intravenous dexamethasone, perineural dexamethasone and perineural dexmedetomidine for prolongation of supraclavicular sensory block duration was 'low', 'very low' and 'low', respectively. Regardless of route, dexamethasone as an adjunct prolonged the durations of sensory and analgesic blockade to a greater extent than dexmedetomidine. Differences in block characteristics between perineural and intravenous dexamethasone were not clinically important. Intravenous dexmedetomidine did not affect block characteristics.

N-glycome analysis detects dysglycosylation missed by conventional methods in SLC39A8 deficiency.

Congenital disorders of glycosylation (CDG) are a growing group of inborn metabolic disorders with multiorgan presentation. SLC39A8-CDG is a severe subtype caused by biallelic mutations in the manganese transporter SLC39A8, reducing levels of this essential cofactor for many enzymes including glycosyltransferases. The current diagnostic standard for disorders of N-glycosylation is the analysis of serum transferrin. Exome and Sanger sequencing were performed in two patients with severe neurodevelopmental phenotypes suggestive of CDG. Transferrin glycosylation was analyzed by high-performance liquid chromatography (HPLC) and isoelectric focusing in addition to comprehensive N-glycome analysis using matrix-assisted laser desorption ionization time of flight (MALDI-TOF) mass spectrometry (MS). Atomic absorption spectroscopy was used to quantify whole blood manganese levels. Both patients presented with a severe, multisystem disorder, and a complex neurological phenotype. Magnetic resonance imaging (MRI) revealed a Leigh-like syndrome with bilateral T2 hyperintensities of the basal ganglia. In patient 1, exome sequencing identified the previously undescribed homozygous variant c.608T>C [p.F203S] in SLC39A8. Patient 2 was found to be homozygous for c.112G>C [p.G38R]. Both individuals showed a reduction of whole blood manganese, though transferrin glycosylation was normal. N-glycome using MALDI-TOF MS identified an increase of the asialo-agalactosylated precursor N-glycan A2G1S1 and a decrease in bisected structures. In addition, analysis of heterozygous CDG-allele carriers identified similar but less severe glycosylation changes. Despite its reliance as a clinical gold standard, analysis of transferrin glycosylation cannot be categorically used to rule out SLC39A8-CDG. These results emphasize that SLC39A8-CDG presents as a spectrum of dysregulated glycosylation, and MS is an important tool for identifying deficiencies not detected by conventional methods.

Pathogenic variants in SQOR encoding sulfide:quinone oxidoreductase are a potentially treatable cause of Leigh disease.

Hydrogen sulfide, a signaling molecule formed mainly from cysteine, is catabolized by sulfide:quinone oxidoreductase (gene SQOR). Toxic hydrogen sulfide exposure inhibits complex IV. We describe children of two families with pathogenic variants in SQOR. Exome sequencing identified variants; SQOR enzyme activity was measured spectrophotometrically, protein levels evaluated by western blotting, and mitochondrial function was assayed. In family A, following a brief illness, a 4-year-old girl presented comatose with lactic acidosis and multiorgan failure. After stabilization, she remained comatose, hypotonic, had neurostorming episodes, elevated lactate, and Leigh-like lesions on brain imaging. She died shortly after. Her 8-year-old sister presented with a rapidly fatal episode of coma with lactic acidosis, and lesions in the basal ganglia and left cortex. Muscle and liver tissue had isolated decreased complex IV activity, but normal complex IV protein levels and complex formation. Both patients were homozygous for c.637G > A, which we identified as a founder mutation in the Lehrerleut Hutterite with a carrier frequency of 1 in 13. The resulting p.Glu213Lys change disrupts hydrogen bonding with neighboring residues, resulting in severely reduced SQOR protein and enzyme activity, whereas sulfide generating enzyme levels were unchanged. In family B, a boy had episodes of encephalopathy and basal ganglia lesions. He was homozygous for c.446delT and had severely reduced fibroblast SQOR enzyme activity and protein levels. SQOR dysfunction can result in hydrogen sulfide accumulation, which, consistent with its known toxicity, inhibits complex IV resulting in energy failure. In conclusion, SQOR deficiency represents a new, potentially treatable, cause of Leigh disease.

Peri-articular infiltration analgesia for shoulder surgery: a systematic review and meta-analysis.

Effective analgesic alternatives to interscalene brachial plexus block are sought for shoulder surgery. Peri-articular infiltration analgesia is a novel, less invasive technique, but evidence surrounding its use is unclear. This systematic review and meta-analysis aims to evaluate the utility of peri-articular infiltration analgesia in shoulder surgery. We searched literature for trials comparing peri-articular infiltration analgesia with control or with interscalene brachial plexus block. Control groups received no intervention, placebo or systemic opioids. The primary outcome was cumulative oral morphine equivalent consumption during the first 24 h postoperatively. Secondary outcomes included: rest pain scores up to 48 h; risk of side-effects; and durations of post-anaesthetic care unit and hospital stay. Data were pooled with random-effects modelling. Seven trials (383 patients) were included. Compared with control, peri-articular infiltration analgesia reduced 24-h oral morphine consumption by a mean difference (95%CI) of -38.0 mg (-65.5 to -10.5; p = 0.007). It also improved pain scores up to 6 h, 36 h and 48 h, with the greatest improvement observed at 0 h (-2.4 (-2.7 to -1.6); p < 0.001). Peri-articular infiltration analgesia decreased postoperative nausea and vomiting by an odds ratio (95%CI) of 0.3 (0.1-0.7; p = 0.006). In contrast, peri-articular infiltration analgesia was not different from interscalene brachial plexus block for analgesic consumption, pain scores or side-effects. This review provides moderate evidence supporting peri-articular infiltration for postoperative analgesia following shoulder surgery. The absence of difference between peri-articular infiltration analgesia and interscalene brachial plexus block for analgesic outcomes suggests that these interventions are comparable, but further trials are needed to support this conclusion and identify the optimal peri-articular infiltration technique.

Analgesic benefits and clinical role of the posterior suprascapular nerve block in shoulder surgery: a systematic review, meta-analysis and trial sequential analysis.

The posterior suprascapular nerve block has been proposed as an analgesic alternative for shoulder surgery based on the publication of several comparisons with interscalene block that failed to detect differences in analgesic outcomes. However, quantification of the absolute treatment effect of suprascapular nerve block on its own, in comparison with no block (control), to corroborate the aforementioned conclusions has been lacking. This study examines the absolute analgesic efficacy of suprascapular nerve block compared with control for shoulder surgery. We systematically sought electronic databases for studies comparing suprascapular nerve block with control. The primary outcomes included postoperative 24-h cumulative oral morphine consumption and the difference in area under the curve for 24-h pooled pain scores. Secondary outcomes included the incidence of opioid-related side-effects (postoperative nausea and vomiting) and patient satisfaction. Data were pooled using random-effects modelling. Ten studies (700 patients) were analysed; all studies examined landmark-guided posterior suprascapular nerve block performed in the suprascapular fossa. Suprascapular nerve block was statistically but not clinically superior to control for postoperative 24-h cumulative oral morphine consumption, with a weighted mean difference (99%CI) of 11.41 mg (-21.28 to -1.54; p = 0.003). Suprascapular nerve block was also statistically but not clinically superior to control for area under the curve of pain scores, with a mean difference of 1.01 cm.h. Nonetheless, suprascapular nerve block reduced the odds of postoperative nausea and vomiting and improved patient satisfaction. This review suggests that the landmark-guided posterior suprascapular nerve block does not provide clinically important analgesic benefits for shoulder surgery. Investigation of other interscalene block alternatives is warranted.

SLC35A2-CDG: Functional characterization, expanded molecular, clinical, and biochemical phenotypes of 30 unreported Individuals.

Pathogenic de novo variants in the X-linked gene SLC35A2 encoding the major Golgi-localized UDP-galactose transporter required for proper protein and lipid glycosylation cause a rare type of congenital disorder of glycosylation known as SLC35A2-congenital disorders of glycosylation (CDG; formerly CDG-IIm). To date, 29 unique de novo variants from 32 unrelated individuals have been described in the literature. The majority of affected individuals are primarily characterized by varying degrees of neurological impairments with or without skeletal abnormalities. Surprisingly, most affected individuals do not show abnormalities in serum transferrin N-glycosylation, a common biomarker for most types of CDG. Here we present data characterizing 30 individuals and add 26 new variants, the single largest study involving SLC35A2-CDG. The great majority of these individuals had normal transferrin glycosylation. In addition, expanding the molecular and clinical spectrum of this rare disorder, we developed a robust and reliable biochemical assay to assess SLC35A2-dependent UDP-galactose transport activity in primary fibroblasts. Finally, we show that transport activity is directly correlated to the ratio of wild-type to mutant alleles in fibroblasts from affected individuals.

Clinical, neuroradiological, and biochemical features of SLC35A2-CDG patients.

SLC35A2-CDG is caused by mutations in the X-linked SLC35A2 gene encoding the UDP-galactose transporter. SLC35A2 mutations lead to hypogalactosylation of N-glycans. SLC35A2-CDG is characterized by severe neurological symptoms and, in many patients, early-onset epileptic encephalopathy. In view of the diagnostic challenges, we studied the clinical, neuroradiological, and biochemical features of 15 patients (11 females and 4 males) with SLC35A2-CDG from various centers. We describe nine novel pathogenic variations in SLC35A2. All affected individuals presented with a global developmental delay, and hypotonia, while 70% were nonambulatory. Epilepsy was present in 80% of the patients, and in EEG hypsarrhythmia and findings consistent with epileptic encephalopathy were frequently seen. The most common brain MRI abnormality was cerebral atrophy with delayed myelination and multifocal inhomogeneous abnormal patchy white matter hyperintensities, which seemed to be nonprogressive. Thin corpus callosum was also common, and all the patients had a corpus callosum shorter than normal for their age. Variable dysmorphic features and growth deficiency were noted. Biochemically, normal mucin type O-glycosylation and lipid glycosylation were found, while transferrin mass spectrometry was found to be more specific in the identification of SLC35A2-CDG, as compared to routine screening tests. Although normal glycosylation studies together with clinical variability and genetic results complicate the diagnosis of SLC35A2-CDG, our data indicate that the combination of these three elements can support the pathogenicity of mutations in SLC35A2.

Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction.

Deletion and truncation mutations in the X-linked gene CASK are associated with severe intellectual disability (ID), microcephaly and pontine and cerebellar hypoplasia in girls (MICPCH). The molecular origin of CASK-linked MICPCH is presumed to be due to disruption of the CASK-Tbr-1 interaction. This hypothesis, however, has not been directly tested. Missense variants in CASK are typically asymptomatic in girls. We report three severely affected girls with heterozygous CASK missense mutations (M519T (2), G659D (1)) who exhibit ID, microcephaly, and hindbrain hypoplasia. The mutation M519T results in the replacement of an evolutionarily invariant methionine located in the PDZ signaling domain known to be critical for the CASK-neurexin interaction. CASKM519T is incapable of binding to neurexin, suggesting a critically important role for the CASK-neurexin interaction. The mutation G659D is in the SH3 (Src homology 3) domain of CASK, replacing a semi-conserved glycine with aspartate. We demonstrate that the CASKG659D mutation affects the CASK protein in two independent ways: (1) it increases the protein's propensity to aggregate; and (2) it disrupts the interface between CASK's PDZ (PSD95, Dlg, ZO-1) and SH3 domains, inhibiting the CASK-neurexin interaction despite residing outside of the domain deemed critical for neurexin interaction. Since heterozygosity of other aggregation-inducing mutations (e.g., CASKW919R) does not produce MICPCH, we suggest that the G659D mutation produces microcephaly by disrupting the CASK-neurexin interaction. Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. These findings underscore the importance of functional validation for variant classification.

Should continuous rather than single-injection interscalene block be routinely offered for major shoulder surgery? A meta-analysis of the analgesic and side-effects profiles.

BACKGROUND: Major shoulder surgery is associated with moderate-to-severe pain, but consensus on the optimal analgesic approach is lacking. Continuous catheter-based interscalene block (CISB) prolongs the analgesic benefits of its single-injection counterpart (SISB), but concerns over CISB complications and difficulties in interpreting comparative evidence examining major and minor shoulder procedures simultaneously, despite their differences in postoperative pain, have limited CISB popularity. This meta-analysis evaluates the CISB analgesic role and complications compared with SISB for major shoulder surgery. METHODS: We retrieved randomised controlled trials (RCTs) comparing the effects of CISB to SISB on analgesic outcomes and side-effects after major shoulder surgery. Postoperative opioid consumption at 24 h was designated as the primary outcome. Secondary outcomes included 24-48 h opioid consumption, postoperative rest and dynamic pain scores up to 72 h, time-to-first analgesic, recovery room and hospital stay durations, patient satisfaction, postoperative nausea and vomiting, respiratory function, and block-related complications. RESULTS: Data from 15 RCTs were pooled using random-effects modelling. Compared with SISB, CISB reduced 24- and 48-h oral morphine consumption by a weighted mean difference [95% confidence interval] of 50.9 mg [-81.6, -20.2], (P=0.001) and 44.7 mg [-80.9, -8.7], (P<0.0001), respectively. Additionally, CISB provided superior rest and dynamic pain control beyond 48 h, prolonged time-to-first analgesic, enhanced satisfaction, and reduced postoperative nausea and vomiting without complications. CISB caused an 11.0-11.7% decrease in respiratory indices. Result heterogeneity was successfully explained. CONCLUSIONS: High-level evidence indicates that CISB provides superior analgesia up to 48 h after major shoulder surgery, without increasing side-effects, compared with SISB. The importance of CISB-related changes in respiratory indices is questionable.

Local anaesthetic-induced myotoxicity in regional anaesthesia: a systematic review and empirical analysis.

Recent reports of local-anaesthetic (LA)-induced myotoxicity after peripheral nerve blocks have increased the interest in this less commonly known complication. Basic science evidence investigating LA-induced myotoxicity seems to demonstrate a pattern, but findings from human studies vary. This systematic review summarises the existing myotoxicity evidence and empirically examines its implications. Databases were searched for all in vitro animal and human studies evaluating LA-induced myotoxicity. Studies were stratified by design. Data sought included the model examined, LA used, injury mechanisms, nature of damage, and extent of recovery. For human studies, we also aimed to estimate prevalence and recovery rates. One hundred and fifteen studies, mainly animal and ophthalmic, were included. Myotoxicity risk factors included higher concentrations and prolonged exposure to LA, and use of bupivacaine. Injury mechanisms involved early and late aberrations to cytoplasmic calcium (Ca2+) homeostasis by the sarcoplasmic reticulum Ca2+ ATPase. Incidence in ophthalmic studies was 0.77% (392 of 50 618). Inflammatory changes within a few days after exposure marked the onset of myotoxicity, and myo-degeneration followed within the first week post-exposure. Time to recovery in human muscles ranged between 4 days to 1 yr. None/partial and complete recovery were observed in 61% and 38% of patients, respectively. Across all experimental models, skeletal muscles exposed to LA consistently display myotoxic effects. Evidence is robust in animal and ophthalmic studies, and displays a concerning signal with continuous adductor canal block use in human case reports. Exploring the clinical prevalence, severity, and risk-reducing strategies of myotoxicity should be prioritised.

Overrepresentation of pregnancies conceived by artificial reproductive technology in prenatally identified fetuses with Beckwith-Wiedemann syndrome.

OBJECTIVES: In vitro fertilization (IVF) has been linked to an increased risk for imprinting disorders in offspring. The data so far have predominantly been retrospective, comparing the rate of IVF conceptions in affected patients with controls. We describe a series of fetuses with omphalocele that were tested for Beckwith-Wiedemann syndrome (BWS) and subsequently ascertained as to whether pregnancies were conceived by assisted reproductive technologies (ART). METHODS: Fetuses were tested for BWS by Southern blot, PCR based methods, and methylation analysis to identify the imprinting status at primarily the IC2 locus, KCNQ1OT1, as well as IC1, H19/IGF-2. Some fetuses were also tested for uniparental disomy of chromosome 11p. RESULTS: We tested 301 fetuses with omphalocele for BWS. Forty samples were positive. Sixteen were from IVF pregnancies, for an overall rate of 40%. Such as high proportion of IVF pregnancies in a series of BWS-positive fetuses has not been described previously. Possible factors such as twinning and ascertainment bias are discussed. CONCLUSION: We found about a 20-fold overrepresentation of IVF cases in fetuses with BWS/omphalocele when compared with the rate of ART pregnancies in the USA (p < .0001). Our series provides support for an association of IVF and BWS. Patients should be counseled about these risks and made aware of the availability of prenatal diagnosis for detection.