Defatting of donor transplant livers during normothermic perfusion-a randomised clinical trial: study protocol for the DeFat study.

BACKGROUND: Liver disease is the third leading cause of premature death in the UK. Transplantation is the only successful treatment for end-stage liver disease but is limited by a shortage of suitable donor organs. As a result, up to 20% of patients on liver transplant waiting lists die before receiving a transplant. A third of donated livers are not suitable for transplant, often due to steatosis. Hepatic steatosis, which affects 33% of the UK population, is strongly associated with obesity, an increasing problem in the potential donor pool. We have recently tested defatting interventions during normothermic machine perfusion (NMP) in discarded steatotic human livers that were not transplanted. A combination of therapies including forskolin (NKH477) and L-carnitine to defat liver cells and lipoprotein apheresis filtration were investigated. These interventions resulted in functional improvement during perfusion and reduced the intrahepatocellular triglyceride (IHTG) content. We hypothesise that defatting during NMP will allow more steatotic livers to be transplanted with improved outcomes. METHODS: In the proposed multi-centre clinical trial, we will randomly assign 60 livers from donors with a high-risk of hepatic steatosis to either NMP alone or NMP with defatting interventions. We aim to test the safety and feasibility of the defatting intervention and will explore efficacy by comparing ex-situ and post-reperfusion liver function between the groups. The primary endpoint will be the proportion of livers that achieve predefined functional criteria during perfusion which indicate potential suitability for transplantation. These criteria reflect hepatic metabolism and injury and include lactate clearance, perfusate pH, glucose metabolism, bile composition, vascular flows and transaminase levels. Clinical secondary endpoints will include proportion of livers transplanted in the two arms, graft function; cell-free DNA (cfDNA) at follow-up visits; patient and graft survival; hospital and ITU stay; evidence of ischemia-reperfusion injury (IRI); non-anastomotic biliary strictures and recurrence of steatosis (determined on MRI at 6 months). DISCUSSION: This study explores ex-situ pharmacological optimisation of steatotic donor livers during NMP. If the intervention proves effective, it will allow the safe transplantation of livers that are currently very likely to be discarded, thereby reducing waiting list deaths. TRIAL REGISTRATION: ISRCTN ISRCTN14957538. Registered in October 2022.

Meta-regression of sulcal patterns, clinical and environmental factors on neurodevelopmental outcomes in participants with multiple CHD types.

Congenital heart disease affects 1% of infants and is associated with impaired neurodevelopment. Right- or left-sided sulcal features correlate with executive function among people with Tetralogy of Fallot or single ventricle congenital heart disease. Studies of multiple congenital heart disease types are needed to understand regional differences. Further, sulcal pattern has not been studied in people with d-transposition of the great arteries. Therefore, we assessed the relationship between sulcal pattern and executive function, general memory, and processing speed in a meta-regression of 247 participants with three congenital heart disease types (114 single ventricle, 92 d-transposition of the great arteries, and 41 Tetralogy of Fallot) and 94 participants without congenital heart disease. Higher right hemisphere sulcal pattern similarity was associated with improved executive function (Pearson r = 0.19, false discovery rate-adjusted P = 0.005), general memory (r = 0.15, false discovery rate P = 0.02), and processing speed (r = 0.17, false discovery rate P = 0.01) scores. These positive associations remained significant in for the d-transposition of the great arteries and Tetralogy of Fallot cohorts only in multivariable linear regression (estimated change ß = 0.7, false discovery rate P = 0.004; ß = 4.1, false discovery rate P = 0.03; and ß = 5.4, false discovery rate P = 0.003, respectively). Duration of deep hypothermic circulatory arrest was also associated with outcomes in the multivariate model and regression tree analysis. This suggests that sulcal pattern may provide an early biomarker for prediction of later neurocognitive challenges among people with congenital heart disease.

Predictive value of early postoperative lactate (<6†h) during normothermic machine perfusion and outcome after liver transplantation: results from a multicentre study.

BACKGROUND: Biomarkers with strong predictive capacity towards transplantation outcome for livers undergoing normothermic machine perfusion (NMP) are needed. We investigated lactate clearing capacity as a basic function of liver viability during the first 6 h of NMP. METHODS: A trial conducted in 6 high-volume transplant centres in Europe. All centres applied a back-to-base NMP approach with the OrganOx metra system. Perfusate lactate levels at start, 1, 2, 4 and 6 h of NMP were assessed individually and as area under the curve (AUC) and correlated with EAD (early allograft dysfunction), MEAF (model for early allograft function) and modified L-GrAFT (liver graft assessment following transplantation) scores. RESULTS: A total of 509 livers underwent ≥6 h of NMP before transplantation in 6 centres in the UK, Germany and Austria. The donor age was 53 (40-63) years (median, i.q.r.).The total NMP time was 10.8 (7.9-15.7) h. EAD occurred in 26%, MEAF was 4.72 (3.54-6.05) and L-GrAFT10 -0.96 (-1.52--0.32). Lactate at 1, 2 and 6 h correlated with increasing robustness with MEAF. Rather than a binary assessment with a cut-off value at 2 h, the actual 2 h lactate level correlated with the MEAF (P = 0.0306 versus P = 0.0002, Pearson r = 0.01087 versus r = 0.1734). The absolute lactate concentration at 6 h, the AUC of 0-6 h and 1-6 h (P < 0.0001, r = 0.3176) were the strongest predictors of MEAF. CONCLUSION: Lactate measured 1-6 h and lactate levels at 6 h correlate strongly with risk of liver allograft dysfunction upon transplantation. The robustness of predicting MEAF by lactate increases with perfusion duration. Monitoring lactate levels should be extended to at least 6 h of NMP routinely to improve clinical outcome.

A Short Review on Obeticholic Acid: An Effective Modulator of Farnesoid X Receptor.

Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.

Desirability of Outcome Ranking and Response Adjusted for Antibiotic Risk (DOOR/RADAR) Post Hoc Analysis Supports Equipoise for Antibiotic Initiation Strategies in Intensive Care Unit-Acquired Pneumonia.

Background: Pneumonia is the most common intensive care unit (ICU)-acquired infection and source of potential sepsis in ICU populations but can be difficult to diagnose in real-time. Despite limited data, rapid initiation of antibiotic agents is endorsed by society guidelines. We hypothesized that a post hoc analysis of a recent randomized pilot study would show no difference between two antibiotic initiation strategies. Patients and Methods: The recent Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP) was a pragmatic cluster-randomized pilot of antibiotic initiation strategies for patients with suspected ICU-acquired pneumonia. Participating ICUs were cluster-randomized to either an immediate initiation protocol or a specimen-initiated protocol where a gram stain was required for initiation of antibiotics. Patients in the study were divided into one of seven mutually exclusive outcome rankings (desirability of outcome ranking; DOOR): (1) Survival, No Pneumonia, No adverse events; (2) Survival, Pneumonia, No adverse events; (3) Survival, No Pneumonia, ventilator-free-alive days ≤14; (4) Survival, Pneumonia, ventilator-free-alive days ≤14; (5) Survival, No Pneumonia, Subsequent episode of suspected pneumonia; (6) Survival, Pneumonia, Subsequent episode of suspected pneumonia; and (7) Death. These rankings were further refined using the duration of antibiotics prescribed for pneumonia (response adjusted for antibiotic risk; RADAR). Results: There were 186 patients enrolled in the study. After applying the DOOR analysis, a randomly selected patient was equally likely to have a better outcome in specimen-initiated arm as in the immediate initiation arm (DOOR probability: 50.8%; 95% confidence interval [CI], 42.7%-58.9%). Outcome probabilities were similar after applying the RADAR analysis (52.5%; 95% CI, 44.2%-60.6%; p = 0.31). Conclusions: We found that patients for whom antibiotic agents were withheld until there was objective evidence (specimen-initiated group) had similar outcome rankings to patients for whom antibiotic agents were started immediately. This supports the findings of the TARPP pilot trial and provides further evidence for equipoise between these two treatment strategies.

Biallelic variants in Plexin B2 (PLXNB2) cause amelogenesis imperfecta, hearing loss and intellectual disability.

BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.

Bile Chemistry During Ex Situ Normothermic Liver Perfusion Does Not Always Predict Cholangiopathy.

BACKGROUND: Bile chemistry during normothermic ex situ liver perfusion (NESLiP) has been suggested to be an indicator of cholangiopathy. The normal range of biochemical variables in bile of livers undergoing NESLiP has not been defined, nor have published biliary viability criteria been assessed against instances of posttransplant nonanastomotic bile strictures (NASs). METHODS: The bile and perfusate chemistry of 200 livers undergoing NESLiP between February 1, 2018, and October 30, 2023, was compared. In addition, 11 livers that underwent NESLiP and later developed NAS were selected and their bile chemistry was also examined. RESULTS: In livers that did not develop cholangiopathy, concentrations of sodium, potassium, and chloride were slightly higher in bile than in perfusate, whereas the concentration of calcium was slightly lower. Bile was alkali and had a lower glucose concentration than perfusate. Cholangiocyte glucose reabsorption was shown to saturate at high perfusate concentrations and was more impaired in livers donated after circulatory death than in livers donated after brain death. Published criteria failed to identify all livers that went on to develop NASs. CONCLUSIONS: A significant false-negative rate exists with current biliary viability criteria, probably reflecting the patchy and incomplete nature of the development of NASs in the biliary tree. The data presented here provide a benchmark for future assessment of bile duct chemistry during NESLiP.

Localized Liver Injury During Normothermic Ex Situ Liver Perfusion Has No Impact on Short-term Liver Transplant Outcomes.

BACKGROUND: Normothermic ex situ liver perfusion (NESLiP) has the potential to increase organ utilization. Radiological evidence of localized liver injury due to compression at the time of NESLiP, termed cradle compression, is a recognized phenomenon but is poorly characterized. METHODS: A retrospective analysis of a prospectively collected database was performed of transplanted livers that underwent NESLiP and subsequently had a computed tomography performed within the first 14 d posttransplant. The primary study outcome was 1-y graft survival. RESULTS: Seventy livers (63%) were included in the analysis. Radiological evidence of cradle compression was observed in 21 of 70 (30%). There was no difference in rate of cradle compression between donor after circulatory death and donated after brain death donors ( P  = 0.37) or with duration of NESLiP. Univariate analysis demonstrated younger (area under the receiver operating characteristic, 0.68; P = 0.008; 95% confidence interval [CI], 0.55-0.82) and heavier (area under the receiver operating characteristic, 0.80; P  < 0.001; 95% CI, 0.69-0.91) livers to be at risk of cradle compression. Only liver weight was associated with cradle compression on multivariate analysis (odds ratio, 1.003; P  = 0.005; 95% CI, 1.001-1.005). There was no difference in 1-y graft survival (16/17 [94.1%] versus 44/48 [91.6%]; odds ratio, 0.69; P  = 0.75; 95% CI, 0.07-6.62). CONCLUSIONS: This is the first study assessing the impact of cradle compression on outcome. We have identified increased donor liver weight and younger age as risk factors for the development of this phenomenon. Increasing utilization of NESLiP will result in the increased incidence of cradle compression but the apparent absence of long-term sequelae is reassuring. Routine postoperative axial imaging may be warranted.

Global and regional ocean mass budget closure since 2003.

In recent sea level studies, discrepancies have arisen in ocean mass observations obtained from the Gravity Recovery and Climate Experiment and its successor, GRACE Follow-On, with GRACE estimates consistently appearing lower than density-corrected ocean volume observations since 2015. These disparities have raised concerns about potential systematic biases in sea-level observations, with significant implications for our understanding of this essential climate variable. Here, we reconstruct the global and regional ocean mass change through models of ice and water mass changes on land and find that it closely aligns with both GRACE and density-corrected ocean volume observations after implementing recent adjustments to the wet troposphere correction and halosteric sea level. While natural variability in terrestrial water storage is important on interannual timescales, we find that the net increase in ocean mass over 20 years can be almost entirely attributed to ice wastage and human management of water resources.

Current Techniques and Indications for Machine Perfusion and Regional Perfusion in Deceased Donor Liver Transplantation.

Since the advent of University of Wisconsin preservation solution in the 1980s, clinicians have learned to work within its confines. While affording improved outcomes, considerable limitations still exist and contribute to the large number of livers that go unused each year, often for fear they may never work. The last 10 years have seen the widespread availability of new perfusion modalities which provide an opportunity for assessing organ viability and prolonged organ storage. This review will discuss the role of in situ normothermic regional perfusion for livers donated after circulatory death. It will also describe the different modalities of ex situ perfusion, both normothermic and hypothermic, and discuss how they are thought to work and the opportunities afforded by them.

The American Society of Transplant Surgeons Consensus Statement on Normothermic Regional Perfusion.

On June 3, 2023, the American Society of Transplant Surgeons convened a meeting in San Diego, California to (1) develop a consensus statement with supporting data on the ethical tenets of thoracoabdominal normothermic regional perfusion (NRP) and abdominal NRP; (2) provide guidelines for the standards of practice that should govern thoracoabdominal NRP and abdominal NRP; and (3) develop and implement a central database for the collection of NRP donor and recipient data in the United States. National and international leaders in the fields of neuroscience, transplantation, critical care, NRP, Organ Procurement Organizations, transplant centers, and donor families participated. The conference was designed to focus on the controversial issues of neurological flow and function in donation after circulatory death donors during NRP and propose technical standards necessary to ensure that this procedure is performed safely and effectively. This article discusses major topics and conclusions addressed at the meeting.

Infection and Prophylaxis During Normothermic Liver Perfusion: Audit of Incidence and Pharmacokinetics of Antimicrobial Therapy.

BACKGROUND: Ex situ normothermic liver perfusion (NMP) in a blood-based perfusate is associated with a risk of microbe growth, resulting in life-threatening posttransplant sepsis. Antibiotics are widely used, but the pharmacokinetics of these agents are unknown as is their efficacy. We wished to assess the perfusate concentrations of the meropenem and fluconazole that we use and to audit the incidence of infection with this antimicrobial therapy. METHODS: Fluconazole and meropenem (100 mg each) were added to the perfusate before NMP began, and serial samples were taken and assayed for drug concentrations. Perfusate cultures were available from 210 of the 242 perfusions performed between February 1, 2018, and April 6, 2023; these were reviewed. RESULTS: Following administration of 100 mg fluconazole, levels fell slightly from a median of 24.9 mg/L at 1 h to 22.6 mg/L at 10 h. In contrast, meropenem concentrations fell over time, from a median of 21.8 mg/L at 1 h to 9.4 mg/L at 10 h. There were 4 significant microorganisms grown in the perfusions, including 3 Candida species and an Enterococcus faecium . All the Candida -infected livers were transplanted with no adverse consequences, the recipients being treated with anidulafungin upon identification of the infecting organism; the Enterococcus -infected liver was not transplanted. CONCLUSIONS: Serious infection is a risk with NMP but appears to be mitigated with a protocol combining fluconazole and meropenem. This combination may not be appropriate in areas where resistance is prevalent. Routine culture of NMP perfusate is essential to identify breakthrough organisms early and enable recipient treatment.

Homozygous SMAD6 variants in two unrelated patients with craniosynostosis and radioulnar synostosis.

BACKGROUND: SMAD6 encodes an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway. Until now, rare heterozygous loss-of-function variants in SMAD6 were demonstrated to increase the risk of disparate clinical disorders including cardiovascular disease, craniosynostosis and radioulnar synostosis. Only two unrelated patients harbouring biallelic SMAD6 variants presenting a complex cardiovascular phenotype and facial dysmorphism have been described. CASES: Here, we present the first two patients with craniosynostosis harbouring homozygous SMAD6 variants. The male probands, both born to healthy consanguineous parents, were diagnosed with metopic synostosis and bilateral or unilateral radioulnar synostosis. Additionally, one proband had global developmental delay. Echocardiographic evaluation did not reveal cardiac or outflow tract abnormalities. MOLECULAR ANALYSES: The novel missense (c.[584T>G];[584T>G], p.[(Val195Gly)];[(Val195Gly)]) and missense/splice-site variant (c.[817G>A];[817G>A], r.[(817g>a,817delins[a;817+2_817+228])];[(817g>a,817delins[a;817+2_817+228])], p.[(Glu273Lys,Glu273Serfs*72)];[(Glu273Lys,Glu273Serfs*72)]) both locate in the functional MH1 domain of the protein and have not been reported in gnomAD database. Functional analyses of the variants showed reduced inhibition of BMP signalling or abnormal splicing, respectively, consistent with a hypomorphic mechanism of action. CONCLUSION: Our data expand the spectrum of variants and phenotypic spectrum associated with homozygous variants of SMAD6 to include craniosynostosis.

Provider Perceptions of Antibiotic Initiation Strategies for Hospital-Acquired Pneumonia.

Background: The practice of rapidly initiating antibiotic therapy for patients with suspected infection has recently been criticized yet remains commonplace. Provider comfort level has been an understudied aspect of this practice. Hypothesis: We hypothesized that there would be no significant differences in provider comfort level between the two treatment groups. Methods: We prospectively surveyed critical care intensivists who provided care for patients enrolled in the Trial of Antibiotic Restraint in Presumed Pneumonia (TARPP), which was a multicenter cluster-randomized crossover trial that evaluated an immediate antibiotic initiation protocol compared with a protocol of specimen-initiated antibiotic initiation in ventilated patients with suspected new-onset pneumonia. At the end of each enrollment arm, physicians at each center were surveyed regarding their overall comfort level with the recently completed treatment arm, and perception of adherence. Both a paired and unpaired analysis was performed. Results: We collected 51 survey responses from 31 unique participants. Providers perceived a higher rate of adherence to the immediate initiation arm than the specimen-initiated arm (Always Adherent: 37.5% vs. 11.1%; p = 0.045). Providers were less comfortable waiting for objective evidence of infection in the specimen-initiated arm than with starting antibiotic agents immediately (Very Comfortable: 83.3% vs. 40.7%; p = 0.004). For the smaller paired analysis, there was no longer a difference in comfort level. Conclusions: There may be differences in provider comfort levels and perceptions of adherence when considering two different antibiotic initiation strategies for suspected pneumonia in ventilated patients. These findings should be considered when planning future studies.

The taphonomic impact of scavenger guilds in peri-urban and rural regions of central and southern Alberta. Part I - Identification of forensically relevant vertebrate scavengers.

As a body decomposes in an outdoor environment, numerous taphonomic agents can act on the process of human decomposition. It is important to understand the impact of these agents as they can vary the rate of soft and hard tissue loss which may alter postmortem interval estimations. One taphonomic factor which has not been extensively investigated in many regions of the world, including Canada, are vertebrate scavengers. The current study aimed to identify scavenger guilds in the peri-urban and rural regions of two major cities in Alberta (Calgary and Edmonton) where human remains are frequently located. Vertebrate scavenger activity was recorded continuously using cellular and noncellular trail cameras. Images were analyzed to determine how the scavenging profiles (i.e., scavenger species, arrival time, and feeding behavior) impacted the loss of soft and hard tissue. We identified a range of mammalian and avian scavengers and found that coyote and black-billed magpie were the predominant scavengers recorded at the Edmonton peri-urban and rural sites, and the Calgary peri-urban sites. In contrast, when a site was within bear territory such as the Calgary rural sites, black and grizzly bears were the predominant scavengers. At all sites, the large mammalian scavengers were responsible for most soft tissue loss and subsequent hard tissue dispersal. None of the scavengers demonstrated a clear preference for open versus closed sites. This taphonomic information is important to consider when searching for human remains at these locations or in other North American regions with comparable scavenger guilds.

Heterozygous COL17A1 variants are a frequent cause of amelogenesis imperfecta.

BACKGROUND: Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised. METHODS: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth. RESULTS: Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting. CONCLUSION: These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.

Intrathoracic plates versus extrathoracic plates: a comparison of postoperative pain in surgical stabilization of rib fracture technique.

Background: Surgical stabilization of rib fractures (SSRF) has been shown to improve outcomes, yet there is an absence of studies comparing SSRF techniques. An intrathoracic system that minimizes incision length has recently been developed and adopted by multiple institutions. We hypothesized that SSRF with an intrathoracic system plus intercostal nerve cryoneurolysis (IC) leads to improved pain control compared with an extrathoracic system plus IC. Methods: A single-center, retrospective chart review was performed comparing intrathoracic SSRF versus extrathoracic SSRF, and included patients undergoing SSRF from 2015 to 2021 at a level 1 trauma center. Patients who did not undergo intercostal nerve cryoablation were excluded. The primary outcome was opioid consumption based on morphine milligram equivalent (MME) consumption. We collected Rib score, Blunt Pulmonary Contusion 18 Score, number of rib fractures, number of ribs plated, and Injury Severity Score (ISS) to compare baseline characteristics of each group. Results: A total of 112 patients were evaluated for study inclusion. Thirty-one patients were excluded due to missing outcomes data and/or lack of cryoablation. There was no difference in ISS or Rib Score between the intrathoracic (n=33) and extrathoracic (n=48) groups. At 7-day follow-up, the median MME requirement was significantly lower in the intrathoracic group (21.25) versus the extrathoracic group (46.20) (p=0.02). Conclusion: Intrathoracic SSRF was associated with a lower postoperative MME consumption compared with extrathoracic SSRF. These data support the use of intrathoracic SSRF to improve pain control compared to extrathoracic SSRF. Level of evidence: III.

Left bundle branch area pacing vs biventricular pacing for cardiac resynchronization: A systematic review and meta-analysis.

Background: Left bundle branch area pacing (LBBAP) may offer greater physiological benefits than traditional biventricular pacing (BiVP). However, there are limited data comparing the efficacy of LBBAP vs BiVP in patients with systolic heart failure (HF). Objective: The purpose of this meta-analysis was to compare the feasibility and electromechanical and clinical outcomes of both LBBAP and BiVP. Methods: We conducted a systematic review of studies retrieved from various databases including PubMed, Embase, Google Scholar, Scopus, and Cochrane Central Register of Control Trials (CENTRAL) published up to May 22, 2023. The risk ratio (RR) and standardized mean difference (SMD) with corresponding 95% confidence intervals (CIs) were calculated for dichotomous and continuous outcomes, respectively. Results: We included 12 studies with a total of 3004 patients (LBBAP = 1242, BiVP = 1762). Pooled results showed that LBBAP resulted in a significant increase in left ventricular ejection fraction (SMD 0.40, 95% CI 0.25, 0.54, P < .00001), echocardiographic response (RR 1.19, 95% CI 1.10 to 1.29, P < .0001), improvement in New York Heart Association functional class (SMD -0.44, 95% CI -0.65 to -0.23, P < .0001), QRS duration reduction (SMD -0.90, 95% CI -1.14 to -0.66, P < .00001), left ventricular end-diastolic diameter reduction (SMD -0.31, 95% CI -0.57 to -0.05, P = .02), fewer HF hospitalizations (RR 0.72, 95% CI 0.62, 0.85, P < .0001), and improved survival (RR 0.73, 95% CI 0.58, 0.92, P = .007). In addition, LBBAP was associated with shorter fluoroscopy time (SMD -0.94, 95% CI -1.42 to -0.47, P < .0001) and lower pacing threshold at implantation (SMD -1.03, 95% CI -1.32 to -0.74, P < .00001) and at 6 months (SMD -1.44, 95% CI -2.11 to -0.77, P < .0001) as compared with BiVP. Conclusion: Compared with BiVP, LBBAP was associated with better electromechanical and clinical outcomes, including left ventricular ejection fraction, QRS duration, echocardiographic response, New York Heart Association functional class, HF hospitalization, and all-cause mortality in patients with systolic HF.

Contralateral Constrictor Dose Predicts Swallowing Function After Radiation for Head and Neck Cancer.

Background: Radiation therapy can cause long-term dysphagia that seriously affects quality of life for survivors of head and neck cancer. This study evaluates a novel organ at risk, the contralateral pharyngeal constrictor muscles, to find out whether radiation dose to this structure predicts late swallowing function in patients with head and neck cancer. Methods: The study included patients with head and neck cancer treated with radiation and concurrent systemic therapy at a single institution over 3 years. One-year dysphagia was defined as either the presence of a gastrostomy tube or an abnormal modified barium swallow ≥ 1 year after completion of radiation. Results: Fifty-five patients met inclusion criteria, of which 46 were alive at 1 year. One-year dysphagia was present in 37% (n = 17) of this population. Contralateral constrictor V60 < 40% was associated with a 1-year dysphagia rate of 6%, compared with 57% in patients with V60 ≥ 40% (P < .001). An uninvolved pharynx mean dose < 45 Gy was associated with a 1-year dysphagia rate of 22%, compared with 52% in patients with an uninvolved pharynx mean dose ≥ 45 Gy (P = .03). Editing the clinical target volume off air cavities was associated with a decrease in 1-year dysphagia from 67% to 12% (P < .001), and with a reduction of contralateral constrictor V60 from 62% to 33% (P < .001). Air cavity editing was not associated with a change in locoregional recurrence or 1-year survival. Conclusions: This is the first study to report a connection between contralateral constrictor dose and late swallowing function. The correlation between air cavity editing and contralateral constrictor V60 suggests that contralateral constrictor dose may depend partly on technique. Further studies are needed to explore whether these findings can be replicated prospectively and in other practice settings.