Search

OBJECTIVE: To compare long-term risk of reintervention across four uterus-preserving surgical treatments for leiomyomas and to assess effect modification by sociodemographic factors in a prospective cohort study in an integrated health care delivery system. METHODS: We studied a cohort of 10,324 patients aged 18-50 (19.9% Asian, 21.2% Black, 21.3% Hispanic, 32.5% White, 5.2% additional races and ethnicities) who had a first uterus-preserving procedure (abdominal, laparoscopic, or vaginal myomectomy [referred to as myomectomy]; hysteroscopic myomectomy; endometrial ablation; uterine artery embolization) after leiomyoma diagnosis in the 2009-2021 electronic health records of Kaiser Permanente Northern California. We followed up patients until reintervention (second uterus-preserving procedure or hysterectomy) or censoring. We used a Kaplan-Meier estimator to calculate the cumulative incidence of reintervention and Cox regression models to estimate hazard ratios and 95% CIs comparing rates of reintervention across procedures, adjusting for age, parity, race and ethnicity, body mass index (BMI), Neighborhood Deprivation Index, and year. We also assessed effect modification by demographic characteristics. RESULTS: Median follow-up was 3.8 years (interquartile range 1.8-7.4 years). Index procedures were 18.0% (1,857) hysteroscopic myomectomies, 16.2% (1,669) uterine artery embolizations, 21.4% (2,211) endometrial ablations, and 44.4% (4,587) myomectomies. Accounting for censoring, the 7-year reintervention risk was 20.6% for myomectomy, 26.0% for uterine artery embolization, 35.5% for endometrial ablation, and 37.0% for hysteroscopic myomectomy; 63.2% of reinterventions were hysterectomies. Within each procedure type, reintervention rates did not vary by BMI, race and ethnicity, or Neighborhood Deprivation Index. However, rates of reintervention after uterine artery embolization, endometrial ablation, and hysteroscopic myomectomy decreased with age, and reintervention rates for hysteroscopic myomectomy were higher for parous than nulliparous patients. CONCLUSION: Long-term reintervention risks for uterine artery embolization, endometrial ablation, and hysteroscopic myomectomy are greater than for myomectomy, with potential variation by patient age and parity but not BMI, race and ethnicity, or Neighborhood Deprivation Index.

PURPOSE: Tethered cord syndrome (TCS) is characterized by abnormal attachment of the spinal cord neural elements to surrounding tissues. The most common symptoms include pain, motor or sensory dysfunction, and urologic deficits. Although TCS is common in children, there is a significant heterogeneity in outcomes reporting. We systematically reviewed surgical indications and postoperative outcomes to assess the need for a grading/classification system. METHODS: PubMed and EMBASE searches identified pediatric TCS literature published between 1950 and 2023. Studies reporting surgical interventions, ≥ 6-month follow-up, and ≥ 5 patients were included. RESULTS: Fifty-five studies representing 3798 patients were included. The most commonly reported non-urologic symptoms were nonspecific lower-extremity motor disturbances (36.4% of studies), lower-extremity/back pain (32.7%), nonspecific lower-extremity sensory disturbances (29.1%), gait abnormalities (29.1%), and nonspecific bowel dysfunction/fecal incontinence (25.5%). Urologic symptoms were most commonly reported as nonspecific complaints (40.0%). After detethering surgery, retethering was the most widely reported non-urologic outcome (40.0%), followed by other nonspecific findings: motor deficits (32.7%), lower-extremity/back/perianal pain (18.2%), gait/ambulation function (18.2%), sensory deficits (12.7%), and bowel deficits/fecal incontinence (12.7%). Commonly reported urologic outcomes included nonspecific bladder/urinary deficits (27.3%), bladder capacity (20.0%), bladder compliance (18.2%), urinary incontinence/enuresis/neurogenic bladder (18.2%), and nonspecific urodynamics/urodynamics score change (16.4%). CONCLUSION: TCS surgical literature is highly variable regarding surgical indications and reporting of postsurgical outcomes. The lack of common data elements and consistent quantitative measures inhibits higher-level analysis. The development and validation of a standardized outcomes measurement tool-ideally encompassing both patient-reported outcome and objective measures-would significantly benefit future TCS research and surgical management.

BACKGROUND: Pulsed field ablation (PFA) induces cell death through electroporation using ultrarapid electrical pulses. We sought to compare the procedural efficiency characteristics, safety, and efficacy of ablation of atrial fibrillation (AF) using PFA compared with thermal energy ablation. METHODS: We performed an extensive literature search and systematic review of studies that compared ablation of AF with PFA versus thermal energy sources. Risk ratio (RR) 95% confidence intervals (CI) were measured for dichotomous variables and mean difference (MD) 95% CI were measured for continuous variables, where RR

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

ObjectiveThis study compares clinical pain outcomes between patients in a pain treatment program that received a Fitbit, to patients that did not. We also explored: (1) cognitive, emotional, and psychological factors that may have impacted the decision to opt in to receiving a Fitbit; and (2) whether the choice to receive a Fitbit impacted changes in cognitive, emotional, and psychological factors following treatment.MethodsAmong 58 patients in a multidisciplinary pain treatment program at a Veterans Affairs Healthcare System hospital, 31 patients opted to receive a Fitbit as adjunct treatment, while 27 did not. This study utilized patient-reported and practitioner-collected data from the pain treatment program.ResultsCompared to the non-Fitbit group, the Fitbit group displayed a significant decrease in average pain intensity, however showed no correlation between Fitbit activity and average pain intensity. Additionally, treatment satisfaction was the only predictor of treatment group, when modeling pre- and post-treatment outcomes changes.ConclusionThe implementation of a Fitbit may lead to improved pain intensity. Initial evidence suggests that opting to receive a Fitbit during a pain treatment program indicates treatment engagement leading to greater treatment satisfaction. Future work is needed to verify and expand upon this potential mechanism.

PURPOSE: NF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory. METHODS: The trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL). RESULTS: Eight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores. CONCLUSIONS: Volumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Cipaglucosidase alfa plus miglustat (cipa + mig) is a novel, two-component therapy for Pompe disease. We report data from the Phase I/II ATB200-02 study for up to 48 months of treatment. Four adult cohorts, including one non-ambulatory ERT-experienced (n = 6) and three ambulatory cohorts, (two enzyme replacement therapy [ERT]-experienced cohorts [2-6 years (n = 11) and ≥ 7 years (n = 6)]), one ERT-naïve cohort (n = 6), received 20 mg/kg intravenous-infused cipa plus 260 mg oral mig biweekly. Change from baseline (CFBL) for multiple efficacy endpoints at 12, 24, 36, and 48 months, pharmacodynamics, pharmacokinetics, safety, and immunogenicity data were assessed. Six-minute walking distance (% predicted) improved at 12, 24, 36, and 48 months: pooled ambulatory ERT-experienced cohorts, mean(± standard deviation [SD]) CFBL: 6.1(± 7.84), n = 16; 5.4(± 10.56), n = 13; 3.4(± 14.66), n = 12; 5.9(± 17.36), n = 9, respectively; ERT-naïve cohort: 10.7(± 3.93), n = 6; 11.0(± 5.06), n = 6; 9.0(± 7.98), n = 5; 11.7(± 7.69), n = 4, respectively. Percent predicted forced vital capacity was generally stable in ERT-experienced cohorts, mean(± SD) CFBL - 1.2(± 5.95), n = 16; 1.0(± 7.96), n = 13; - 0.3(± 6.68), n = 10; 1.0(± 6.42), n = 6, respectively, and improved in the ERT-naïve cohort: 3.2(± 8.42), n = 6; 4.7(± 5.09), n = 6; 6.2(± 3.35), n = 5; 8.3(± 4.50), n = 4, respectively. Over 48 months, CK and Hex4 biomarkers improved in ambulatory cohorts. Overall, cipa + mig was well tolerated with a safety profile like alglucosidase alfa. ATB200-02 results show the potential benefits of cipa + mig as a long-term treatment option for Pompe disease. Trial registration number: NCT02675465 January 26, 2016.

BACKGROUND: Approximately half of patients who achieve successful reperfusion do not achieve functional independence. The present study sought to investigate the clinical outcomes and safety of intraarterial or intravenous tirofiban as adjunct therapy in patients with acute basilar artery occlusion who had achieved successful recanalization with endovascular treatment. METHODS AND RESULTS: In the national, prospective BASILAR (Endovascular Treatment for Acute Basilar Artery Occlusion Study) registry, 458 patients who met inclusion criteria were divided into 3 groups based on tirofiban administration (no tirofiban, n=262; intravenous tirofiban, n=101; intraarterial+intravenous tirofiban, n=95). Their clinical outcomes were compared with 90-day modified Rankin Scale scores. Adjusted odds ratios (aORs) and 95% CIs were obtained by logistic regression models and propensity score matching. Safety outcomes included any intracranial hemorrhage (ICH), symptomatic ICH, and mortality. Among 458 included patients, 184 (40.2%) achieved a favorable outcome (modified Rankin Scale score 0-3). There were no differences between the intravenous tirofiban group and the no tirofiban group in terms of safety and clinical outcomes (all P>0.05). Compared with the no tirofiban group, the intraarterial+intravenous tirofiban group had higher odds of 90-day modified Rankin Scale score 0 to 3 (aOR, 2.44 [95% CI, 1.30-4.64], P=0.006) and lower 3-month mortality (aOR, 0.38 [95% CI, 0.19-0.71], P=0.002) without an increase in any ICH (aOR, 0.34 [95% CI, 0.09-1.01], P=0.07) or symptomatic ICH (aOR, 0.23 [95% CI, 0.03-0.90], P=0.05). Similar results of intraarterial+intravenous tirofiban on improving clinical outcomes were detected in novel cohorts constructed by propensity score matching. CONCLUSIONS: Intraarterial+intravenous rather than intravenous tirofiban improved clinical outcomes without increasing the frequency of symptomatic ICH among patients with basilar artery occlusion after successful endovascular treatment. Further studies are needed to delineate the roles of intraarterial+intravenous tirofiban in patients with basilar artery occlusion receiving endovascular treatment.

BACKGROUND: The choice of an appropriate strategy for intracanalicular vestibular schwannoma (ICVS) is still debated. We conducted a systematic review and meta-analysis with the aim to compare treatment outcomes amongst management strategies (conservative surveillance (CS), microsurgical resection (MR), or stereotactic radiosurgery (SRS)) aiming to inform guideline recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2021 referenced in PubMed or Embase. Inclusion criteria were peer-reviewed clinical studies or case series reporting a cohort of ICVS managed with CS, MR, or SRS. Primary outcome measures included tumor control, the need for additional treatment, hearing outcomes, and posttreatment neurological deficits. These were pooled using meta-analytical techniques and compared using meta-regression with random effect. RESULTS: Forty studies were included (2371 patients). The weighted pooled estimates for tumor control were 96% and 65% in SRS and CS series, respectively (P

INTRODUCTION: Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag. METHODS: Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures. RESULTS: In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4%; diarrhea, 37.8%; jaw pain, 33.3%). There was a notable decline in AEs after reaching and maintaining a stable dose. At month 24 after entering the OLE, 6MWD significantly increased by a mean of 36.3 m (P = 0.004) from OLE baseline, and most participants remained stable in their functional class (84.8%). Post-baseline PVR in 1 or 2 years decreased by a median of 52.2 dyn.s/cm5 and mean pulmonary arterial pressure decreased by a median of 2.0 mmHg (P = 0.05). CONCLUSION: Ralinepag produced sustained, durable improvements in 6MWD along with durable reductions in PVR and a manageable AE profile. Most participants continuing treatment with ralinepag maintained functional measures throughout the OLE and those switching from placebo to ralinepag often experienced functional improvements.

BACKGROUND: Patients with atopic dermatitis (AD), particularly infants and young children, are at greater risk of developing skin infections. In this study, we assessed infection rates in AD patients aged 6 months to 5 years treated with dupilumab. METHODS: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo, with concomitant low-potency topical corticosteroids, every 4 weeks for 16 weeks. Exposure-adjusted infection rates were used to compare treatment groups. RESULTS: The analysis included 162 patients, of whom 83 received dupilumab and 79 received placebo. Total infection rates were not significantly different between the dupilumab and placebo groups (rate ratio [RR] 0.75, 95% CI 0.48-1.19; p = 0.223). Non-herpetic adjudicated skin infections and bacterial infections were significantly less frequent with dupilumab versus placebo (non-herpetic skin infections: RR 0.46, 95% CI 0.21-0.99; p = 0.047; bacterial infections: RR 0.09, 95% CI 0.01-0.67; p = 0.019), and the number of patients using systemic anti-infective medication was significantly lower in the dupilumab group (RR 0.52, 95% CI 0.30-0.89; p = 0.019). There were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31-4.35; p = 0.817). The number of patients with two or more infection events was significantly higher in the placebo group (RR 0.29, 95% CI 0.12-0.68; p = 0.004), and no severe or serious infections (including eczema herpeticum) were observed among patients receiving dupilumab. CONCLUSIONS: These data suggest that dupilumab treatment in infants and children younger than 6 years with AD does not increase overall risk of infections and is associated with a reduced risk of bacterial and non-herpetic skin infections compared with placebo, resulting in a reduced need for anti-infective medication. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov with ID number NCT03346434 on November 17, 2017. INFOGRAPHIC.

Repetitive transcranial magnetic stimulation (rTMS) is a rapidly developing therapeutic modality for the safe and effective treatment of neuropsychiatric disorders. However, clinical rTMS driving systems and head coils are large, heavy, and expensive, so miniaturized, affordable rTMS devices may facilitate treatment access for patients at home, in underserved areas, in field and mobile hospitals, on ships and submarines, and in space. The central component of a portable rTMS system is a miniaturized, lightweight coil. Such a coil, when mated to lightweight driving circuits, must be able to induce B and E fields of sufficient intensity for medical use. This paper newly identifies and validates salient theoretical considerations specific to the dimensional scaling and miniaturization of coil geometries, particularly figure-8 coils, and delineates novel, key design criteria. In this context, the essential requirement of matching coil inductance with the characteristic resistance of the driver switches is highlighted. Computer simulations predicted E- and B-fields which were validated via benchtop experiments. Using a miniaturized coil with dimensions of 76 mm × 38 mm and weighing only 12.6 g, the peak E-field was 87 V/m at a distance of 1.5 cm. Practical considerations limited the maximum voltage and current to 350 V and 3.1 kA, respectively; nonetheless, this peak E-field value was well within the intensity range, 60-120 V/m, generally held to be therapeutically relevant. The presented parameters and results delineate coil and circuit guidelines for a future miniaturized, power-scalable rTMS system able to generate pulsed E-fields of sufficient amplitude for potential clinical use.

INTRODUCTION: In two-stage exchange for periprosthetic joint infection (PJI), adding antibiotics to cement spacers is the standard of care; however, little is known about optimal dosage. There is emphasis on using >3.6 g of total antibiotic, including ≥2.0 g of vancomycin, per 40 g of cement, but these recommendations lack clinical evidence. We examined whether recommended antibiotic spacer doses affect treatment success. METHODS: This was a retrospective review of 202 patients who underwent two-stage exchange for PJI from 2004 to 2020 with at least 1-year follow-up. Patients were separated into high (>3.6 g of total antibiotic per 40 g of cement) and low-dose spacer groups. Primary outcomes were overall and infectious failure. RESULTS: High-dose spacers were used in 80% (162/202) of patients. High-dose spacers had a reduced risk of overall (OR, 0.37; P = 0.024) and infectious (OR, 0.35; P = 0.020) failure for infected primary arthroplasties, but not revisions. In multivariate analysis, vancomycin dose ≥2.0 g decreased the risk of infectious failure (OR, 0.31; P = 0.016), although not overall failure (OR, 0.51; P = 0.147). CONCLUSION: During two-stage exchange for PJI, spacers with greater than 3.6 g of total antibiotic may reduce overall and infectious failure for infected primary arthroplasties. Furthermore, using at least 2.0 g of vancomycin could independently decrease the risk of infectious failure.

BACKGROUND: Adverse radiation effect (ARE) following stereotactic radiosurgery (SRS) for brain metastases is challenging to distinguish from tumor progression. This study characterizes the clinical implications of radiologic uncertainty (RU). METHODS: Cases reviewed retrospectively at a single-institutional, multi-disciplinary SRS Tumor Board between 2015-2022 for RU following SRS were identified. Treatment history, diagnostic or therapeutic interventions performed upon RU resolution, and development of neurologic deficits surrounding intervention were obtained from the medical record. Differences in lesion volume and maximum diameter at RU onset versus resolution were compared with paired t-tests. Median time from RU onset to resolution was estimated using the Kaplan-Meier method. Univariate and multivariate associations between clinical characteristics and time to RU resolution were assessed with Cox proportional-hazards regression. RESULTS: Among 128 lesions with RU, 23.5% had undergone ≥ 2 courses of radiation. Median maximum diameter (20 vs. 16 mm, p  6 and > 12 months in 25% and 7% of cases, respectively. Higher total EQD2 prior to RU onset (HR = 0.45, p = 0.03) and use of MR perfusion (HR = 0.56, p = 0.001) correlated with shorter time to resolution; larger volume (HR = 1.05, p = 0.006) portended longer time to resolution. Most lesions (57%) were diagnosed as ARE. Most patients (58%) underwent an intervention upon RU resolution; of these, 38% developed a neurologic deficit surrounding intervention. CONCLUSIONS: RU resolution took > 6 months in > 25% of cases. RU may lead to suboptimal outcomes and symptom burden. Improved characterization of post-SRS RU is needed.

Methylphenidate (MPH) is highly efficacious in reducing symptoms of attention-deficit/hyperactivity disorder (ADHD) in children. Generally increased doses are found to result in better symptom control; however, it remains unclear whether this pattern can be observed at the individual level, given the large heterogeneity in individual dose-response relationships and observed placebo responses. A double-blind, randomized, placebo-controlled cross-over trial was used to compare weekly treatment with placebo and 5, 10, 15 and 20 mg of MPH twice daily on parent and teacher ratings of child ADHD symptoms and side effects. Participants were 5-13-year-old children with a DSM-5 diagnosis of ADHD (N = 45). MPH response was assessed at group and individual levels and predictors of individual dose-response curves were examined. Mixed model analysis showed positive linear dose-response curves at group level for parent and teacher rated ADHD symptoms and parent rated side effects, but not for teacher rated side effects. Teachers reported all dosages to improve ADHD symptoms compared to placebo, while parents only reported > 5 mg/dose as effective. At the individual level, most (73-88%) children, but not all, showed positive linear dose-response curves. Higher severity of hyperactive-impulsive symptoms and lower internalizing problems, lower weight, younger age and more positive opinions towards diagnosis and medication partly predicted steeper linear individual dose-response curves. Our study confirms that increased doses of MPH yield greater symptom control at a group level. However, large interindividual variation in the dose-response relationship was found and increased doses did not lead to greater symptom improvement for all children. This trial was registered in the Netherlands trial register (# NL8121).

AIMS: Gastrointestinal disease is a leading cause of morbidity in bottlenose dolphins (Tursiops truncatus) under managed care. Fecal microbiota transplantation (FMT) holds promise as a therapeutic tool to restore gut microbiota without antibiotic use. This prospective clinical study aimed to develop a screening protocol for FMT donors to ensure safety, determine an effective FMT administration protocol for managed dolphins, and evaluate the efficacy of FMTs in four recipient dolphins. METHODS AND RESULTS: Comprehensive health monitoring was performed on donor and recipient dolphins. Fecal samples were collected before, during, and after FMT therapy. Screening of donor and recipient fecal samples was accomplished by in-house and reference lab diagnostic tests. Shotgun metagenomics was used for sequencing. Following FMT treatment, all four recipient communities experienced engraftment of novel microbial species from donor communities. Engraftment coincided with resolution of clinical signs and a sustained increase in alpha diversity. CONCLUSION: The donor screening protocol proved to be safe in this study and no adverse effects were observed in four recipient dolphins. Treatment coincided with improvement in clinical signs.

ObjectiveThoracic outlet syndrome (TOS) has life-changing impacts on young athletes. As the level of competition increases between the high school (HS) and collegiate (CO) stage of athletics, the impact of TOS may differ. Our objective is to compare surgical outcomes of TOS in HS and CO athletes.MethodsThis was a retrospective review of HS and CO athletes within a prospective surgical TOS database. The primary outcome was postoperative return to sport. Secondary outcomes were resolution of symptoms assessed with somatic pain scale (SPS), QuickDASH, and Derkash scores. Categorical and continuous variables were compared using χ2 and analysis of variance, respectively. Significance was defined as P < .05.ResultsThirty-two HS and 52 CO athletes were identified. Females comprised 82.9% HS and 61.5% CO athletes (P = .08). Primary diagnoses were similar between groups (venous TOS: HS 50.0% vs CO 42.3%; neurogenic TOS: 43.9% vs 57.7%; pectoralis minor syndrome: 6.3% vs 0.0%) (P = .12). Pectoralis minor syndrome was a secondary diagnosis in 3.1% and 3.8% of HS and CO athletes, respectively (P = 1.00). The most common sports were those with overhead motion, specifically baseball/softball (39.3%), volleyball (12.4%), and water polo (10.1%), and did not differ between groups (P = .145). Distribution of TOS operations were similar in HS and CO (First rib resection: 94.3% vs 98.1%; scalenectomy: 0.0% vs 1.9%, pectoralis minor tenotomy: 6.3% vs 0.0%) (P = .15). Operating room time was 90.0 vs 105.3 minutes for HS and CO athletes, respectively (P = .14). Mean length of stay was 2.0 vs 1.9 days for HS and CO athletes (P = .91). Mean follow-up was 6.9 months for HS athletes and 10.5 months for CO athletes (P = .39). The majority of patients experienced symptom resolution (HS 80.0% vs CO 77.8%; P = 1.00), as well as improvement in SPS, QuickDASH, and Derkash scores. Return to sport was similar between HS and CO athletes (72.4% vs 73.3%; P = .93). Medical disability was reported in 100% HS athletes and 58.3% CO athletes who did not return to sport (P = .035).ConclusionsDespite increased level of competition, HS and CO athletes demonstrate similar rates of symptom resolution and return to competition. Of those that did not return to their sport, HS athletes reported higher rates of medical disability as a reason for not returning to sport compared with CO athletes.

OBJECTIVE: Cystic vestibular schwannomas (cVSs) have more variable and less favorable clinical outcomes after microsurgical resection compared with solid VS (sVS). This study compares the preoperative presentation and postoperative outcomes between cVS and sVS. STUDY DESIGN: Retrospective cohort study. SETTING: Two tertiary skull base referral centers. METHODS: Consecutive adult patients who underwent VS resection from 2016 to 2021 were included. Univariate and multivariate analyses compared differences in baseline symptoms and postoperative outcomes between cVS and sVS. RESULTS: There were a total of 315 patients (64% female; mean age, 54 yrs) and 46 (15%) were cystic. cVS were significantly larger than sVS (maximum diameter, 28 vs. 18 mm, p < 0.001) and had higher rates of dysphagia and dysphonia preoperatively (p < 0.02). cVSs were more likely to undergo translabyrinthine resection (76 vs. 50%, p = 0.001) and have a higher rate of subtotal resection (STR) compared with sVS (30 vs. 13%, p = 0.003). At latest follow-up, fewer cVS achieved good facial nerve (FN) outcome (House-Brackmann [HB] I/II) (80 vs. 90%, p = 0.048). Subanalysis of cVS and sVS matched in tumor size, and surgical approach did not show differences in the rate of STR or FN outcomes (HB I/II, 82 vs. 78%, p = 0.79). CONCLUSION: In this large multi-institutional series, cVSs represent a distinct entity and are characterized by larger tumor size and higher incidence of atypical symptoms. Although cVSs were more likely to undergo STR and portend worse FN outcomes than sVSs, this may be due to their larger tumor size rather than the presence of the cystic component.

INTRODUCTION: High sustained anti-rhGAA antibody titers (HSAT; ≥12,800) are directly linked to reduced efficacy of enzyme replacement therapy (ERT) and subsequent clinical deterioration in infantile-onset Pompe disease (IOPD). We have previously demonstrated the safety and effectiveness of a bortezomib-based immune-tolerance induction (ITI) regimen (bortezomib, rituximab, methotrexate, and IVIG) in eliminating HSAT. METHODS: Here, we describe two IOPD cases (patients 6 and 8) who developed HSAT at 8 and 10 weeks on ERT despite transient low-dose methotrexate ITI administration in the ERT-naïve setting and were treated with a bortezomib-based ITI regimen, and we compare their courses to a series of six historical patients (patients 1-5, and 7) with a similar presentation who exemplify our evolving approach to treatment. RESULTS: In total, patients 6 and 8 received 16 and 8 doses of bortezomib (4 doses=1 cycle) respectively reducing titers from 25,600 to seronegative, but differences in the course of their therapy were instructive regarding the optimal approach to initial treatment of HSAT; specifically, patient 6 was treated initially with only a single course of bortezomib rescue therapy, while patient 8 received two back-to-back courses. Patient 8 received IVIG therapy throughout the immunosuppression whereas patient 6 received IVIG therapy and was switched to subcutaneous IgG replacement. Patient 6 had a transient reduction in anti-rhGAA antibodies, after receiving a single initial cycle of bortezomib, but had a recurrence of high anti-rhGAA antibody titer after 160 weeks that required 3 additional cycles of bortezomib to ultimately achieve tolerance. In contrast, patient 8 achieved tolerance after being given two consecutive cycles of bortezomib during their initial treatment and had B cell recovery by week 54. Since the reduction in anti-rhGAA antibodies, both patients are doing well clinically, and have decreasing ALT, AST, and CK. No major infections leading to interruption of treatment were observed in either patient. The bortezomib-based ITI was safe and well-tolerated, and patients continue to receive ERT at 40 mg/kg/week. DISCUSSION: These case studies and our previous experience suggest that to achieve an effective reduction of anti-rhGAA antibodies in the setting of HSAT, bortezomib should be initiated at the earliest sign of high anti-rhGAA antibodies with a minimum of two consecutive cycles as shown in the case of patient 8. It is important to note that, despite initiation of ERT at age 2.3 weeks, patient 8 quickly developed HSAT. We recommend close monitoring of anti-rhGAA antibodies and early intervention with ITI as soon as significantly elevated anti-rhGAA antibody titers are noted.

OBJECTIVES: There is little evidence guiding the management of grade I-II traumatic splenic injuries with contrast blush (CB). We aimed to analyze the failure rate of nonoperative management (NOM) of grade I-II splenic injuries with CB in hemodynamically stable patients. METHODS: A multicenter, retrospective cohort study examining all grade I-II splenic injuries with CB was performed at 21 institutions from January 1, 2014, to October 31, 2019. Patients >18 years old with grade I or II splenic injury due to blunt trauma with CB on CT were included. The primary outcome was the failure of NOM requiring angioembolization/operation. We determined the failure rate of NOM for grade I versus grade II splenic injuries. We then performed bivariate comparisons of patients who failed NOM with those who did not. RESULTS: A total of 145 patients were included. Median Injury Severity Score was 17. The combined rate of failure for grade I-II injuries was 20.0%. There was no statistical difference in failure of NOM between grade I and II injuries with CB (18.2% vs 21.1%, p>0.05). Patients who failed NOM had an increased median hospital length of stay (p=0.024) and increased need for blood transfusion (p=0.004) and massive transfusion (p=0.030). Five patients (3.4%) died and 96 (66.2%) were discharged home, with no differences between those who failed and those who did not fail NOM (both p>0.05). CONCLUSION: NOM of grade I-II splenic injuries with CB fails in 20% of patients. LEVEL OF EVIDENCE: IV.

The Japanese national guidelines recommend significantly lower doses of carvedilol for heart failure with reduced ejection fraction (HFrEF) management than the US guidelines. Using real-world data, we determined whether initial and target doses of carvedilol in Japanese patients (JPNs) differ from those in US patients (USPs), especially in Asian Americans (ASA) and Caucasians (CA), and investigated differences in outcomes. We collected data from the electronic medical records, including demographics, carvedilol dosing, tolerability, cardiac functional indicators like EF, cardiovascular events including all-cause deaths, and laboratory values from the University of California, San Diego Health and Osaka University. JPNs had significantly lower doses (mg/day) of carvedilol initiation (66 USPs composed of 38 CAs and 28 ASAs, 17.1±16.2; 93 JPNs, 4.3±4.2, p

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

BackgroundHepatocellular carcinoma (HCC) is a common liver malignancy with limited treatment options. Previous studies expressed the potential synergy of sorafenib and NK cell immunotherapy as a promising approach against HCC. MRI is commonly used to assess response of HCC to therapy. However, traditional MRI-based metrics for treatment efficacy are inadequate for capturing complex changes in the tumor microenvironment, especially with immunotherapy. In this study, we investigated potent MRI radiomics analysis to non-invasively assess early responses to combined sorafenib and NK cell therapy in a HCC rat model, aiming to predict multiple treatment outcomes and optimize HCC treatment evaluations.MethodsSprague Dawley (SD) rats underwent tumor implantation with the N1-S1 cell line. Tumor progression and treatment efficacy were assessed using MRI following NK cell immunotherapy and sorafenib administration. Radiomics features were extracted, processed, and selected from both T1w and T2w MRI images. The quantitative models were developed to predict treatment outcomes and their performances were evaluated with area under the receiver operating characteristic (AUROC) curve. Additionally, multivariable linear regression models were constructed to determine the correlation between MRI radiomics and histology, aiming for a noninvasive evaluation of tumor biomarkers. These models were evaluated using root-mean-squared-error (RMSE) and the Spearman correlation coefficient.ResultsA total of 743 radiomics features were extracted from T1w and T2w MRI data separately. Subsequently, a feature selection process was conducted to identify a subset of five features for modeling. For therapeutic prediction, four classification models were developed. Support vector machine (SVM) model, utilizing combined T1w + T2w MRI data, achieved 96% accuracy and an AUROC of 1.00 in differentiating the control and treatment groups. For multi-class treatment outcome prediction, Linear regression model attained 85% accuracy and an AUC of 0.93. Histological analysis showed that combination therapy of NK cell and sorafenib had the lowest tumor cell viability and the highest NK cell activity. Correlation analyses between MRI features and histological biomarkers indicated robust relationships (r = 0.94).ConclusionsOur study underscored the significant potential of texture-based MRI imaging features in the early assessment of multiple HCC treatment outcomes.

This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10-15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.

In preclinical studies, a new antituberculosis drug regimen markedly reduced the time required to achieve relapse-free cure. This study aimed to preliminarily evaluate the efficacy and safety of this four-month regimen, consisting of clofazimine, prothionamide, pyrazinamide and ethambutol, with a standard six-month regimen in patients with drug-susceptible tuberculosis. An open-label pilot randomized clinical trial was conducted among the patients with newly diagnosed bacteriologically-confirmed pulmonary tuberculosis. The primary efficacy end-point was sputum culture negative conversion. Totally, 93 patients were included in the modified intention-to-treat population. The rates of sputum culture conversion were 65.2% (30/46) and 87.2% (41/47) for short-course and standard regimen group, respectively. There was no difference on two-month culture conversion rates, time to culture conversion, nor early bactericidal activity (P > 0.05). However, patients on short-course regimen were observed with lower rates of radiological improvement or recovery and sustained treatment success, which was mainly attributed to higher percent of patients permanently changed assigned regimen (32.1% vs. 12.3%, P = 0.012). The main cause for it was drug-induced hepatitis (16/17). Although lowering the dose of prothionamide was approved, the alternative option of changing assigned regimen was chosen in this study. While in per-protocol population, sputum culture conversion rates were 87.0% (20/23) and 94.4% (34/36) for the respective groups. Overall, the short-course regimen appeared to have inferior efficacy and higher incidence of hepatitis but desired efficacy in per-protocol population. It provides the first proof-of-concept in humans of the capacity of the short-course approach to identify drug regimens that can shorten the treatment time for tuberculosis.

BACKGROUND: The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear. METHODS: In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was

Management of intracoronary calcium (ICC) continues to be a challenge for interventional cardiologists. There have been significant advances in calcium treatment devices. However, there still exists a knowledge gap regarding which devices to choose for the treatment of ICC. The purpose of this manuscript is to review the principles of intravascular lithotripsy (IVL) and clinical data. The technique of IVL will then be compared to alternative calcium treatment devices. Clinical data will be reviewed concerning the treatment of coronary, peripheral artery and valvular calcifications. Controversies to be discussed include how to incorporate IVL into your practice, what is the best approach for treating calcium subtypes, how to approach under-expanded stents, what is the ideal technique for performing IVL, how safe is IVL, whether imaging adds value when performing IVL, and how IVL fits into a treatment program for peripheral arteries and calcified valves.

Evidence-based treatments for binge eating disorder (BED), such as cognitive behavioral therapy (CBT) lead to successful outcomes only about half the time. Individuals with BED often have measurable deficits in executive function (EF) that may challenge adherence to or impact of cognitive behavioral intervention components. The aim of this study was to evaluate the impact of adding EF training to CBT by combining CBT with a compensatory cognitive training approach (EF-CBT). Participants were 32 adults with BED, overweight/obesity, and comorbid anxiety or depression who were randomly assigned to four months of group treatment in either standard CBT or EF-CBT. Outcomes were assessed at baseline, post-treatment, and at 2-month follow-up. Results showed that EF-CBT was feasible and acceptable, comparable to CBT. Both groups significantly decreased loss of control (LOC) days, clinical impairment, and depression at post-treatment and 2-month follow-up; though there were no differences between groups. Neither group significantly reduced anxiety or weight. Exploratory analyses found that participants with lower EF treated with EF-CBT were less likely to have LOC at post-treatment than those with lower EF treated with CBT. Higher self-monitoring rates during treatment were associated with lower LOC at post-treatment and participants with lower EF were more likely to self-monitor in the EF-CBT arm relative to the CBT arm. These findings suggest that EF-CBT is feasible, acceptable and efficacious, although larger scale research is needed. EF-CBT may be particularly suited for individuals with BED who have lower EF.

OBJECTIVES: The purpose of this systematic review was to appraise the existing literature on the effect of hard tissue defects on the clinical outcome of endodontic microsurgery (EMS). METHODS: MEDLINE (PubMed), Embase, Web of Science, Cochrane Library and grey literature were searched from January 2000 to May 2023. Study selection and data extraction were performed in duplicate. Eligible studies were critically appraised for the risk of bias using the Cochrane Risk of bias tool. The quality of evidence was assessed using GRADE. Review Manager (RevMan Computer program Version 5.4, The Cochrane Collaboration, 2020) was utilized and the Mantel Haenszel fixed or random effects model was applied, depending on the heterogeneity of the studies. Meta-analysis was performed to estimate the Risk ratio (RR) and 95% Confidence Interval (CIs) to correlate the effects of these factors on treatment outcomes. RESULTS: Nineteen studies were included. The EMS overall pooled success rate was 84.5%. Five characteristics of hard tissue were identified. The size of the lesion (Small ≤ 5 mm: 78.4% vs. Large > 5 mm: 63.3%, RR = 1.12, 95% CI 1.00-1.26, P ≤ .05), significantly affected the outcomes of EMS. Endodontic lesions exhibited slightly better outcomes than endodontic-periodontal lesions (81.4% vs. 68.2%, RR = 1.14 95% CI 0.98-1.33, P > .05). Cases with the height of the buccal bone > 3 mm also exhibited slightly better outcomes (91.5% vs. 71.4%, RR = 1.20, 95% CI 0.88-1.62, P > .05). Additionally, through and through lesions exhibited better outcomes when grafting was completed during the EMS procedure both in 2D (RR = 1.12 95% CI 0.97-1.29, P > .05) and 3D evaluation ((RR = 1.28 95% CI 0.69-2.37 P > .05). The overall quality of evidence was graded as low to high. CONCLUSION: With a low to high quality of evidence, the size of the lesion is a key prognostic variable that significantly affects the outcome of EMS, as lesions ≤ 5 mm exhibit better outcomes as compared to larger lesions. CLINICAL SIGNIFICANCE: The presence of hard tissue defects can affect the outcome of endodontic microsurgery (EMS). The presented data can aid the clinicians decision-making process by examining certain pre-operative prognostic variables, when considering EMS as a treatment option. Clinical cases with more favorable hard tissue characteristics lead to a better prognosis in EMS.

BACKGROUND: Catheter ablation improves outcomes in symptomatic atrial fibrillation (AF) patients. However, its safety and efficacy in the very elderly (≥80 years old) is not well described. HYPOTHESIS: Ablation of AF in the very elderly is safe and effective. METHODS: We performed a retrospective study of all patients who underwent catheter ablation enrolled in the University of California, San Diego AF Ablation Registry. The primary outcome was freedom from atrial arrhythmias on or off antiarrhythmic drugs (AADs). RESULTS: Of 847 patients, 42 (5.0%) were 80 years of age or greater with a median age of 81.5 (80-82.3) and 805 (95.0%) were less than 80 years of age with a median age of 64.4 (57.6-70.2). Among those who were ≥80 years old, 29 were undergoing de novo ablation (69.0%), whereas in the younger cohort, 518 (64.5%) were undergoing de novo ablation (p = .548). There were no statistically significant differences in fluoroscopy (p = .406) or total procedure times (p = .076), AAD use (p = .611), or procedural complications (p = .500) between groups. After multivariable adjustment, there were no statistically significant differences in recurrence of any atrial arrhythmias on or off AAD (adjusted hazard ratio [AHR]: 0.75; 95% confidence interval [CI]: 0.45-1.23; p = .252), all-cause hospitalizations (AHR: 0.86; 95% CI: 0.46-1.60; p = .626), or all-cause mortality (AHR: 4.48; 95% CI: 0.59-34.07; p = .147) between the very elderly and the younger cohort. CONCLUSION: In this registry analysis, catheter ablation of AF appears similarly effective and safe in patients 80 years or older when compared to a younger cohort.

BackgroundMyotomy length in type 3 achalasia is generally tailored based on segment of spasticity on high-resolution manometry (HRM). Potential of length of tertiary contractions on barium esophagram (BE) or length of thickened circular muscle on endoscopic ultrasound (EUS) to guide tailored myotomy is less understood. This study aimed to assess agreement between spastic segments lengths on HRM, BE, and EUS among patients with type 3 achalasia.MethodsThis retrospective study included adults with type 3 achalasia on HRM between November 2019 and August 2022 who underwent evaluation with EUS and/or BE. Spastic segments were defined as HRM-distance between proximal borders of lower esophageal sphincter and high-pressure area (isobaric contour ≥70 mmHg); EUS-length of thickened circular muscle (≥1.2 mm) from proximal border of esophagogastric junction (EGJ) to the transition to a non-thickened circular muscle; BE-distance between EGJ to proximal border of tertiary contractions. Pairwise comparisons assessed for correlation (Pearson's) and intraclass correlation classification (ICC) agreement.Key resultsTwenty-six patients were included: mean age 66.9 years (SD 13.8), 15 (57.7%) male. Spastic segments were positively correlated on HRM and BE with good agreement (ICC 0.751, [95% CI 0.51, 0.88]). Spastic segments were negatively correlated with poor agreement on HRM and EUS (ICC -0.04, [-0.45, 0.39]) as well as BE and EUS (ICC -0.03, [-0.47, 0.42]).Conclusions & inferencesLength of spastic segment was positively correlated on HRM and BE while negatively correlated when compared to EUS, supporting the common use of HRM and highlighting the uncertain role for EUS in tailoring myotomy length for type 3 achalasia.

The aim was to test the hypothesis that left ventricular (LV) and right ventricular (RV) activation from body surface electrical mapping (CardioInsight 252-electrode vest, Medtronic) identifies optimal cardiac resynchronization therapy (CRT) pacing strategies and outcomes in 30 patients. The LV80, RV80, and BIV80 were defined as the times to 80% LV, RV, or biventricular electrical activation. Smaller differences in the LV80 and RV80 (|LV80-RV80|) with synchronized LV pacing predicted better LV function post-CRT (p = 0.0004) than the LV-paced QRS duration (p = 0.32). Likewise, a lower RV80 was associated with a better pre-CRT RV ejection fraction by CMR (r =  - 0.40, p = 0.04) and predicted post-CRT improvements in myocardial oxygen uptake (p = 0.01) better than the biventricular-paced QRS (p = 0.38), while a lower LV80 with BIV pacing predicted lower post-CRT B-type natriuretic peptide (BNP) (p = 0.02). RV pacing improved LV function with smaller |LV80-RV80| (p = 0.009). In conclusion, 3-D electrical mapping predicted favorable post-CRT outcomes and informed effective pacing strategies.

BackgroundAlcohol use is common among people with HIV and is a risk factor for tuberculosis disease and non-adherence to isoniazid preventive therapy (IPT). Few interventions exist to reduce alcohol use and increase IPT adherence in sub-Saharan Africa. The aim of this study was to test the hypothesis that financial incentives conditional on point-of-care negative urine alcohol biomarker testing and positive urine isoniazid testing would reduce alcohol use and increase isoniazid adherence, respectively, in people with HIV who have latent tuberculosis infection and hazardous alcohol use.MethodsWe conducted an open-label, 2×2 factorial randomised controlled trial in Uganda. Eligible for the study were non-pregnant HIV-positive adults (aged ≥18 years) prescribed antiretroviral therapy for at least 6 months, with current heavy alcohol use confirmed by urine ethyl glucuronide (biomarker of recent alcohol use) and a positive Alcohol Use Disorders Identification Test-Consumption (AUDIT-C; ≥3 for women, ≥4 for men) for the past 3 months' drinking, no history of active tuberculosis, tuberculosis treatment, or tuberculosis preventive therapy, and a positive tuberculin skin test. We randomly assigned participants (1:1:1:1) initiating 6 months of IPT to: no incentives (group 1); or incentives for recent alcohol abstinence (group 2), isoniazid adherence (group 3), or both (group 4). Escalating incentives were contingent on monthly point-of-care urine tests negative for ethyl glucuronide (groups 2 and 4), or positive on IsoScreen (biomarker of recent isoniazid use; groups 3 and 4). The primary alcohol outcome was non-hazardous use by self-report (AUDIT-C

PURPOSE: To evaluate the efficacy of combination therapy using transarterial chemoembolization with microwave ablation (MWA) therapy vs. MWA monotherapy for hepatocellular carcinomas (HCCs) >3 cm in size. METHODS: This two-arm retrospective observational study included patients with HCCs >3 cm who underwent either combination therapy (29 patients) or MWA monotherapy (35 patients) between 2014 and 2020. The treatment outcomes related to primary treatment efficacy, local tumor progression (LTP), tumor control rate, and overall survival were compared between each cohort. RESULTS: The technical success and primary efficacy were 96.56% and 100.00% in the combination therapy cohort, and 91.42% and 100.00% in the MWA cohort, respectively, over a mean follow-up period of 27.6 months. The 1- and 3-year rates of LTP-free survival were 78.57% and 69.56% in the combination therapy cohort, vs. 72.45% and 35.44% in the MWA cohort, respectively (P = 0.001). The overall progression-free survival was longer in the combination therapy cohort compared with the MWA cohort (median: 56.0 vs. 13.0 months; P = 0.017). With the incorporation of additional locoregional therapy, the overall survival rates were not significantly different, with 1- and 3-year overall survival rates of 100.00% and 88.71% in the combination therapy cohort and rates of 90.15% and 82.76% in the MWA cohort, respectively (P = 0.235). CONCLUSION: The combination therapy provided significantly longer upfront LTP-free survival in HCCs >3 cm when compared with the MWA treatment alone, albeit with similar local tumor control and overall survival rates when accounting for additional locoregional therapies.

BACKGROUND: Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. METHODS: We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. FINDINGS: Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. INTERPRETATION: A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. FUNDING: Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

ImportanceMany patients with focal epilepsy experience seizures despite treatment with currently available antiseizure medications (ASMs) and may benefit from novel therapeutics.ObjectiveTo evaluate the efficacy and safety of XEN1101, a novel small-molecule selective Kv7.2/Kv7.3 potassium channel opener, in the treatment of focal-onset seizures (FOSs).Design, setting, and participantsThis phase 2b, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging adjunctive trial investigated XEN1101 over an 8-week treatment period from January 30, 2019, to September 2, 2021, and included a 6-week safety follow-up. Adults experiencing 4 or more monthly FOSs while receiving stable treatment (1-3 ASMs) were enrolled at 97 sites in North America and Europe.InterventionsPatients were randomized 2:1:1:2 to receive XEN1101, 25, 20, or 10 mg, or placebo with food once daily for 8 weeks. Dosage titration was not used. On completion of the double-blind phase, patients were offered the option of entering an open-label extension (OLE). Patients not participating in the OLE had follow-up safety visits (1 and 6 weeks after the final dose).Main outcomes and measuresThe primary efficacy end point was the median percent change from baseline in monthly FOS frequency. Treatment-emergent adverse events (TEAEs) were recorded and comprehensive laboratory assessments were made. Modified intention-to-treat analysis was conducted.ResultsA total of 325 patients who were randomized and treated were included in the safety analysis; 285 completed the 8-week double-blind phase. In the 325 patients included, mean (SD) age was 40.8 (13.3) years, 168 (51.7%) were female, and 298 (91.7%) identified their race as White. Treatment with XEN1101 was associated with seizure reduction in a robust dose-response manner. The median (IQR) percent reduction from baseline in monthly FOS frequency was 52.8% (P

OBJECTIVE: This study aimed to investigate whether treatment with adjunct intravenous tirofiban is associated with improved outcomes following successful reperfusion in patients with intracranial atherosclerotic stroke. METHODS: Patients with intracranial large artery atherosclerotic (LAA) stroke and an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3 from the Effect of Intravenous Tirofiban versus Placebo Before Endovascular Thrombectomy on Functional Outcomes in Large Vessel Occlusion Stroke (RESCUE BT) trial were included. The primary outcome was the difference in proportion of independent functional outcome (modified Rankin score of 0-2 at 90 days). Safety outcomes included the rates of symptomatic intracranial hemorrhage (sICH) and 90-day mortality. RESULTS: Among the 382 patients with intracranial LAA stroke and successful reperfusion, 175 patients (45.8%) were treated with intravenous tirofiban and 207 (54.2%) with placebo. The proportion of patients with independent functional outcome at 90 days was 54.3% (95 out of 175) with tirofiban and 44.0% (91 out of 207) with placebo (adjusted odds ratio [aOR], 1.58; 95% CI, 1.02-2.44; p = 0.04). Intravenous tirofiban was not significantly associated with an increased risk of sICH (12/175 [6.9%] vs. 11/207 [5.3%]; aOR, 1.41; 95% CI, 0.59-3.34; p = 0.44) or 90-day mortality (21/175 [12.0%] vs. 34/207 [16.4%]; aOR, 0.71; 95% CI, 0.38-1.31; p = 0.27). INTERPRETATION: Among patients with acute intracranial LAA stroke and successful reperfusion following endovascular thrombectomy, adjunct intravenous tirofiban was associated with a higher rate of independent functional outcome, without higher rates of sICH or mortality. Confirmatory randomized trials in these patients are desirable.

Controversy remains regarding the optimal technique and suture type for wound closure after carpal tunnel surgery. Adult patients undergoing open carpal tunnel release were prospectively randomized to receive either interrupted, buried Monocryl sutures or traditional nylon horizontal mattress sutures for their wound closures. At the 2-week and 6-week postoperative visits, Patient and Observer Scar Assessment Scale questionnaires were completed. At 2 weeks, patients and observers had a significantly better opinion of incisions closed with Monocryl. By 6 weeks, neither patients nor observers found a difference between suture types in any category. Scars of wounds closed with Monocryl did not change appreciably in appearance between 2 and 6 weeks. However, patients and observers noted significant improvement in scar appearance in the nylon group over time. Monocryl suture represents an effective method for carpal tunnel closure that leads to improved patient- and observer-reported outcome scores in the early postoperative period compared with nylon.Level of evidence: II.

BACKGROUND: Obesity is a major threat to public health and traditional bariatric surgery continues to have low utilization. Endoscopic treatments for obesity have emerged that offer less risk, but questions remain regarding efficacy, durability, and safety. We compared the efficacy of endoscopic bariatric procedures as compared to other existing treatments. METHODS: A literature search of Embase, Cochrane Central, and Pubmed was conducted from January 1, 2014 to December 7, 2021, including endoscopic bariatric therapies that were FDA or CE approved at the time of search to non-endoscopic treatments. Thirty-seven studies involving 15,639 patients were included. Primary outcomes included % total body weight loss (%TBWL), % excess body weight loss (%EBWL), and adverse events. Secondary outcomes included quality of life data and differences in hemoglobin A1C levels. Strength of clinical trial and observational data were graded according to the Cochrane methods. RESULTS: Intragastric balloons achieved greater %TBWL with a range of 7.6-14.1% compared to 3.3-6.7% with lifestyle modification at 6 months, and 7.5-14.0% compared to 3.1-7.9%, respectively, at 12 months. When endoscopic sleeve gastroplasty (ESG) was compared to laparoscopic sleeve gastrectomy (LSG), ESG had less %TBWL at 4.7-14.4% compared to 18.8-26.5% after LSG at 6 months, and 4.5-18.6% as compared to 28.4-29.3%, respectively, at 12 months. For the AspireAssist, there was greater %TBWL with aspiration therapy compared to lifestyle modification at 12 months, 12.1-18.3% TBWL versus 3.5-5.9% TBWL, respectively. All endoscopic interventions had higher adverse events rates compared to lifestyle modification. CONCLUSION: This review is the first to evaluate various endoscopic bariatric therapies using only RCTs and observational studies for evaluation of weight loss compared with conservative management, lifestyle modification, and bariatric surgery. Endoscopic therapies result in greater weight loss compared to lifestyle modification, but not as much as bariatric surgery. Endoscopic therapies may be beneficial as an alternative to bariatric surgery.

UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

A common feature of congenital heart disease is the presence of right ventricular outflow tract (RVOT) obstruction that can range from mild to severe and can lead to atresia of the pulmonary valve, in extreme conditions. RVOT abnormalities can frequently be corrected surgically or via interventional means. However, most of these patients will ultimately develop pulmonary valve insufficiency and eventual right ventricular dilation, which will require a pulmonary valve replacement at some point in their life to mitigate the detrimental effects of pulmonary valve regurgitation (PVR) on the right ventricle (RV). The evolution from the studies done by Philip Bonhoeffer to implant a pulmonary valve via transcatheter means, have provided a bedrock for transcatheter pulmonary valve replacement (TPVR). Yet, several areas of unmet need for a demographic of patients still exist. Here, we discuss the clinical unmet needs in children under 20 Kg and expand the use of hybrid and other TPVR approaches along with the current indications and contraindications for pulmonary valve replacement. The constraints and limitations from commercially available pulmonary valves will be discussed from a clinical standpoint. Finally, we explore the use of hybrid and periventricular delivery of transcatheter pulmonary valves in younger patients.

The current cardiac pacemakers are battery dependent, and the pacing leads are prone to introduce valve damage and infection, plus a complete pacemaker retrieval is needed for battery replacement. Despite the reported wireless bioelectronics to pace the epicardium, open-chest surgery (thoracotomy) is required to implant the device, and the procedure is invasive, requiring prolonged wound healing and health care burden. We hereby demonstrate a fully biocompatible wireless microelectronics with a self-assembled design that can be rolled into a lightweight microtubular pacemaker for intravascular implantation and pacing. The radio frequency was used to transfer energy to the microtubular pacemaker for electrical stimulation. We show that this pacemaker provides effective pacing to restore cardiac contraction from a nonbeating heart and have the capacity to perform overdrive pacing to augment blood circulation in an anesthetized pig model. Thus, this microtubular pacemaker paves the way for the minimally invasive implantation of leadless and battery-free microelectronics.

BACKGROUND: Fosmanogepix is a first-in-class antifungal targeting the fungal enzyme Gwt1, with broad-spectrum activity against yeasts and moulds, including multidrug-resistant fungi, formulated for intravenous (IV) and oral administration. METHODS: This global, multicenter, non-comparative study evaluated the safety and efficacy of fosmanogepix for first-line treatment of candidaemia in non-neutropenic adults. Participants with candidaemia, defined as a positive blood culture for Candida spp. within 96 h prior to study entry, with ≤2 days of prior systemic antifungals, were eligible. Participants received fosmanogepix for 14 days: 1000 mg IV twice daily on Day 1, followed by maintenance 600 mg IV once daily, and optional switch to 700 mg orally once daily from Day 4. Eligible participants who received at least one dose of fosmanogepix and had confirmed diagnosis of candidaemia (

Purpose/objective(s)Radiographic MRI response following prostate radiotherapy, particularly stereotactic body radiotherapy (SBRT), remains poorly understood. Our objective was to describe radiographic changes to the prostate gland and prostate tumor following SBRT of men treated on a prospective, randomized trial.Materials/methodsMIRAGE (NCT04384770) is a single center, randomized phase III trial of patients receiving either CT or MRI guided SBRT for localized prostate cancer. Patients underwent pre-treatment and annual post-treatment MRIs, in addition to routine PSA surveillance. Outcomes reported include percent gland shrinkage, percent PSA response at one year, and presence of residual tumor based on radiographic interpretation. Patient characteristics were compared via two-sample t-test or Fischer's exact test. Both univariate and multivariable logistical analysis were employed to identify potential clinical predictors of residual tumor on 1-year follow up MRI.ResultsThis study cohort included 94 eligible patients with baseline characteristics in Table 1. Residual lesions were seen in 13 patients (14%), 5/27 (18.5%) treated without ADT and 8/67 (12%) with ADT. PSA ablation was deep, with a 79% median decrease without ADT and 98% median decrease with ADT. Patients receiving ADT showed more gland shrinkage (17% vs. 34% shrinkage, p = 0.0001), while radiographic non-responders and responders experienced similar gland shrinkage (median 21% vs 29% shrinkage, p > 0.05). No significant clinical predictors of residual tumor were identified on univariate and multivariate analysis. No patient had any clinical or biochemical evidence of failure.ConclusionA total of 14% of patients were found to have residual tumor detected on MRI one year after SBRT. These data highlight the protracted nature of radiographic tumor response to radiation therapy, even with ablative radiation techniques. The analysis is limited by the lack of biopsy data to quantify whether visualized residual tumor harbor active cancer.

BACKGROUND: The Eckardt score (ES) is used to assess symptom response to Per-Oral Endoscopic Myotomy (POEM), but reliable methods to assess physiologic success are needed. Functional lumen imaging probe (FLIP) panometry has a potential role in post-POEM follow-up to predict long-term outcomes. The aim of this study was to assess the correlation between clinical success and FLIP parameters following POEM to determine if short interval FLIP could predict long-term outcomes. METHODS: This was a prospective study of adult patients who underwent POEM with short interval follow-up FLIP between 11/2017 and 3/2020. Clinical success was defined as post-procedure ES ≤ 3. Physiologic success was based on an esophago-gastric junction distensibility index (EGJ-DI) > 2.8 mm2/mmHg on FLIP. RESULTS: 47 patients (55% female, mean age 55 years) were included in the study. Clinical success after POEM was seen in 45 (96%) patients (mean ES 6.5 ± 2.2 pre and 0.83 ± 1.0 post-POEM, p

BACKGROUND: Central sleep apnea (CSA) is associated with increased mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Treatment of CSA with a certain type of adaptive servo-ventilation (ASV) device that targets minute ventilation (ASVmv) was found to be harmful in these patients. A newer generation of ASV devices that target peak flow (ASVpf) is presumed to have different effects on ventilation and airway patency. We analyzed our registry of patients with HFrEF-CSA to examine the effect of exposure to ASV and role of each type of ASV device on mortality. METHODS: This is a retrospective cohort study in patients with HFrEF and CSA who were treated with ASV devices between 2008 and 2015 at a single institution. Mortality data were collected through the institutional data honest broker. Usage data were obtained from vendors and manufacturers servers. Median follow-up was 64 months. RESULTS: The registry included 90 patients with HFrEF-CSA who were prescribed ASV devices. Applying a 3-h-per-night usage cutoff, we found a survival advantage at 64 months for those who used the ASV device above the cutoff (n = 59; survival 76%) compared to those who did not (n = 31; survival 49%; hazard ratio 0.44; CI 95%, 0.20 to 0.97; P = 0.04). The majority (n = 77) of patients received ASVpf devices with automatically adjusting end-expiratory pressure (EPAP) and the remainder (n = 13) received ASVmv devices mostly with fixed EPAP (n = 12). There was a trend towards a negative correlation between ASVmv with fixed EPAP and survival. CONCLUSION: In this population of patients with HFrEF and CSA, there was no evidence that usage of ASV devices was associated with increased mortality. However, there was evidence of differential effects of type of ASV technology on mortality.

OBJECTIVE: Smoking is known to increase complications, including poor wound healing, coagulation abnormalities, and cardiac and pulmonary ramifications. Across specialties, elective surgical procedures are commonly denied to active smokers. Given the base population of active smokers with vascular disease, smoking cessation is encouraged but is not required the way it is for elective general surgery procedures. We aim to study the outcomes of elective lower extremity bypass (LEB) in actively smoking claudicants. METHODS: We queried the Vascular Quality Initiative Vascular Implant Surveillance and Interventional Outcomes Network LEB database from 2003 to 2019. In this database we found 609 (10.0%) never smokers (NS), 3388 (55.3%) former smokers (FS), and 2123 (34.7%) current smokers (CS) who underwent LEB for claudication. We performed two separate propensity score matches without replacement on 36 clinical variables (age, gender, race, ethnicity, obesity, insurance, hypertension, diabetes, coronary artery disease, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, previous coronary artery bypass graft, carotid endarterectomy, major amputation, inflow treatment, preoperative medications and treatment type), one of FS to NS and a second analysis of CS to FS. Primary outcomes included 5-year overall survival (OS), limb salvage (LS), freedom from reintervention (FR), and amputation-free survival (AFS). RESULTS: Propensity score matches resulted in 497 well-matched pairs of NS and FS. In this analysis we found no difference in terms of OS (HR, 0.93; 95% CI, 0.70-1.24; P = .61), LS (HR, 1.07; 95% CI, 0.63-1.82; P = .80), FR (HR, 0.9; 95% CI,0.71-1.21; P = .59), or AFS (HR, 0.93; 95% CI,0.71-1.22; P = .62). In the second analysis, we had 1451 well-matched pairs of CS and FS. There was no difference in LS (HR, 1.36; 95% CI,0.94-1.97; P = .11) or FR (HR, 1.02; 95% CI,0.88-1.19; P = .76). However, we did find a significant increase in OS (HR, 1.37; 95% CI,1.15-1.64, P

BACKGROUND AND AIMS: With distinct mechanisms of action, the combination of tropifexor (TXR) and cenicriviroc (CVC) may provide an effective treatment for NASH. This randomized, multicenter, double-blind, phase 2b study assessed the safety and efficacy of TXR and CVC combination, compared with respective monotherapies. APPROACH AND RESULTS: Patients (N = 193) were randomized 1:1:1:1 to once-daily TXR 140 μg (TXR 140 ), CVC 150 mg (CVC), TXR 140 μg + CVC 150 mg (TXR 140 + CVC), or TXR 90 μg + CVC 150 mg (TXR 90 + CVC) for 48 weeks. The primary and secondary end points were safety and histological improvement, respectively. Rates of adverse events (AEs) were similar across treatment groups. Pruritus was the most frequently experienced AE, with highest incidence in the TXR 140 group (40.0%). In TXR and combination groups, alanine aminotransferase (ALT) decreased from baseline to 48 weeks (geometric mean change: -21%, TXR 140 ; -16%, TXR 140 + CVC; -13%, TXR 90 + CVC; and +17%, CVC). Reductions in body weight observed at week 24 (mean changes from baseline: TXR 140 , -2.5 kg; TXR 140 + CVC, -1.7 kg; TXR 90 + CVC, -1.0 kg; and CVC, -0.1 kg) were sustained to week 48. At least 1-point improvement in fibrosis stage/steatohepatitis resolution without worsening of fibrosis was observed in 32.3%/25.8%, 31.6%/15.8%, 29.7%/13.5%, and 32.5%/22.5% of patients in the TXR 140 , CVC, TXR 140 + CVC, and TXR 90 + CVC groups, respectively. CONCLUSIONS: The safety profile of TXR + CVC combination was similar to respective monotherapies, with no new signals. TXR monotherapy showed sustained ALT and body weight decreases. No substantial incremental efficacy was observed with TXR + CVC combination on ALT, body weight, or in histological end points compared with monotherapy.