Perioperative Analgesic Interventions for Reduction of Persistent Postsurgical Pain After Total Hip and Knee Arthroplasty: A Systematic Review and Meta-analysis.

BACKGROUND: High pain levels immediately after surgery have been associated with persistent postsurgical pain. Still, it is uncertain if analgesic treatment of immediate postsurgical pain prevents the development of persistent postsurgical pain. METHODS: We searched MEDLINE, CENTRAL, and Embase up to September 12, 2023, for randomized controlled trials investigating perioperative analgesic interventions and with reported pain levels 3 to 24 months after total hip or knee arthroplasty in patients with osteoarthritis. The primary outcome was pain score 3 to 24 months after surgery, assessed at rest and during movement separately. Two authors independently screened, extracted data, and assessed risk of bias using the Cochrane Risk of Bias 2 tool. We conducted meta-analyses and tested their robustness with trial sequential analyses and worst-best and best-worst case analyses. RESULTS: We included 49 trials with 68 intervention arms. All but 4 trials were at high risk of bias for the primary outcome. Moreover, the included trials were heterogeneous in terms of exclusion criteria, baseline pain severity, and which cointerventions the participants were offered. For pain at rest, no interventions demonstrated a statistically significant difference between intervention and control. For pain during movement, perioperative treatment with duloxetine (7 trials with 641 participants) reduced pain scores at 3 to 24 months after surgery (mean difference -4.9 mm [95% confidence interval {CI}, -6.5 to -3.4] on the 0-100 visual analog scale) compared to placebo. This difference was lower than our predefined threshold for clinical importance of 10 mm. CONCLUSIONS: We found no perioperative analgesic interventions that reduced pain 3 to 24 months after total hip or knee arthroplasty for osteoarthritis. The literature on perioperative analgesia focused little on potential long-term effects. We encourage the assessment of long-term pain outcomes.

Opioids and personalized analgesia in the perioperative setting: A protocol for five systematic reviews.

BACKGROUND: Treatment with opioids is a mainstay in perioperative pain management. While the leading treatment paradigm has been procedure-specific pain management, efforts regarding personalized pain treatment are increasing. The OPI•AID project aims to develop personalized algorithms for perioperative pain management, taking demographic, surgical, and anaesthesiologic factors into account. We will undertake five parallel reviews to illuminate current evidence on different aspects of individual responses to perioperative opioid treatment. METHODS: Inclusion of adult populations in English-written studies. Review-specific searches are developed for the following databases: CENTRAL, MEDLINE, Embase, clinicaltrials.gov, and clinicaltrial.eu. Two authors will independently screen citations, extract data, and assess the risks of bias in each review (QUIPS, PROBAST and RoB2, as relevant). CONCLUSION: These reviews will evaluate various aspects of perioperative opioid treatment, including individualized treatment strategies, selection of specific opioids, and individual patient responses. These will guide future development of a personalized perioperative opioid treatment algorithm (OPI•AID) that will be validated and tested clinically against standard of care.

Insulin-like growth factor-1 infusion in preterm piglets does not affect growth parameters of skeletal muscle or tendon tissue.

Prematurity has physical consequences, such as lower birth weight, decreased muscle mass and increased risk of adult-onset metabolic disease. Insulin-like growth factor 1 (IGF-1) has therapeutic potential to improve the growth and quality of muscle and tendon in premature births, and thus attenuate some of these sequalae. We investigated the effect of IGF-1 on extensor carpi radialis muscle and biceps brachii tendon of preterm piglets. The preterm group consisted of 19-day-old preterm (10 days early) piglets, treated with either IGF-1 or vehicle. Term controls consisted of groups of 9-day-old piglets (D9) and 19-day-old piglets (D19). Muscle samples were analysed by immunofluorescence to determine the cross-sectional area (CSA) of muscle fibres, fibre type composition, satellite cell content and central nuclei-containing fibres in the muscle. Tendon samples were analysed for CSA, collagen content and maturation, and vascularization. Gene expression of the tendon was measured by RT-qPCR. Across all endpoints, we found no significant effect of IGF-1 treatment on preterm piglets. Preterm piglets had smaller muscle fibre CSA compared to D9 and D19 control group. Satellite cell content was similar across all groups. For tendon, we found an effect of age on tendon CSA, and mRNA levels of COL1A1, tenomodulin and scleraxis. Immunoreactivity for elastin and CD31, and several markers of tendon maturation, were increased in D9 compared to the preterm piglets. Collagen content was similar across groups. IGF-1 treatment of preterm-born piglets does not influence the growth and maturation of skeletal muscle and tendon.

Primary outcomes and anticipated effect sizes in randomised clinical trials assessing adjuncts to peripheral nerve blocks: A scoping review.

BACKGROUND: Prolonging effects of adjuncts to local anaesthetics in peripheral nerve blocks have been demonstrated in randomised clinical trials. The chosen primary outcome and anticipated effect size have major impact on the clinical relevance of results in these trials. This scoping review aims to provide an overview of frequently used outcomes and anticipated effect sizes in randomised trials on peripheral nerve block adjuncts. METHODS: For our scoping review, we searched MEDLINE, Embase and CENTRAL for trials assessing effects of adjuncts for peripheral nerve blocks published in 10 major anaesthesia journals. We included randomised clinical trials assessing adjuncts for single-shot ultrasound-guided peripheral nerve blocks, regardless of the type of interventional adjunct and control group, local anaesthetic used and anatomical localization. Our primary outcome was the choice of primary outcomes and corresponding anticipated effect size used for sample size estimation. Secondary outcomes were assessor of primary outcomes, the reporting of sample size calculations and statistically significant and non-significant results related to the anticipated effect sizes. RESULTS: Of 11,854 screened trials, we included 59. The most frequent primary outcome was duration of analgesia (35/59 trials, 59%) with absolute and relative median (interquartile range) anticipated effect sizes for adjunct versus placebo/no adjunct: 240 min (180-318) and 30% (25-40) and for adjunct versus active comparator: 210 min (180-308) and 17% (15-28). Adequate sample size calculations were reported in 78% of trials. Statistically significant results were reported for primary outcomes in 45/59 trials (76%), of which 22% did not reach the anticipated effect size. CONCLUSION: The reported outcomes and associated anticipated effect sizes can be used in future trials on adjuncts for peripheral nerve blocks to increase methodological homogeneity.

The OPI•AID Zone Tool as a composite outcome for postoperative pain management quality-A protocol for an observational pilot study.

BACKGROUND: Managing postoperative pain while minimizing opioid-related adverse drug events (ORADEs) remains a significant challenge. The OPI•AID Zone Tool is proposed as a novel clinical decision support tool that - both graphically and in a scoring-system - represents the relationship between pain management and the occurrence of ORADEs, aiming to enhance patient outcomes in postoperative care. The OPI•AID Zone Tool places pain score on the x-axis and an ORADE score on the y-axis, and stratifies patients into five zones to reflect the composite impact of pain severity and ORADEs on the quality of postoperative patient care. The study will have two key aims: (1) to explore whether the OPI•AID Zone Tool can function as a composite outcome measure for postoperative pain and ORADEs, and (2) to evaluate the use of the OPI•AID Zone Tool in visual presentations and for evaluation of patients' postoperative pain management quality. METHODS: This prospective observational cohort study will include 200 adults undergoing various surgical procedures in general anesthesia with a subsequent stay in the post-anesthesia care unit (PACU) at Bispebjerg Hospital, Denmark. Substudy 1 primary outcome: To assess whether a zone score in the OPI•AID Zone Tool is associated with patient-perceived health (EQ VAS), quality of recovery (QoR-PACU), and time to discharge readiness in PACU, and if the zone score has a stronger association than pain and ORADE score in themselves. Substudy 2 primary outcome: To assess how the use of intraoperative non-opioid analgesics impact where patients are placed in the OPI•AID Zone Tool's XY scatterplot right after surgery. To assess if patients who receive more comprehensive non-opioid analgesic basic regimens, generally fall into lower zones. CONCLUSION: The OPI•AID Zone Tool could potentially be a valuable clinical decision-making tool for optimizing postoperative care by simultaneously addressing pain management and the risk of ORADEs. By computing a composite measure of these two critical outcomes, the tool could guide more nuanced and patient-centered analgesic regimens, potentially improving patient satisfaction and operational efficiency in postoperative settings. The tool's applicability will be explored in this observational pilot and followed up in a planned series of studies (opiaid.dk).

Minimal important difference in postoperative morphine consumption after hip and knee arthroplasty using nausea, vomiting, sedation and dizziness as anchors.

BACKGROUND: Morphine-sparing effects are often used to evaluate non-opioid analgesic interventions. The exact effect that would warrant the implementation of these interventions in clinical practice (a minimally important difference) remains unclear. We aimed to determine this with anchor-based methods. METHODS: This was a post hoc analysis of three studies investigating pain management after hip or knee arthroplasty (PANSAID [NCT02571361], DEX-2-TKA [NCT03506789] and Pain Map [NCT02340052]). The overall population was median aged 70, median ASA 2, 54% female. We examined the correlation between 0 and 24 h postoperative iv morphine equivalent consumption and the severity of nausea, vomiting, sedation and dizziness. The anchor was different severity degrees of these opioid-related adverse events. The primary outcome was the difference in morphine consumption between patients experiencing no versus only mild events. Secondary outcomes included the difference in morphine consumption between patients with mild versus moderate and moderate versus severe events. We used Hodges-Lehmann median differences, exact Wilcoxon-Mann-Whitney tests and quantile regression. RESULTS: The difference in iv morphine consumption was 6 mg (95% confidence interval: 4-8) between patients with no versus only mild events, 5 mg (2-8) between patients with mild versus moderate events and 0 mg (-4 to 4) between patients with moderate versus severe events. CONCLUSIONS: In populations comparable to this post-hoc analysis (orthopaedic surgery, median age 70 and ASA 2), we suggest a minimally important difference of 5 mg for 0-24 h postoperative iv morphine consumption.

A Field Study of Carbon Monoxide Levels in Snow Caves During Short-Term Stove Use.

INTRODUCTION: While the use of camping stoves in poorly ventilated areas is discouraged, the need to address dehydration challenges in harsh arctic conditions has led to their unconventional use inside snow caves for snow melting, subjecting occupants to unknown carbon monoxide (CO) levels. This study, located at sea level in northeastern Greenland, aimed to assess CO levels and dynamics during short cooking sessions in newly constructed emergency snow caves. METHODS: In 5 snow caves, constructed according to the same design principles by 4 different individuals, a single MSR Whisperlite multifuel burner, primed with ethanol and burning white gas, was used to melt snow. CO concentrations were monitored every minute until all the snow in a 5-L pot was converted to water and CO levels returned to below 10 ppm. RESULTS: A total of 16 experiments conducted showed that the priming phase generated the highest CO peaks, with a maximum of 120 ppm. Time-weighted averages ranged from 14 ppm to 67 ppm, with trial durations of 15 to 21 min. A single trial with a dirty burner resulted in up to a 10-fold increase in CO levels. CONCLUSIONS: While single, short cooking sessions of less than 10 min burn time in newly constructed snow caves may be tolerated under specific conditions, the study highlighted substantial variation between caves and the importance of using clean burners, emphasizing the need for further research to gain a comprehensive understanding of CO exposure dynamics in snow caves.

Marked irregular myofiber shape is a hallmark of human skeletal muscle ageing and is reversed by heavy resistance training.

BACKGROUND: Age-related loss of strength is disproportionally greater than the loss of mass, suggesting maladaptations in the neuro-myo-tendinous system. Myofibers are often misshaped in aged and diseased muscle, but systematic analyses of large sample sets are lacking. Our aim was to investigate myofiber shape in relation to age, exercise, myofiber type, species and sex. METHODS: Vastus lateralis muscle biopsies (n = 265) from 197 males and females, covering an age span of 20-97 years, were examined. The gastrocnemius and soleus muscles of 11 + 22-month-old male C57BL/6 mice were also examined. Immunofluorescence and ATPase stainings of muscle cross-sections were used to measure myofiber cross-sectional area (CSA) and perimeter. From these, a shape factor index (SFI) was calculated in a fibre-type-specific manner (type I/II in humans; type I/IIa/IIx/IIb in mice), with higher values indicating increased deformity. Heavy resistance training (RT) was performed three times per week for 3-4 months by a subgroup (n = 59). Correlation analyses were performed comparing SFI and CSA with age, muscle mass, maximal voluntary contraction (MVC), rate of force development and specific force (MVC/muscle mass). RESULTS: In human muscle, SFI was positively correlated with age for both type I (R2  = 0.20) and II (R2  = 0.38) myofibers. When subjects were separated into age cohorts, SFI was lower for type I (4%, P < 0.001) and II (6%, P < 0.001) myofibers in young (20-36) compared with old (60-80) and higher for type I (5%, P < 0.05) and II (14%, P < 0.001) myofibers in the oldest old (>80) compared with old. The increased SFI in old muscle was observed in myofibers of all sizes. Within all three age cohorts, type II myofiber SFI was higher than that for type I myofiber (4-13%, P < 0.001), which was also the case in mice muscles (8-9%, P < 0.001). Across age cohorts, there was no difference between males and females in SFI for either type I (P = 0.496/0.734) or II (P = 0.176/0.585) myofibers. Multiple linear regression revealed that SFI, after adjusting for age and myofiber CSA, has independent explanatory power for 8/10 indices of muscle mass and function. RT reduced SFI of type II myofibers in both young and old (3-4%, P < 0.001). CONCLUSIONS: Here, we identify type I and II myofiber shape in humans as a hallmark of muscle ageing that independently predicts volumetric and functional assessments of muscle health. RT reverts the shape of type II myofibers, suggesting that a lack of myofiber recruitment might lead to myofiber deformity.

Distinct myofibre domains of the human myotendinous junction revealed by single-nucleus RNA sequencing.

The myotendinous junction (MTJ) is a specialized domain of the multinucleated myofibre that is faced with the challenge of maintaining robust cell-matrix contact with the tendon under high mechanical stress and strain. Here, we profiled 24,124 nuclei in semitendinosus muscle-tendon samples from three healthy males by using single-nucleus RNA sequencing (snRNA-seq), alongside spatial transcriptomics, to gain insight into the genes characterizing this specialization in humans. We identified a cluster of MTJ myonuclei represented by 47 enriched transcripts, of which the presence of ABI3BP, ABLIM1, ADAMTSL1, BICD1, CPM, FHOD3, FRAS1 and FREM2 was confirmed at the MTJ at the protein level in immunofluorescence assays. Four distinct subclusters of MTJ myonuclei were apparent, comprising two COL22A1-expressing subclusters and two subclusters lacking COL22A1 expression but with differing fibre type profiles characterized by expression of either MYH7 or MYH1 and/or MYH2. Our findings reveal distinct myonuclei profiles of the human MTJ, which represents a weak link in the musculoskeletal system that is selectively affected in pathological conditions ranging from muscle strains to muscular dystrophies.

Opioid consumption and non-opioid multimodal analgesic treatment in pain management trials after hip and knee arthroplasties: A meta-epidemiological study.

BACKGROUND: The leading principle in peri-operative pain management is multimodal analgesia, which reduces opioid requirements and associated adverse effects. Pragmatic pain trials should optimally test interventions in addition to multimodal non-opioid analgesics and interventions to ensure clinical relevance and baseline levels of opioid consumption that reflect clinical settings. We aimed to investigate opioid consumption and use of non-opioid analgesics administered adjunct to interventions in post-operative pain trials after total hip and knee arthroplasty. METHODS: A systematic literature search was conducted 7 January 2020 in The Cochrane Library's CENTRAL, PubMed, and EMBASE. Trials investigating analgesic interventions for post-operative pain in adults undergoing total hip or knee arthroplasty were included. The primary outcome was the aggregated median 0-24 h post-operative opioid consumption. Further, we assessed the use of paracetamol, non-steroidal anti-inflammatory drugs, gabapentinoids, high-dose glucocorticoids, local infiltration analgesia and nerve blocks administered as co-interventions equally to all participants. We assessed trends over time for all outcomes. RESULTS: Of 14,200 records, 570 trials were included. Median 0-24 h opioid consumption was 21 and 22 mg iv morphine equivalents in hip and knee arthroplasty trials, respectively. Meta-regression showed no overall linear correlation between opioid consumption and publication year. The use of multimodal non-opioid analgesia increased over time, though only 48% of trials published from 2010 to 2020 administered two or more non-opioid analgesics. Applying more non-opioid analgesics was associated with lower opioid consumption in intervention groups. CONCLUSION: Post-operative 0-24 h morphine consumption was median 21-22 mg. The demonstrated differences in non-opioid multimodal analgesic regimens between research and clinical settings, can potentially diminish the demonstrated opioid-sparing effects of trial interventions when such are implemented in a clinical context.

Minimal important difference in opioid consumption based on adverse event reduction-A study protocol.

BACKGROUND: The patient-relevant minimal important difference for opioid consumption remains undetermined, despite its frequent use as primary outcome in trials on postoperative pain management. A minimal important difference is necessary to evaluate whether significant trial results are clinically relevant. Further, it can be used as effect size to ensure that trials are powered to find clinically relevant effects. By exploring the dose-response relationship between postoperative opioid consumption and opioid-related adverse effects, we aim to approximate the minimal important difference in opioid consumption anchored to opioid-related adverse effects. METHODS: This is a post-hoc analysis of aggregated data from two clinical trials (PANSAID NCT02571361 and DEX2TKA NCT03506789) and one observational cohort study (Pain Map NCT02340052) on pain management after total hip and knee arthroplasty. The primary outcome is the Hodges-Lehmann median difference in opioid consumption between patients with no opioid-related adverse effects and patients experiencing the mildest degree of one or more opioid-related adverse effects (i.e., mild nausea, sedation and/or dizziness or vomiting). Secondary outcomes include the Hodges-Lehmann median difference in opioid consumption that corresponds to one point on a cumulated opioid-related adverse event 0-10 scale. Further, we will explore the proportion of patients that experience opioid-related adverse effects for consecutive opioid dose intervals of 2 mg iv morphine equivalents. Quantile regression will be used to assess any significant interactions with patient baseline characteristics. CONCLUSIONS: This study will hopefully bring us one step closer to determining relevant opioid reductions and thereby improve our understanding of intervention effects and planning of future trials.

Aging is associated with an altered macrophage response during human skeletal muscle regeneration.

Skeletal muscle injury in aged rodents is characterized by an asynchronous infiltration of pro- and anti-inflammatory macrophage waves, leading to improper and incomplete regeneration. It is unclear whether this aberration also occurs in aged human muscle. In this study, we quantified the macrophage responses in a human model of muscle damage and regeneration induced by electrical stimulation in 7 young and 21 older adults. At baseline, total resident macrophage (CD68+/DAPI+) content was not different between young and old subjects, but pro-inflammatory (CD206-/CD68+/DAPI+) macrophage content was lower in the old. Following damage, muscle Infiltration of CD206-/CD68+/DAPI+ macrophages was lower in old relative to young subjects. Further, only the increase in CD206-/CD68+ macrophages correlated with the change in muscle satellite cell content. Our data show that older individuals have a compromised macrophage response during muscle regeneration, pointing to an altered inflammatory response as a potential mechanism for reduced muscle regenerative efficacy in aged humans.

Subarachnoid haemorrhage in a patient with undiagnosed aortic coarctation.

A man in his mid-30s was admitted with a thunderclap headache. He was conscious and hypertensive. A decade earlier, severe hypertension had been diagnosed and extensively investigated without revealing an underlying cause. Brain imaging showed subarachnoid haemorrhage caused by a ruptured pericallosal aneurysm. Endovascular occlusion was attempted, but as the sheath could not pass the aortic arch, it was converted to surgical aneurismal clipping. Intraoperative blood pressure measurement revealed a peak-to-peak gradient of 100 mm Hg across the aortic arch and an ankle/brachial index of 0.46 (normal range 0.9-1.2). Aortic coarctation was suspected, and angiographic imaging and echocardiography confirmed the diagnosis. Subacute direct stenting was performed, which normalised the peak-to-peak gradient and ankle/brachial index. To minimise the risk of severe complications, early diagnosis of aortic coarctation is important and can be facilitated by ankle/brachial index and echocardiography in the suprasternal view.

Perioperative prevention of persistent pain after total hip and knee arthroplasty-Protocol for two systematic reviews.

BACKGROUND: Between 9% and 20% of patients experience moderate to severe persistent postoperative pain after total hip or knee arthroplasty. Severe immediate postoperative pain limits rehabilitation and is associated with the development of persistent postoperative pain. Therefore, perioperative analgesic and physiotherapeutic interventions are of interest to reduce persistent pain. In two systematic reviews with identical methodology, we aim to investigate the effects of (a) perioperative analgesic interventions and (b) physiotherapeutic interventions in reducing persistent pain after total hip and knee arthroplasty. METHODS: We will include randomised and cluster-randomised controlled trials on perioperative analgesic and physiotherapeutic interventions for patients undergoing elective total hip or knee arthroplasty for osteoarthritis. After contact with the authors, trials without pain data 3-24 months postoperatively will be excluded. Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and reference lists will be searched for eligible trials. Two authors will independently screen, extract data and assess the risk of bias. The primary outcome is pain scores 3-24 months postoperatively. Meta-analyses will be performed for interventions with two or more trials. We will conduct trial sequential analyses and assign Grading of Recommendations, Assessment, Development and Evaluation (GRADE) ratings. CONCLUSION: No previous review on reduction of persistent postoperative pain has included non-pharmacological or invasive analgesic techniques. These two reviews with identical methodology will summarise the evidence of analgesic and physiotherapeutic perioperative interventions to prevent persistent pain. PROSPERO REGISTRATION: CRD42021284175.

Treatments of new-onset atrial fibrillation in critically ill patients: a systematic review with meta-analysis.

BACKGROUND: New-onset atrial fibrillation (NOAF) is common in hospitalised patients with critical illness and associated with worse outcomes. Several interventions are available in the management of NOAF, but the overall effectiveness and safety of these interventions compared with placebo or no treatment are unknown. METHODS: We conducted a systematic review with meta-analysis and trial sequential analysis (TSA) of randomised clinical trials (RCT) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses, the Cochrane Collaboration, and Grading of Recommendations Assessment, Development and Evaluation statements. We searched RCTs assessing any pharmacological and non-pharmacological treatment compared with placebo or no treatment in critically ill hospitalised patients with NOAF. The primary outcomes were all-cause mortality, adverse events, and health-related quality of life. RESULTS: We included 16 trials (n = 1891) evaluating seven interventions. All trials were adjudicated 'some concerns' or 'high risk' of bias. The evidence is very uncertain for mortality (RR 0.53, 95% CI 0.03-8.30), adverse events (RR 1.28, 95% CI 0.85-1.92), and treatment efficacy i.e. rhythm control (RR 1.54, 95% CI 1.20-1.97; TSA-adjusted CI 0.56-4.53) between pharmacological treatment and placebo/no treatment (very low certainty evidence). There were no data for health-related quality of life or most of our secondary outcomes. CONCLUSIONS: The existing data are insufficient to firmly conclude on effects of any intervention against NOAF on any outcome in hospitalised patients with critical illness. Randomised trials of the most frequently used interventions against NOAF are warranted in these patients.

The proteomic profile of the human myotendinous junction.

Proteomics analysis of skeletal muscle has recently progressed from whole muscle tissue to single myofibers. Here, we further focus on a specific myofiber domain crucial for force transmission from muscle to tendon, the myotendinous junction (MTJ). To overcome the anatomical constraints preventing the isolation of pure MTJs, we performed in-depth analysis of the MTJ by progressive removal of the muscle component in semitendinosus muscle-tendon samples. Using detergents with increasing stringency, we quantified >3000 proteins across all samples, and identified 112 significantly enriched MTJ proteins, including 24 known MTJ-enriched proteins. Of the 88 novel MTJ markers, immunofluorescence analysis confirmed the presence of tetraspanin-24 (CD151), kindlin-2 (FERMT2), cartilage intermediate layer protein 1 (CILP), and integrin-alpha10 (ITGA10), at the human MTJ. Together, these human data constitute the first detailed MTJ proteomics resource that will contribute to advance understanding of the biology of the MTJ and its failure in pathological conditions.

Alpha2 -receptor agonists as adjuvants for brachial plexus nerve blocks-A systematic review with meta-analyses.

BACKGROUND: We review the efficacy and safety of dexmedetomidine and clonidine as perineural or systemic adjuvants for brachial plexus blocks (BPB). METHODS: We included randomised controlled trials on upper limb surgery with BPBs in adults, comparing dexmedetomidine with clonidine or either drug with placebo. The primary outcome was duration of analgesia. Secondary outcomes included adverse and serious adverse events. The review was conducted using Cochrane standards, trial sequential analyses (TSA) and Grading of Recommendations Assessment, Development and Evaluation (GRADE). RESULTS: We included 101 trials with 6248 patients. Overall, duration of analgesia was prolonged with both clonidine (176 min [TSA adj. 95% CI: 118, 205, p < .00001; 33 trials]) and dexmedetomidine (292 min [TSA adj. 95% CI: 245 329, p < .00001; 53 trials]), but was longer for dexmedetomidine than clonidine (205 min [TSA adj. 95% CI: 157, 254, p < .00001; 19 trials]). Compared with placebo, dexmedetomidine was associated with bradycardia (RR 4.2 [95% CI 2.2, 8.3]), and both clonidine (RR 4.5 [95% CI 1.1, 18.3]) and dexmedetomidine (RR 3.9 [95% CI 2.0, 7.5]) were associated with hypotension. Serious adverse events were mostly related to block technique. GRADE-rated quality of evidence was low or very low. CONCLUSION: Alpha2-receptor agonists used as adjuvants for BPBs lead to a prolonged duration of analgesia, with dexmedetomidine as the most efficient. Alpha2-receptor agonists were associated with increased risk of cardiovascular adverse events. The quality of evidence was low to very low.

Nampt controls skeletal muscle development by maintaining Ca2+ homeostasis and mitochondrial integrity.

OBJECTIVE: NAD+ is a co-factor and substrate for enzymes maintaining energy homeostasis. Nicotinamide phosphoribosyltransferase (NAMPT) controls NAD+ synthesis, and in skeletal muscle, NAD+ is essential for muscle integrity. However, the underlying molecular mechanisms by which NAD+ synthesis affects muscle health remain poorly understood. Thus, the objective of the current study was to delineate the role of NAMPT-mediated NAD+ biosynthesis in skeletal muscle development and function. METHODS: To determine the role of Nampt in muscle development and function, we generated skeletal muscle-specific Nampt KO (SMNKO) mice. We performed a comprehensive phenotypic characterization of the SMNKO mice, including metabolic measurements, histological examinations, and RNA sequencing analyses of skeletal muscle from SMNKO mice and WT littermates. RESULTS: SMNKO mice were smaller, with phenotypic changes in skeletal muscle, including reduced fiber area and increased number of centralized nuclei. The majority of SMNKO mice died prematurely. Transcriptomic analysis identified that the gene encoding the mitochondrial permeability transition pore (mPTP) regulator Cyclophilin D (Ppif) was upregulated in skeletal muscle of SMNKO mice from 2 weeks of age, with associated increased sensitivity of mitochondria to the Ca2+-stimulated mPTP opening. Treatment of SMNKO mice with the Cyclophilin D inhibitor, Cyclosporine A, increased membrane integrity, decreased the number of centralized nuclei, and increased survival. CONCLUSIONS: Our study demonstrates that NAMPT is crucial for maintaining cellular Ca2+ homeostasis and skeletal muscle development, which is vital for juvenile survival.