Citations

ObjectiveNeuroinflammatory adverse events have been observed among new users of tumor necrosis factor (TNF) inhibitors. No studies to date have compared the real‐world risk of TNFs with other new users of biologic or targeted synthetic disease‐modifying antirheumatic drugs (b/tsDMARDs). The objective of this study is to describe the risk of neuroinflammatory disease after initiation b/tsDMARDs.MethodsThis new user comparative effectiveness cohort study used a large US‐based electronic health records database to describe the unadjusted incidence of neuroinflammatory adverse events over a 3‐year period. The cohort included patients with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, or ulcerative colitis initiating treatment with a TNF inhibitor (n = 93,661) or other b/tsDMARD (n = 38,354).ResultsAmong 132,015 patients included in the analysis, the most common first biologic agent was a TNF inhibitor; the unadjusted incidence of neuroinflammatory events was numerically lower among new users of TNF inhibitors (incidence 1.34 per 1,000 patient‐years) as compared with the combined non‐TNF group (1.69 per 1,000 patient‐years). There was no significant association between TNF exposure and neuroinflammatory events as compared with the combined non‐TNF b/tsDMARDs overall (hazard ratio 1.01; 95% confidence interval 0.75–1.36) and within each disease group.ConclusionThe overall risk of neuroinflammatory events among new users of TNF inhibitors did not differ substantially as compared with new users of other b/tsDMARDs. Meta‐analyses of randomized trials should be conducted to corroborate these findings, which may be affected by channeling bias.

Abstract Introduction The Accreditation Council for Graduate Medical Education (ACGME) approved the first pain medicine fellowship programs over three decades ago, designed around a pharmacological philosophy. Following that, there has been a rise in the transition of pain medicine education toward a multidisciplinary interventional model based on a tremendous surge of contemporaneous literature in these areas. This trend has created variability in clinical experience and education amongst accredited pain medicine programs with minimal literature evaluating the differences and commonalities in education and experience of different pain medicine fellowships through Program Director (PD) experiences. This study aims to gather insight from pain medicine fellowship program directors across the country to assess clinical and interventional training, providing valuable perspectives on the future of pain medicine education. Methods This study involved 56 PDs of ACGME‐accredited pain fellowship programs in the United States. The recruitment process included three phases: advanced notification, invitation, and follow‐up to maximize response rate. Participants completed a standard online questionnaire, covering various topics such as subcategory fields, online platforms for supplemental education, clinical experience, postgraduate practice success, and training adequacy. Results Surveys were completed by 39/56 (69%) standing members of the Association of Pain Program Directors (APPD). All PDs allowed fellows to participate in industry‐related and professional society‐related procedural workshops, with 59% encouraging these workshops. PDs emphasized the importance of integrity, professionalism, and diligence for long‐term success. Fifty‐four percent of PDs expressed the need for extension of fellowship training to avoid supplemental education by industry or pain/spine societies. Conclusion This study highlights the challenge of providing adequate training in all Pain Medicine subtopics within a 12‐month pain medicine fellowship. PDs suggest the need for additional training for fellows and discuss the importance of curriculum standardization.

Summary: Abdominal-based free flaps are the mainstay of autologous breast reconstruction; however, the region may not be ideal for patients with inadequate soft tissue or history of abdominal surgery. This case describes the use of a novel conjoined flap based on the profunda artery perforator and upper gracilis pedicles, named the perforator and upper gracilis (PUG) flap. This flap design aims to maximize medial thigh flap volume while ensuring robust tissue perforation. Here, we present our experience with the PUG flap in a breast cancer patient undergoing autologous reconstruction. The patient was a 41-year-old woman seeking nipple-sparing mastectomy and immediate autologous reconstruction with the PUG flap due to limited abdominal tissue availability. The gracilis and profunda artery perforator flaps were elevated using one boomerang-style skin paddle. Once harvested, the flaps were inset with antegrade and retrograde flow off the internal mammary arteries and both respective internal mammary veins. The donor site was closed in a V-Y pattern resulting in a thigh lift–type lift and concealed scar. In conclusion, the boomerang-style PUG flap maximizes medial thigh free tissue transfer volume, offers internal blood flow redundancy, and maintains good cosmesis of the donor site.

Abstract Lack of robust activation of Stimulator of Interferon Genes (STING) pathway and subsequent induction of type I IFN responses is considered a barrier to antitumor immunity in acute myeloid leukemia (AML). Using common human AML cell lines as in vitro tools to evaluate the efficacy of novel STING agonists, we found most AML lines to be poor producers of IFNs upon exposure to extremely potent agonists, suggesting cell-intrinsic suppression of STING signaling may occur. We observed unexpected patterns of response that did not correlate with levels of STING pathway components or of known enzymes associated with resistance. To identify a genetic basis for these observations, we cloned and sequenced STING from the cDNA of human AML cell lines and found both frequent mutations and deviations from normal RNA splicing. We identified two novel spliced isoforms of STING in these lines and validated their expression in primary human AML samples. When transduced into reporter cells, these novel STING isoforms exhibited complete insensitivity to agonist stimulation. These observations identify alternative splicing as a mechanism of STING pathway suppression and suggest that most AML silences the STING pathway through direct modification rather than through engagement of external inhibitory factors. Significance: We find that AML acquires resistance to innate immune activation via the STING pathway through aberrant splicing of the STING transcript including two novel forms described herein that act as dominant negatives. These data broaden understanding of how cancers evolve STING resistance, and suggest that the AML tumor microenvironment, not the cancer cell, should be the target of therapeutic interventions to activate STING.

ImportanceRedirection of care refers to withdrawal, withholding, or limiting escalation of treatment. Whether maternal social determinants of health are associated with redirection of care discussions merits understanding.ObjectiveTo examine associations between maternal social determinants of health and redirection of care discussions for infants born extremely preterm.Design, Setting, and ParticipantsThis is a retrospective analysis of a prospective cohort of infants born at less than 29 weeks’ gestation between April 2011 and December 2020 at 19 National Institute of Child Health and Human Development Neonatal Research Network centers in the US. Follow-up occurred between January 2013 and October 2023. Included infants received active treatment at birth and had mothers who identified as Black or White. Race was limited to Black and White based on service disparities between these groups and limited sample size for other races. Maternal social determinant of health exposures were education level (high school nongraduate or graduate), insurance type (public/none or private), race (Black or White), and ethnicity (Hispanic or non-Hispanic).Main Outcomes and MeasuresThe primary outcome was documented discussion about redirection of infant care. Secondary outcomes included subsequent redirection of care occurrence and, for those born at less than 27 weeks’ gestation, death and neurodevelopmental impairment at 22 to 26 months’ corrected age.ResultsOf the 15 629 infants (mean [SD] gestational age, 26 [2] weeks; 7961 [51%] male) from 13 643 mothers, 2324 (15%) had documented redirection of care discussions. In unadjusted comparisons, there was no significant difference in the percentage of infants with redirection of care discussions by race (Black, 1004/6793 [15%]; White, 1320/8836 [15%]) or ethnicity (Hispanic, 291/2105 [14%]; non-Hispanic, 2020/13 408 [15%]). However, after controlling for maternal and neonatal factors, infants whose mothers identified as Black or as Hispanic were less likely to have documented redirection of care discussions than infants whose mothers identified as White (Black vs White adjusted odds ratio [aOR], 0.84; 95% CI, 0.75-0.96) or as non-Hispanic (Hispanic vs non-Hispanic aOR, 0.72; 95% CI, 0.60-0.87). Redirection of care discussion occurrence did not differ by maternal education level or insurance type.Conclusions and RelevanceFor infants born extremely preterm, redirection of care discussions occurred less often for Black and Hispanic infants than for White and non-Hispanic infants. It is important to explore the possible reasons underlying these differences.

AbstractBackgroundEmpirical evidence regarding the development of sensory responsivity in young children at high likelihood to develop autism spectrum disorder (ASD) remains relatively limited. It is unclear how sensory responsivity behaviors may change over time and impact later developmental outcomes. The goals of this study were to (a) characterize developmental trajectories of sensory responsivity across infancy (∼12 months), toddlerhood (∼24 months), and school age (6–11 years) in children at high and low familial likelihood for ASD; and (b) determine if sensory responsivity in infancy predicts adaptive and cognitive functioning at school age among children with ASD.MethodsGeneralized linear mixed effects models were used to examine scores from the Sensory Experiences Questionnaire in three groups of children including high‐likelihood children later diagnosed with ASD (HL‐ASD; n = 30), high‐likelihood children without ASD (HL‐Neg; n = 150), and low‐likelihood control children not meeting ASD diagnostic criteria (LL‐Neg; n = 94). Hierarchical linear regression was then used to examine the association between sensory responsivity scores in infancy and functional adaptive and cognitive outcomes at school age for children at high likelihood of ASD.ResultsDevelopment of sensory responsivity from infancy to later childhood is best estimated by the effects of chronological age and Group for Sensory Seeking and Hypo responsivity and the additional effect of the interaction of Group and chronological age for Total and Hyper responsivity. Early elevated Hypo responsivity and Sensory Seeking scores are negatively associated with later adaptive behavior but not cognitive level.ConclusionOverall, higher degrees of Sensory Seeking and Hypo sensory responsivity are detectable in autistic children's behavioral repertoires by 12 months of age and associate with reduced adaptive functioning in middle childhood. These results point to the potential importance of early detection and treatment implications of early sensory behaviors.

Head and neck cancer (HNC) accounted for 4% of all malignancies in 2022 and is often associated with tobacco and alcohol use, but the incidence of human papillomavirus (HPV)–associated HNC has steadily increased in recent decades. Unlike HPV-negative HNC, HPV-positive HNC has a favorable prognosis and survival is significantly better resulting in a large population of HNC survivors. Survivorship for HNC is of the utmost importance as there is a high burden of side effects that impact function and quality of life, and the patients with HPV HNC are living longer with the sequelae of their treatment.

Abstract Ruxolitinib reduces spleen volume, improves symptoms, and increases survival in patients with intermediate- or high-risk myelofibrosis. However, suboptimal response may occur, potentially because of signaling via the phosphoinositide 3-kinase (PI3K)/protein kinase B pathway. This phase 2 study evaluated dosing, efficacy, and safety of add-on PI3Kδ inhibitor parsaclisib for patients with primary or secondary myelofibrosis with suboptimal response to ruxolitinib. Eligible patients remained on a stable ruxolitinib dose and received add-on parsaclisib 10 or 20 mg, once daily for 8 weeks, and once weekly thereafter (daily-to-weekly dosing; n = 32); or parsaclisib 5 or 20 mg, once daily for 8 weeks, then 5 mg once daily thereafter (all-daily dosing; n = 42). Proportion of patients achieving a ≥10% decrease in spleen volume at 12 weeks was 28% for daily-to-weekly dosing and 59.5% for all-daily dosing. Proportions of patients achieving ≥50% decrease at week 12 in Myelofibrosis Symptom Assessment Form and Myeloproliferative Neoplasms Symptom Assessment Form symptom scores were 14% and 18% for daily-to-weekly dosing, and 28% and 32% for all-daily dosing, respectively. Most common nonhematologic treatment-emergent adverse events were nausea (23%), diarrhea (22%), abdominal pain and fatigue (each 19%), and cough and dyspnea (each 18%). New-onset grade 3 and 4 thrombocytopenia were observed in 19% of patients, each dosed daily-to-weekly, and in 26% and 7% of patients dosed all-daily, respectively, managed with dose interruptions. Hemoglobin levels remained steady. The addition of parsaclisib to stable-dose ruxolitinib can reduce splenomegaly and improve symptoms, with manageable toxicity in patients with myelofibrosis with suboptimal response to ruxolitinib. This trial was registered at www.clinicaltrials.gov as #NCT02718300.

Functional loss of TDP-43, an RNA binding protein genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), leads to the inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote the degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. Here, we show that mRNA transcripts harboring cryptic exons generated de novo proteins in TDP-43–depleted human iPSC–derived neurons in vitro, and de novo peptides were found in cerebrospinal fluid (CSF) samples from patients with ALS or FTD. Using coordinated transcriptomic and proteomic studies of TDP-43–depleted human iPSC–derived neurons, we identified 65 peptides that mapped to 12 cryptic exons. Cryptic exons identified in TDP-43–depleted human iPSC–derived neurons were predictive of cryptic exons expressed in postmortem brain tissue from patients with TDP-43 proteinopathy. These cryptic exons produced transcript variants that generated de novo proteins. We found that the inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Last, we showed that 18 de novo peptides across 13 genes were present in CSF samples from patients with ALS/FTD spectrum disorders. The demonstration of cryptic exon translation suggests new mechanisms for ALS/FTD pathophysiology downstream of TDP-43 dysfunction and may provide a potential strategy to assay TDP-43 function in patient CSF.

Genetic variation at the transmembrane protein 106B gene ( TMEM106B) has been linked to risk of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) through an unknown mechanism. We found that presence of the TMEM106B rs3173615 protective genotype was associated with longer survival after symptom onset in a postmortem FTLD-TDP cohort, suggesting a slower disease course. The seminal discovery that filaments derived from TMEM106B is a common feature in aging and, across a range of neurodegenerative disorders, suggests that genetic variants in TMEM106B could modulate disease risk and progression through modulating TMEM106B aggregation. To explore this possibility and assess the pathological relevance of TMEM106B accumulation, we generated a new antibody targeting the TMEM106B filament core sequence. Analysis of postmortem samples revealed that the TMEM106B rs3173615 risk allele was associated with higher TMEM106B core accumulation in patients with FTLD-TDP. In contrast, minimal TMEM106B core deposition was detected in carriers of the protective allele. Although the abundance of monomeric full-length TMEM106B was unchanged, carriers of the protective genotype exhibited an increase in dimeric full-length TMEM106B. Increased TMEM106B core deposition was also associated with enhanced TDP-43 dysfunction, and interactome data suggested a role for TMEM106B core filaments in impaired RNA transport, local translation, and endolysosomal function in FTLD-TDP. Overall, these findings suggest that prevention of TMEM106B core accumulation is central to the mechanism by which the TMEM106B protective haplotype reduces disease risk and slows progression.