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Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background/Objectives: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. Methods: A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. Results: In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. Conclusions: The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.

Background: Whether oral anticoagulation (OAC) can be discontinued after the resolution of left ventricular thrombus (LVT) remains controversial, particularly in patients without risk factors such as left ventricular aneurysms. This study aimed to identify patients who may safely discontinue OAC. Methods: We conducted a retrospective cohort study of patients with LVT resolution who completed their anticoagulation course and excluded patients with left ventricular (LV) aneurysm. Clinical and echocardiographic factors were compared between patients who experienced LVT recurrence (n = 22) and those without recurrence during follow-up (n = 94). Results: The cohort had a mean age of 64.5 ± 15.0 years, and half (50%) were male. Most had an ischemic cardiomyopathy (64.6%). LVT recurred in 19% (22/116) of patients following initial resolution. Patients with recurrence were older (mean age 71.3 ± 11.9 vs. 63.4 ± 15.7 years, p = 0.03) and were more likely to have prior ischemic stroke and arterial thromboembolism (18.2% vs. 4.3%, p = 0.02 for both). At the time of thrombus resolution, LVEF was significantly lower among patients who had recurrence (33.4 ± 13.6% vs. 42.5 ± 15.5%, p = 0.012). Stroke, systemic embolism, and mortality rates were similar regardless of recurrence status. Recurrence risk by presence or absence of stroke and LEVF >50% on the LVT resolution echocardiogram is shown in Figure 1. Notably, no recurrences were observed among patients with both LVEF > 50% and no history of stroke (0/32), which was statistically significant compared to each other category. Conclusion: Among patients without left ventricular aneurysm who discontinued oral anticoagulation after LVT resolution, those with preserved LVEF (>50%) and no prior history of stroke had a very low risk of recurrence, with no events observed in this subgroup. These findings suggest that some patients may safely discontinue anticoagulation after LVT resolution.

Introduction: Pressure-adjusted heart rate (PAHR) provides an integrated assessment of hemodynamic decompensation in critically ill patients. Research Question: How does PAHR perform in critically ill patients with cardiovascular disease? Aims: We sought to evaluate the prognostic value of PAHR on mortality in patients admitted to the cardiovascular intensive care unit (CICU). Methods: A retrospective cohort of patients admitted to the CICU at a tertiary-care academic institution, between 2007 and 2018, who had a transthoracic echocardiogram (TTE) within one day of admission were evaluated. Heart rate (HR), right atrial pressure (RAP), and mean arterial pressure (MAP), obtained from TTE, were used to calculate PAHR as RAP * HR / MAP. Results: Among 5411 patients included for analysis (median age 70.1 years, 38.6% female, 92.4% White), higher PAHR was associated with greater severity of acute illness, burden of comorbidities, and use of critical care therapies. Median values (25 th percentile, 75 th percentile) for HR were 73.0 (63.0, 87.0) beats per minute (bpm), RAP 10.0 (5.0, 14.0) mm Hg, and MAP 81.3 (72.3, 91.7) mm Hg. Median PAHR was significantly higher among patients who died during hospitalization (14.3 bpm vs 6.8 bpm, p <0.001). In addition, TTE measurements of biventricular function, intracardiac filling pressures, and cardiac output were worse among those with higher PAHR (Table). Adjusted in-hospital mortality increased incrementally with higher PAHR, regardless of admission diagnosis, biventricular function, and critical care therapies (adjusted odds ratio [OR] 1.03 per 1 bpm higher, 95% confidence interval [CI] 1.01-1.05, p = 0.001; adjusted OR per quartile 1.37, 95% CI 1.19-1.59, p <0.001, Figure 1). Similarly, one-year mortality increased incrementally with higher PAHR (adjusted hazard ratio 1.03 per 1 bpm higher, 95% CI 1.02-1.04, p <0.001, Figure 2). When compared to component values, including the modified shock index, which is defined by HR / MAP, PAHR had the highest area under the curve (C-statistic 0.75). Conclusions: PAHR is a readily determinable composite measure of filling pressures and vascular resistance that enhances clinical risk stratification of critically ill patients by TTE. Among a diverse cohort of CICU patients, higher PAHR was associated with greater in-hospital and one-year mortality, regardless of admission diagnosis, biventricular function, or illness severity.

Background: Little is known about the epidemiology and prognostic significance of acid-base disturbances in the cardiovascular intensive care unit (CICU). This study examines the association of acid-base status at admission with in-hospital mortality among CICU patients. Methods: We conducted a retrospective analysis of adults admitted to the Mayo Clinic CICU from 2007-2018 who had available blood gas data, utilizing laboratory values obtained closest to the time of CICU admission. Arterial pH, serum bicarbonate, base excess, and partial pressure of carbon dioxide (PaCO 2 ) were examined as predictors of in-hospital mortality. Logistic regression models were used to assess associations, with adjustment for demographics, comorbidities, illness severity, and interventions. A composite acidosis score (CAS, range 0–5), incorporating predefined cut-offs for arterial pH, base excess, and anion gap was calculated to quantify acid-base disturbance severity. Results: A total of 3,229 patients were included for analysis. Of all acid-base variables, acidemia (pH<7.35) emerged as the strongest predictor of in-hospital mortality (adjusted odds ratio [aOR] 1.60, 95% confidence interval [CI] 1.29-1.98, p <0.003). Metabolic acidosis (HCO 3 <20 mEq/L) aOR 1.55, 95% CI 1.24-1.95, p <0.001) and respiratory acidosis (PaCO 2 >45 mmHg, aOR 1.44, 95% CI 1.14-1.81, p =0.002) were associated with worse adjusted in-hospital mortality, whereas alkalemia, metabolic alkalosis, and respiratory alkalosis were not (Fig. 1A-C). After adjustment, lower pH and more negative base excess were associated with higher in-hospital mortality (both p <0.001), whereas HCO 3 and PaCO 2 were not ( p =0.053&p=0.051, respectively; Fig. 2). Patients with combined metabolic and respiratory acidosis had the highest in-hospital mortality (56.3%), followed by patients with isolated or compensated metabolic acidosis (Fig.1D). Patients with severe acidosis (CAS>1) had higher mortality (aOR 2.34, 95% CI 1.88–2.90; p<0.001, Fig. 3AB). In-hospital mortality rose with increasing CAS (aOR 1.36 per point higher, 95% CI 1.26–1.47; p<0.001), with consistent effects across admission diagnoses (Fig. 3C). Conclusions: Acidemia, especially in the context of combined metabolic and respiratory acidosis, strongly predicts in-hospital mortality in the CICU. Incorporating combined acid-base disorders into risk stratification scores may facilitate earlier recognition and prevent progression of hemometabolic shock, thereby improving prognosis.

OBJECTIVE Cervical dystonia (or spasmodic torticollis) is a neurological condition that results in abnormal movements and head posture, for which initial surgical intervention typically involves selective denervation of the sternocleidomastoid (SCM) and paraspinal muscles. However, muscle reactivation of the distal SCM stump can result in recurrent symptoms. In this study, the authors present their preliminary experience with distal SCM stump resection following selective denervation, with the aim of evaluating the effectiveness of the procedure and identifying patients who may benefit from this technique. METHODS This is a retrospective single-center cohort study of patients who underwent SCM stump resection as revision surgery for cervical dystonia. RESULTS A total of 18 patients (10 males [56%]) were included with a median (range) age of 54 (40–70) years. All patients received selective denervation of the SCM at the authors’ institution prior to SCM stump resection at a median (range) time of 12 (3–198) months between surgical procedures. At preoperative baseline, 13 patients (72%) possessed a rotational torticollis component to their head deviation, 12 (67%) possessed a laterocollis component, and 2 (11%) possessed a retrocollis component. At the most recent follow-up (median [range] 16 [4–119] months), 6 patients had complete resolution of their cervical dystonia (33%), while 10 had residual deviation (56%) and 2 had recurrent deviation (11%). However, compared to their post–selective denervation head position, 12 patients experienced improvement in their head position (67%), 4 patients had no change in their head position (22%), and 2 had worsening of their cervical dystonia (11%) following SCM stump resection. Importantly, 12 patients experienced improvement in their pain following SCM stump resection (67%). Patients who had a history of other movement/spasmodic disorders were more likely to have improvement in head position and improvement in pain after SCM stump resection, though neither of these results achieved statistical significance (p = 0.054). Additionally, patients who experienced full resolution of their cervical dystonia had shorter time between initial selective denervation surgery and SCM stump resection, though this result also did not achieve statistical significance (p = 0.068). CONCLUSIONS Distal SCM stump resection following selective denervation is a simple, safe, and effective option for many patients in treating refractory cervical dystonia. Patients with more severe preoperative presentations may experience greater benefit from SCM stump resection, though additional investigations are needed.

Abstract Background Dystonia and Parkinson's disease (PD) exhibit clinical and genetic overlap, but the relevance of dystonia gene variants in PD remains unclear. Objective The aim was to assess the frequency of dystonia‐linked pathogenic variants in PD. Methods We screened sequencing data from 15,684 individuals (8272 PD, 3200 atypical parkinsonism, and 4212 unaffected) from the Global Parkinson's Genetics Program (GP2) and Accelerating Medicines Partnership‐Parkinson's Disease (AMP‐PD) for variants in genes linked to isolated dystonia, dystonia‐parkinsonism, and myoclonus‐dystonia. Results Pathogenic variants were identified only in PD patients. Forty‐five PD individuals (0.54%) carried 26 distinct (likely) pathogenic variants in nine dystonia‐linked genes, most frequently in GCH1 , followed by VPS16 . Conclusion Though rare, pathogenic variants in dystonia‐linked genes are present in clinically and pathologically diagnosed PD. Our results reinforce GCH1 as a PD‐relevant gene with clinical implications, whereas variants identified in other genes are rare and of uncertain relation to the PD phenotype. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

PURPOSE Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer-predisposing signals. METHODS To address this gap, we interrogated 189 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts. RESULTS Analysis across all cases with cancer revealed enrichment of TP53 PV. Cancer-specific analyses confirmed known associations including germline TP53 PV in adrenocortical carcinoma, high-grade glioma (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in neuroblastoma. In addition, four novel associations were uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5 in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the SMARCAL1 :OS association was significant in the discovery (6/230, 2.6%, false discovery rate [FDR] logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; P Fisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, P Fisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, P Fisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data. CONCLUSION Our study confirms the relevance DDR genetic variation in pediatric cancer risk and establishes SMARCAL1 as a novel OS predisposing gene, providing insights into tumor biology and creating opportunities to optimize care for patients with this challenging tumor.

OBJECTIVE Resection of common peroneal nerve (CPN) schwannomas is generally believed to be associated with a high risk of postoperative deficit, especially the chance for development of a foot drop. The goal of this study was to investigate the surgical results for resection of schwannomas from the CPN around the knee and specifically the chance of developing a postoperative motor deficit. METHODS Data from 36 patients with sporadic schwannomas and 8 patients with schwannomatosis (12 schwannomas total) treated at two centers were retrospectively analyzed. For sporadic cases, different locations around the knee were compared (i.e., proximal to the fibular head [FH], at the FH, and distal to the FH), taking into account the preoperative duration of symptoms, size at presentation, and surgical results of resection. The literature was systematically reviewed for reported cases by searching the PubMed and Embase databases. RESULTS A total of 24 schwannomas proximal to the FH were surgically treated: 11 at the FH, and 13 distal to the FH. For the entire cohort, the mean size of CPN schwannomas distal to the FH at presentation was smaller (1.4 × 1.8 cm) compared with those proximal to (2.0 × 2.2 cm) and at (2.2 × 2.3 cm) the FH, although these differences were not statistically significant. The mean preoperative duration of symptoms was slightly longer for schwannomas distal to the FH (35 months) than for those proximal to the FH (21 months) and at the FH (27 months); however, this difference was not significant. Postoperative deficits occurred in 3 sporadic cases: 2 patients with temporary weakness (Medical Research Council grade 4) that completely resolved within several months and 1 patient who had previously undergone surgery elsewhere and presented with deficits and in whom weakness increased after resection. Improvement in preoperative deficits was observed in 1 patient with extensor hallucis longus muscle paralysis that completely recovered. One patient with schwannomatosis developed muscle weakness after resection of a plexiform schwannoma. A systematic review of 21 previously reported cases in the literature showed that larger CPN schwannomas (> 5 cm) were more likely to result in permanent motor deficits. CONCLUSIONS This retrospective study of 44 patients shows that peroneal nerve schwannomas around the knee can be safely removed with a low risk of deficits. The systematic review of the literature suggests that larger schwannomas are more likely to result in permanent deficit. In the authors’ opinion, CPN schwannomas can best be resected, preferably when the lesion is relatively small.

Of the thousands of genes and substrates identified in KRAS-mutant signaling networks in pancreatic ductal adenocarcinoma (PDAC), more than 200 are transcription factors, implying extensive and complex transcriptional regulation. However, we observed that genetic suppression of the transcription factor MYC alone was sufficient to phenocopy the effect of KRAS suppression in signaling, growth, and metabolic processes in PDAC cells. We determined the gene transcription changes caused by acute suppression of MYC function in KRAS -mutant PDAC cell lines and performed dependency map and pathway analyses on the affected gene sets. The expression of 1685 genes was increased upon suppression of MYC, and this gene set may comprise the bulk of the MYC-regulated genes essential for PDAC growth. In contrast, the 1325 genes whose expression was inhibited may comprise a compensatory response to oncogenic stress, mediated in part by the GTPase RHO. MYC-dependent transcriptional activity was largely ERK dependent, and almost one-third of ERK-regulated genes were also regulated by MYC in PDAC cells. Furthermore, chemical proteomic profiling revealed MYC-regulated protein kinases that can be targeted therapeutically. Together, these data provide a molecular portrait of MYC-dependent signaling that encompasses potentially exploitable mechanisms for treating PDAC.