Citations

AbstractPatients with viral myocarditis are at risk of sudden death and may progress to dilated cardiomyopathy (DCM). Currently, no disease‐specific therapies exist to treat viral myocarditis. Here it is examined whether reconstituted, lyophilized extracellular vesicles (EVs) from platelets from healthy men and women reduce acute or chronic myocarditis in male mice. Human‐platelet‐derived EVs (PEV) do not cause toxicity, damage, or inflammation in naïve mice. PEV administered during the innate immune response significantly reduces myocarditis with fewer epidermal growth factor (EGF)‐like module‐containing mucin‐like hormone receptor‐like 1 (F4/80) macrophages, T cells (cluster of differentiation molecules 4 and 8, CD4 and CD8), and mast cells, and improved cardiac function. Innate immune mediators known to increase myocarditis are decreased by innate PEV treatment including Toll‐like receptor (TLR)4 and complement. PEV also significantly reduces perivascular fibrosis and remodeling including interleukin 1 beta (IL‐1β), transforming growth factor‐beta 1, matrix metalloproteinase, collagen genes, and mast cell degranulation. PEV given at days 7–9 after infection reduces myocarditis and improves cardiac function. MicroRNA (miR) sequencing reveals that PEV contains miRs that decrease viral replication, TLR4 signaling, and T‐cell activation. These data show that EVs from the platelets of healthy individuals can significantly reduce myocarditis and improve cardiac function.

Abstract In the pivotal study ECHELON-1, brentuximab vedotin (BV), doxorubicin, vinblastine, and dacarbazine (A + AVD) demonstrated superior efficacy compared with bleomycin + AVD for the treatment of advanced-stage classic Hodgkin lymphoma (cHL). However, there are minimal available data regarding the frequency of dose reductions or omission of BV during curative therapy and the potential impact on patient outcomes. In a real-world analysis, we retrospectively reviewed the characteristics and outcomes of 179 patients with stage III or IV cHL treated with frontline A + AVD from January 2010 to April 2022. Treatment consisted of up to 1.2 mg/kg of BV and standard dose AVD IV on days 1 and 15 of each 28-day cycle for up to 6 cycles. At the time of treatment, the median patient age was 37 years, and a high-risk International Prognostic Score was observed in 46% of patients. Overall, 91% of patients received 6 cycles of AVD; 55% of patients did not receive the intended cumulative dose of BV (CDB); 28% of patients received two-thirds or less than the planned CDB. At a median follow-up time of 27.4 months (95% confidence interval [CI], 24.8-29), the median progression-free survival (PFS) was not reached, and the 12-month PFS was 90.3% (95% CI, 85.9-95.0). The impact of CDB on PFS was not significant (P = .15), nor was high CDB significantly associated with increased adverse events. In real-world experience, A + AVD is a highly effective treatment for patients with advanced-stage cHL, including for patients with prominent dose reductions of BV.

Abstract Background Patients often turn to online reviews as a source of information to inform their decisions regarding care. Existing literature has analyzed factors associated with positive online patient ratings among hand and wrist surgeons. However, there is limited in-depth analysis of factors associated with low patient satisfaction for hand and wrist surgeons. The focus of this study is to examine and characterize extremely negative reviews of hand and wrist surgeons on Yelp.com. Methods A search was performed using the keywords “hand surgery” on Yelp.com for eight major metropolitan areas including Washington DC, Dallas, New York, Phoenix, Los Angeles, San Francisco, Boston, and Seattle. Only single-star reviews (out of a possible 5 stars) of hand and wrist surgeons were included. The complaints in the 1-star reviews were then categorized into clinical and nonclinical categories. Result A total of 233 single-star reviews were included for analysis, which resulted in 468 total complaints. Of these complaints, 81 (18.8%) were clinically related and 351 (81.3%) were nonclinical in nature. The most common clinical complaints were for complication (24 complaints, 6%), misdiagnosis (16 complaints, 4%), unclear treatment plan (16 complaints, 4%), and uncontrolled pain (15 complaints, 3%). The most common nonclinical complaints were for physician bedside manner (93 complaints, 22%), financially related (80 complaints, 19%), unprofessional nonclinical staff (61 complaints, 14%), and wait time (46 complaints, 11%). The difference in the number of complaints for surgical and nonsurgical patients was statistically significant (p < 0.05) for complication and uncontrolled pain. Clinical Relevance Patient satisfaction is dependent on a multitude of clinical and nonclinical factors. An awareness of online physician ratings is essential for hand and wrist surgeons to maintain and improve patient care and patient satisfaction. We believe the results of our study could be used to further improve the quality of care provided by hand and wrist surgeons.

Abstract Aims Invasive haemodynamic assessment with a pulmonary artery catheter is often used to guide the management of patients with cardiogenic shock (CS) and may provide important prognostic information. We aimed to assess prognostic associations and relationships to end-organ dysfunction of presenting haemodynamic parameters in CS. Methods and results The Critical Care Cardiology Trials Network is an investigator-initiated multicenter registry of cardiac intensive care units (CICUs) in North America coordinated by the TIMI Study Group. Patients with CS (2018–2022) who underwent invasive haemodynamic assessment within 24 h of CICU admission were included. Associations of haemodynamic parameters with in-hospital mortality were assessed using logistic regression, and associations with presenting serum lactate were assessed using least squares means regression. Sensitivity analyses were performed excluding patients on temporary mechanical circulatory support and adjusted for vasoactive-inotropic score. Among the 3603 admissions with CS, 1473 had haemodynamic data collected within 24 h of CICU admission. The median cardiac index was 1.9 (25th–75th percentile, 1.6–2.4) L/min/m2 and mean arterial pressure (MAP) was 74 (66–86) mmHg. Parameters associated with mortality included low MAP, low systolic blood pressure, low systemic vascular resistance, elevated right atrial pressure (RAP), elevated RAP/pulmonary capillary wedge pressure ratio, and low pulmonary artery pulsatility index. These associations were generally consistent when controlling for the intensity of background pharmacologic and mechanical haemodynamic support. These parameters were also associated with higher presenting serum lactate. Conclusion In a contemporary CS population, presenting haemodynamic parameters reflecting decreased systemic arterial tone and right ventricular dysfunction are associated with adverse outcomes and systemic hypoperfusion.

AbstractPurposeTo determine whether a 24 MHz transducer significantly improves sensitivity, specificity and accuracy in evaluating flexor tendon repair integrity compared with an 18 MHz transducer.MethodsOne hundred and twelve cadaveric digits were randomised to an intact repair or simulated ‘failed’ repair, and to a two‐ or eight‐strand repair of a flexor digitorum profundus laceration. A blinded sonologist evaluated specimens in static mode using 18 and 24 MHz transducers. Gaps were remeasured after scanning, and final gap width recorded. McNemar's exact test calculated differences between sensitivity, specificity and accuracy, and chi‐squared test to compare sensitivity, specificity and accuracy between number of strands (2 vs. 8) and repair gap (≥4 mm).ResultsThe 24 MHz transducer had higher sensitivity (81 vs. 59%), lower specificity (67 vs. 70%) and higher overall accuracy (74 vs. 64%), than the 18 MHz transducer. The difference for sensitivity was significant (P = 0.011), but not differences for specificity and overall accuracy (P > 0.05). Pearson's correlation (r = 0.61) demonstrated a moderate‐to‐strong positive correlation between measured and true gap sizes. Increased number of suture strands (2 vs. 8) did not impair sensitivity, specificity nor accuracy.DiscussionUltrasound may tend to overestimate gap width, and a slight risk that some intact repairs, or those with small, clinically insignificant gaps may undergo surgical exploration that may not be indicated.ConclusionsA 24 MHz transducer is a more sensitive and accurate transducer for assessing flexor tendon repair integrity and measuring small gaps.

Abstract 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

ImportanceRespiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide.ObjectiveTo evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission.Design, Setting, and ParticipantsThis cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection.ExposureRespiratory syncytial virus.Main Outcomes and MeasuresData were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity.ResultsThe first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age &amp;lt;37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days.Conclusions and RelevanceIn this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.

OBJECTIVE Compared with laminectomy with posterior cervical fusion (PCF), cervical laminoplasty (CL) may result in different outcomes for those operated on for cervical spondylotic myelopathy (CSM). The aim of this study was to compare 24-month patient-reported outcomes (PROs) for laminoplasty versus PCF by using the Quality Outcomes Database (QOD) CSM data set. METHODS This was a retrospective study using an augmented data set from the prospectively collected QOD Registry Cervical Module. Patients undergoing laminoplasty or PCF for CSM were included. Using the nearest-neighbor method, the authors performed 1:1 propensity matching based on age, operated levels, and baseline modified Japanese Orthopaedic Association (mJOA) and visual analog scale (VAS) neck pain scores. The 24-month PROs, i.e., mJOA, Neck Disability Index (NDI), VAS neck pain, VAS arm pain, EQ-5D, EQ-VAS, and North American Spine Society (NASS) satisfaction scores, were compared. Only cases in the subaxial cervical region were included; those that crossed the cervicothoracic junction were excluded. RESULTS From the 1141 patients included in the QOD CSM data set who underwent anterior or posterior surgery for cervical myelopathy, 946 (82.9%) had 24 months of follow-up. Of these, 43 patients who underwent laminoplasty and 191 who underwent PCF met the inclusion criteria. After matching, the groups were similar for baseline characteristics, including operative levels (CL group: 4.0 ± 0.9 vs PCF group: 4.2 ± 1.1, p = 0.337) and baseline PROs (p > 0.05), except for a higher percentage involved in activities outside the home in the CL group (95.3% vs 81.4%, p = 0.044). The 24-month follow-up for the matched cohorts was similar (CL group: 88.4% vs PCF group: 83.7%, p = 0.534). Patients undergoing laminoplasty had significantly lower estimated blood loss (99.3 ± 91.7 mL vs 186.7 ± 142.7 mL, p = 0.003), decreased length of stay (3.0 ± 1.6 days vs 4.5 ± 3.3 days, p = 0.012), and a higher rate of routine discharge (88.4% vs 62.8%, p = 0.006). The CL cohort also demonstrated a higher rate of return to activities (47.2% vs 21.2%, p = 0.023) after 3 months. Laminoplasty was associated with a larger improvement in 24-month NDI score (−19.6 ± 18.9 vs −9.1 ± 21.9, p = 0.031). Otherwise, there were no 3- or 24-month differences in mJOA, mean NDI, VAS neck pain, VAS arm pain, EQ-5D, EQ-VAS, and distribution of NASS satisfaction scores (p > 0.05) between the cohorts. CONCLUSIONS Compared with PCF, laminoplasty was associated with decreased blood loss, decreased length of hospitalization, and higher rates of home discharge. At 3 months, laminoplasty was associated with a higher rate of return to baseline activities. At 24 months, laminoplasty was associated with greater improvements in neck disability. Otherwise, laminoplasty and PCF shared similar outcomes for functional status, pain, quality of life, and satisfaction. Laminoplasty and PCF achieved similar neck pain scores, suggesting that moderate preoperative neck pain may not necessarily be a contraindication for laminoplasty.

Background: Removal of well-fixed femoral components during revision total hip arthroplasty (THA) can be difficult and time-consuming 1 , leading to numerous complications, such as femoral perforation, bone loss, and fracture. Extended trochanteric osteotomies (ETOs), which provide wide exposure and direct access to the femoral canal under controlled conditions, have become a popular method to circumvent these challenges. ETOs were popularized by Wagner (i.e., the anterior-based osteotomy), and later modified by Paprosky (i.e., the lateral-based osteotomy) 2 . Description: The decision to utilize the laterally based Paprosky ETO versus the anteriorly based Wagner ETO is primarily based on surgeon preference, the location and type of in situ implants, and the osseous anatomy. Typically, a laterally based ETO is most facile in conjunction with a posterior approach and an anteriorly based ETO is most commonly paired with a lateral or anterolateral approach. Attention must be paid to maintaining vascularity to the osteotomy fragment, including minimizing stripping of the vastus lateralis from the osteotomy fragment and maintaining abductor attachments to the osteotomy fragment. When utilizing a laterally based ETO, the posterior border of the vastus lateralis must be carefully elevated to provide exposure for performance of the osteotomy. When an anteriorly based osteotomy is performed, the surgeon may instead extend the abductor tenotomy proximally with use of a longitudinal split of the vastus lateralis distally, which helps to keep the anterior and posterior sleeves of soft tissue in continuity. In either approach, dissection of the vastus lateralis involves managing several large vascular perforators. We prefer performing careful blunt dissection to identify the perforators and prophylactically controlling them, with ligation of large vessels and electrocautery of smaller vessels. Vascular clips are also available in case difficult-to-control bleeding is encountered. In general, an oscillating saw (with preference for a thin blade) is utilized to complete the posterior longitudinal limb of the ETO, extending approximately 12 to 16 cm distally from the tip of the greater trochanter. Although a 12 to 16-cm zone is required to maintain maximum vascularity to the osteotomized fragment, the osteotomy length must ultimately be determined by (1) the length of the femoral component to be removed; (2) the presence of distal bone ingrowth, ongrowth, or cement; and (3) the presence of distal hardware or stemmed knee components. A smaller oscillating saw is then utilized to complete the transverse limb at the previously identified distal extent. A high-speed pencil-tip burr is utilized to complete the corners of the osteotomy in a rounded configuration, and a combination of saws and pencil-tip burrs is utilized to create partial proximal and distal anterior longitudinal limbs of the osteotomy to the extent allowed by the soft-tissue attachments. The anterior longitudinal limb may be further weakened in a controlled fashion with use of serial drill holes. The anterior longitudinal limb then undergoes controlled fracture by placement of 2 to 4 broad straight osteotomes in the posterior longitudinal limb. These osteotomes are carefully levered anteriorly in unison with a gentle, steady force. After the ETO is completed, intramedullary prostheses, hardware, and cement are removed; the acetabulum is addressed as needed; and a final femoral stem is implanted, if appropriate. After completion of the osteotomy, the osteotomized fragment must be retracted gently, with care taken to avoid a fracture and maintain vascularity. To this end, debridement of the endosteum of the osteotomized fragment, including any cement removal, should be avoided until the end of the procedure, when the osteotomy is ready to be closed. Our preferred method for closure is to place 1 prophylactic cable 1 cm distal to the osteotomy, 1 to 2 cables along the diaphyseal segment of the osteotomy, and 1 Luque wire above the less trochanter. A Luque wire is our specific choice for the location above the lesser trochanter because it sits in the effective joint space; however, the use of Luque wires distal to the lesser trochanter is also acceptable. A strut allograft or locking plate can be utilized to reinforce the osteotomy in rare cases or to bridge interprosthetic stress risers. Trochanteric implants are typically avoided because of the low rate of clinically relevant trochanteric migration with this closure technique and because of the high rate of symptomatic implants with trochanteric claws or plates. Alternatives: An alternative osteotomy of similar exposure is the transfemoral osteotomy. Additionally, a variety of non-extended trochanteric osteotomies, such as trochanteric slide osteotomies, offer more limited exposure. Rationale: Femoral surgical exposure for revision THA can be aided by performing transfemoral osteotomies, but these provide less precise control of the separate proximal femoral osteotomized segment(s), and healing and fixation can be less reliable. Less invasive osteotomies such as non-extended trochanteric osteotomies typically do not provide adequate exposure in challenging cases for which ETO is being considered. Expected Outcomes: ETOs have high union rates, and notable trochanteric migration is infrequent. The most common complications are fracture of the osteotomy fragment intraoperatively or postoperatively. Radiographic and clinical union is achieved in 98% of patients. The mean proximal trochanteric osteotomy fragment migration prior to union is 3 mm. ETO fragment migration of >1 cm occurs in just 7% of hips. Postoperative greater trochanter fractures occur in 9% of hips. The 10-year survivorship free of revision for aseptic femoral loosening, free of femoral or acetabular component removal or revision for any reason, and free of reoperation for any reason is 97%, 91%, and 82%, respectively 3 . Important Tips: Attention should be paid to patient anatomy, deformity, surgical approach, and implant type when choosing to perform a laterally based Paprosky or anteriorly based Wagner ETO. Appropriate length of the posterior longitudinal limb of the ETO is approximately 12 to 16 cm distally from the tip of the greater trochanter. Attention must be paid to maintaining vascularity to the osteotomy fragment, including minimizing stripping of the vastus lateralis from the osteotomy fragment and maintaining abductor attachments to the osteotomy fragment. A high-speed pencil-tip burr should be utilized to complete the corners of the osteotomy in a rounded configuration in order to avoid stress risers. The anterior longitudinal limb is completed by controlled fracture of the remaining intervening segment in order to maintain vastus lateralis attachments and vascular supply to the osteotomy fragment. The ETO is closed with use of cerclage cables and/or double-stranded Luque wires, typically utilizing a total of 3 to 4 in order to obtain secure fixation without compromising local biology. Acronyms and Abbreviations: MFT = modular fluted tapered

ObjectiveErdheim‐Chester disease (ECD) is rare histiocytosis with a wide range of clinical manifestations. Somatic mutations are key to the pathogenesis of the disease; however, the relationship between germline genetic variants and ECD has not been examined so far. The present study aims to explore the inherited genetic component of ECD by performing the first genome‐wide association study.MethodsAfter quality controls, a cohort of 255 patients with ECD and 7,471 healthy donors was included in this study. Afterward, a logistic regression followed by in silico functional annotation was performed.ResultsA signal at the 18q12.3 genomic region was identified as a new susceptibility locus for ECD (P = 2.75 × 10−11; Odds Ratio = 2.09). This association was annotated to the SETBP1 gene, which is involved in clonal haematopoiesis. Functional annotation of this region and of the identified suggestive signals revealed additional genes that could be potentially involved in the pathogenesis of the disease.ConclusionOverall, this work demonstrates that germline genetic variants can impact on the development of ECD and suggests new pathways with a potential pathogenic role.image