Yttrium-90 Anti-CD25-BEAM-Conditioning for Autologous Hematopoietic Cell Transplantation in Peripheral T Cell Lymphoma.

Peripheral T cell lymphomas (PTCL) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemosensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCL. In this phase 1 clinical trial, we tested the addition of beta-emitting 90Y-labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, melphalan) as conditioning for AHCT in patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5 and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure [median time of death 17 mo (range: 9-21 mo)] post-AHCT. Median follow-up was 24 mo (range: 9-26 mo) overall and 24 mo (range: 13-26 mo) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% CI: 34-77%) and 68% (95% CI: 42-84%), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.clinicaltrials.gov as # NCT02342782.

Thoracic Stent Grafts Induce Persistent Aortic Remodeling in Aortic Coarctation.

OBJECTIVE: This study's objective is to describe outcomes of adult patients who underwent thoracic stent graft placement treatment for primary or recurrent aortic coarctation. METHODS: This is a retrospective study of 30 adult patients who underwent thoracic stent graft placement for aortic coarctation at our institution. Average age was 46.5 years, with 53.3% of patients presented with no prior treatment or repair for coarctation. Indications for repair included gradient ≥20 mm Hg with anatomic evidence of coarctation on imaging with left ventricular hypertrophy, pseudoaneurysm, aneurysm, refractory hypertension, or claudication. Stent grafts used for repair included MDT (Medtronic, Santa Rosa, CA) and GORE TAG (W. L. Gore & Associates, Flagstaff, AZ). RESULTS: Patients were observed for a median of 979 days, with one death during the study. All patients had complete resolution of symptoms with no recurrences. TEVAR significantly reduced the gradient across the coarctation (p <0.0001). Aortic coarctation diameter significantly increased at 30-days postoperatively and continued to increase up to 5 years post-treatment. At 3+ years, aortic remodeling was observed at the coarctation site and surrounding regions. At 30 days, systolic, diastolic, and mean arterial pressure were all reduced. Systolic and diastolic blood pressure as well as MAP continued to significantly improve 1-year post-treatment. CONCLUSIONS: Stent grafts are a safe and effective treatment for aortic coarctation. We observed a clinically significant improvement in blood pressure, and longitudinal aortic remodeling of the coarctation segment and the entire aorta that persisted over more than 3 years.

Immediate Sequential Bilateral Cataract Surgery in Patients with Bilateral Visually Significant Cataracts.

Purpose: To report our experience of performing immediate sequential bilateral cataract surgery (ISBCS) in patients with visually significant cataracts and reduced preoperative corrected distance visual acuity (CDVA). Methods: Data of patients who underwent ISBCS for visually significant cataracts and had preoperative CDVA ≤20/32 (≤0.2 logMAR) in each eye were retrospectively reviewed. Refractive and visual outcomes were evaluated for the last available postoperative visit. Intraoperative and serious postoperative adverse events occurring within the first three months of surgery were reviewed. Results: A total of 1335 patients (2670 eyes) were included in the analysis, with a mean age of 71.9 ± 9.5 years. On the last visit, 50.2% and 89.1% of eyes achieved uncorrected distance visual acuity (UDVA) ≥20/20 (0.0 logMAR) and ≥20/32 (0.2 logMAR), respectively. Of all eyes, 83.8% were within ±0.50D, and 96.4% were within ±1.00 D of emmetropia. Ten patients had postoperative bilateral ametropia of more than 1.00D in each eye, but eight of them still achieved binocular UDVA ≥20/40. Intraoperative events occurred in 14 eyes of 13 patients (per-eye incidence: 0.524% or 1 in 191 eyes). A total of 86 postoperative adverse events occurred in 80 eyes of 53 patients (per-eye incidence 2.996% or 1 in 33 eyes), of which cystoid macular edema was the most common. Only three eyes had CDVA reduced by more than two Snellen lines compared to preoperative CDVA, two of which were not related to cataract surgery. There was no patient with bilateral CDVA loss. Conclusion: In our cohort of patients with visually significant cataracts, ISBCS resulted in good refractive predictability and a low incidence of serious adverse events.

Reconstruction after Mohs Surgery for Digit Melanoma: Description of Techniques and Postoperative Limb Function.

Introduction: Mohs surgery and reconstruction has enabled tissue-preserving resection of cutaneous malignancies. The goal of our case series evaluation is to present reconstructive techniques and functional outcomes in patients undergoing digit-sparing treatment for primary melanoma. Materials and Methods: A chart review was performed to identify consecutive patients undergoing Mohs surgery and reconstruction for melanoma of the digits. Quality of life (QOL) survey was performed to assess function after the procedure. Results: Thirty-two patients (13 hand, 19 foot, Age: 65.03 +/-17.78 years) who were undergoing Mohs surgery were identified. No recurrence was identified with an average follow-up of 16.1 months (1-95 months). The average defect size was 5.79 +/-4.54 cm2. Reconstruction was performed 0-4 days after resection. The most common techniques included full-thickness skin graft (FTSG) (N = 7), collagen matrix + FTSG (N = 4), and volar advancement flap (N = 7). The reconstructive technique choice appears correlated with defect size (p = 0.0125). Neuro-QOL upper extremity survey results showed a difference that approached statistical significance between patients who underwent digit-sparing treatment (n = 7) versus direct to amputation controls (n = 5) (p = 0.072). No survey differences between digit-sparing treatment (n = 10) and amputation (n = 8) were identified in the lower extremity (p = 0.61). Conclusion: Our results show digit-sparing treatment can confirm clear surgical margins and a trend toward improvement in upper extremity function compared with immediate amputation.

Correction to: Improvements in Gut Microbiome Composition and Clinical Symptoms Following Familial Fecal Microbiota Transplantation in a Nineteen-Year-Old Adolescent With Severe Autism.

[This corrects the article DOI: 10.14740/jmc4209.].

Femtosecond laser writing of fiber Bragg gratings using the phase mask technique: a geometrical optics analysis based on the Bravais refractive index.

Material modification is produced inside silica-based optical fibers of different diameters using tightly focused near-infrared (central wavelength at 800 nm) femtosecond laser pulses and the phase mask technique which is often employed for laser inscription of fiber Bragg gratings. 1st-, 2nd-, and 3rd-order phase masks designed for the operation at 800 nm are used in the experiments. The inscription is performed at different distances from the fiber's front surface by translating the focusing cylindrical lens along the laser beam propagation direction. The results show that the material modification produced by means of the 2nd- and 3rd-order phase mask can be positioned at any predetermined distance from the fiber's front surface. In contrast, when the 1st-order mask is used for laser writing, the maximum distance from the fiber's front surface at which material modification can be produced is limited and determined by three main parameters: the diffraction angle of the phase mask, the refractive index of the fiber and the diameter of the fiber.

Compassionate Release: A Call to Social Workers.

An increase in the number of older people incarcerated in prisons has given rise to increased costs of correctional health care. Despite the many benefits of compassionate release, it is rarely used. Citing barriers at the micro, mezzo, and macro levels, we contend that social workers are uniquely suited to increase the number of people released through this mechanism owing to a unique knowledge and skill set. We offer eight specific strategies for how social workers can increase the use of compassionate release by working with individuals, conducting and disseminating research, and engaging in advocacy as shaped by core professional principles and values and related curricula.

Outcomes of isolated medial tibial plateau fractures by fracture morphology.

PURPOSE: To identify a cohort of isolated medial tibial plateau fractures treated with surgical fixation and to categorize them by Moore and Wahlquist classifications in order to determine the rate of complications with each fracture morphology and the predictive value of each classification system. We hypothesized there would be high rates of neurovascular injury, compartment syndrome, and complications overall with a higher incidence of neurovascular injury in Moore type III rim avulsion fractures and Wahlquist type C fractures that enter the plateau lateral to the tibial spines. METHODS: Patients who presented to six Level I trauma centers between 2010 and 2021 who underwent surgical fixation for isolated medial tibial plateau fractures were retrospectively reviewed. Data including demographics, radiographs, complications, and functional outcomes were collected. RESULTS: One hundred and fifty isolated medial tibial plateau fractures were included. All patients were classified by the Wahlquist classification of medial tibial plateau fractures, and 139 patients were classifiable by the Moore classification of tibial plateau fracture-dislocations. Nine percent of fractures presented with neurovascular injury: 5 % with isolated vascular injury and 6 % with isolated nerve injury. There were no significant differences in neurovascular injury by fracture type (Wahlquist p = 0.16, Moore p = 0.33). Compartment syndrome developed in two patients (1.3 %). The average final range of motion was 0.8-122° with no difference by Wahlquist or Moore classifications (p = 0.11, p = 0.52). The overall complication rate was 32 % without differences by fracture morphology. The overall rate of return to the operating room (OR) was 25 %. CONCLUSIONS: Isolated medial tibial plateau fractures often represent fracture-dislocations of the knee and should receive a meticulous neurovascular exam on presentation with a high suspicion for neurovascular injury. No specific fracture pattern was found to be predictive of neurovascular injuries, complications, or final knee range of motion. Patients should be counseled pre-operatively regarding high rates of return to the OR after the index surgery.

Factors Influencing Primary Care Career Choice: A Multi-Institutional Cross-sectional Survey of Internal Medicine Primary Care Residency Graduates.

BACKGROUND: Although primary care is associated with population health benefits, the supply of primary care physicians continues to decline. Internal medicine (IM) primary care residency programs have produced graduates that pursue primary care; however, it is uncertain what characteristics and training factors most affect primary care career choice. OBJECTIVE: To assess factors that influenced IM primary care residents to pursue a career in primary care versus a non-primary care career. DESIGN: Multi-institutional cross-sectional study. PARTICIPANTS: IM primary care residency graduates from seven residency programs from 2014 to 2019. MAIN MEASURES: Descriptive analyses of respondent characteristics, residency training experiences, and graduate outcomes were performed. Bivariate logistic regression analyses were used to assess associations between primary care career choice with both graduate characteristics and training experiences. KEY RESULTS: There were 256/314 (82%) residents completing the survey. Sixty-six percent of respondents (n = 169) practiced primary care or primary care with a specialized focus such as geriatrics, HIV primary care, or women's health. Respondents who pursued a primary care career were more likely to report the following as positive influences on their career choice: resident continuity clinic experience, nature of the PCP-patient relationship, ability to care for a broad spectrum of patient pathology, breadth of knowledge and skills, relationship with primary care mentors during residency training, relationship with fellow primary care residents during training, and lifestyle/work hours (all p < 0.05). Respondents who did not pursue a primary care career were more likely to agree that the following factors detracted them from a primary care career: excessive administrative burden, demanding clinical work, and concern about burnout in a primary care career (all p < 0.05). CONCLUSIONS: Efforts to optimize the outpatient continuity clinic experience for residents, cultivate a supportive learning community of primary care mentors and residents, and decrease administrative burden in primary care may promote primary care career choice.

In-hospital outcome of type A aortic dissection repair in patients with chronic obstructive pulmonary disease: A population study of National Inpatient Sample from 2015 to 2020.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common comorbidity that has been linked to higher mortality and respiratory complications in cardiac surgery. However, the postoperative outcomes for COPD patients undergoing Type A Aortic Dissection (TAAD) repair remain unexplored. Thus, this study aimed to assess the impact of COPD on in-hospital outcomes of TAAD repair in a national registry. METHODS: Patients undergoing TAAD repair were identified in National Inpatient Sample from the last quarter of 2015-2020. Multivariable logistic regressions were used to compare in-hospital outcomes between patients with and without COPD, where demographics, comorbidities, hospital characteristics, primary payer status, and transfer status were adjusted. RESULTS: There were 701 (16.37 %) COPD patients and 3581 (83.63 %) non-COPD patients who went under TAAD repair, where the prevalence of COPD was higher than in the general population (6 %). COPD and non-COPD patients have comparable rates of in-hospital mortality (14.69 % vs 15.19 %, aOR 1.016, 95 CI 0.797-1.295, p = 0.9) and there was no indication of delayed surgery. However, COPD patients had a higher risk of mechanical ventilation (37.80 % vs 31.42 %, aOR 1.521, 95 CI 1.267-1.825, p < 0.01) and a higher rate of transferring out to other facilities (38.37 % vs 32.23 %, aOR 1.271, 95 CI 1.054-1.533, p = 0.01). In addition, COPD patients had a longer hospital length of stay (14.28 ± 11.32 vs 13.85 ± 12.78 days, F = 5.61, p = 0.01). CONCLUSION: The presence of COPD could be a risk factor for the development of aortic dissection. However, outcomes for COPD patients were largely similar to those without COPD. These findings can be valuable for preoperative assessments and tailoring perioperative care for COPD patients undergoing TAAD repair.

Proceedings of the dengue endgame summit: Imagining a world with dengue control.

The first dengue "endgame" summit was held in Syracuse, NY over August 9 and 10, 2023. Organized and hosted by the Institute for Global Health and Translational Sciences at SUNY Upstate Medical University, the gathering brought together researchers, clinicians, drug and vaccine developers, government officials, and other key stakeholders in the dengue field for a highly collaborative and discussion-oriented event. The objective of the gathering was to discuss the current state of dengue around the world, what dengue "control" might look like, and what a potential roadmap might look like to achieve functional dengue control. Over the course of 7 sessions, speakers with a diverse array of expertise highlighted both current and historic challenges associated with dengue control, the state of dengue countermeasure development and deployment, as well as fundamental virologic, immunologic, and medical barriers to achieving dengue control. While sustained eradication of dengue was considered challenging, attendees were optimistic that significant reduction in the burden of dengue can be achieved by integration of vector control with effective application of therapeutics and vaccines.

Immune imprinting in early life shapes cross-reactivity to influenza B virus haemagglutinin.

Influenza exposures early in life are believed to shape future susceptibility to influenza infections by imprinting immunological biases that affect cross-reactivity to future influenza viruses. However, direct serological evidence linked to susceptibility is limited. Here we analysed haemagglutination-inhibition titres in 1,451 cross-sectional samples collected between 1992 and 2020, from individuals born between 1917 and 2008, against influenza B virus (IBV) isolates from 1940 to 2021. We included testing of 'future' isolates that circulated after sample collection. We show that immunological biases are conferred by early life IBV infection and result in lineage-specific cross-reactivity of a birth cohort towards future IBV isolates. This translates into differential estimates of susceptibility between birth cohorts towards the B/Yamagata and B/Victoria lineages, predicting lineage-specific birth-cohort distributions of observed medically attended IBV infections. Our data suggest that immunological measurements of imprinting could be important in modelling and predicting virus epidemiology.

An alternative to the igneous crust fluid + sediment melt paradigm for arc lava geochemistry.

A long-standing paradigm of arc geochemistry is that the trace element compositions of arc lavas arise from two compositionally distinct slab components: an aqueous dehydration fluid from the subducting igneous ocean crust that transports "fluid-mobile" elements, such as barium (Ba), and a sediment melt that supplies thorium (Th) and the light rare earth elements. This two-component framework has been widely called upon to explain global geochemical trends as well as geochemical variations within individual arcs, such as the Marianas. Here, we show that this paradigm is inconsistent with mass balance, due to the low Ba contents of igneous ocean crust, and with experimental data, which show that aqueous fluids from the igneous oceanic crust would be too dilute to substantially affect arc compositions. Observations previously attributed to the sediment melt/igneous-crust-fluid hypothesis are better explained by diverse subducting sediment compositions coupled with ambient mantle wedge heterogeneity, both globally and for the Marianas.

Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident.

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

Dietary NO3- does not enhance endothelial dependent cutaneous vascular conductance in older women.

Prior work has yet to determine whether the reduction of dietary nitrate (NO3-) to NO, via the enterosalivary pathway, may modify cutaneous vascular conductance (CVC) responses to local heating in older women. Changes occurring with the transition to menopause related to hormonal flux, increased adiposity, and/or decreased physical activity may further compound the negative influence of aging on nitric oxide (NO)-dependent CVC. Herein, we characterized changes in NO-dependent CVC following acute ingestion of 140 mL of NO3--rich beetroot juice in 24 older women (age: 65 ± 5 y, BMI: 31.2 ± 3.7 kg/m2). Red blood cell (RBC) flux was measured continuously via laser-Doppler flowmetry on the dorsal aspect of the forearm during local skin heating to 39 °C/44 °C before and 3 h after NO3- ingestion. NO-dependent changes in CVC were calculated as RBC flux/mean arterial blood pressure at 39 °C and normalized as a proportion of maximal CVC at 44 °C (%CVCmax). Changes (Δ) in fractional exhaled NO (FeNO) following NO3- ingestion were used an index of NO bioavailability. Despite increased FeNO (+81 ± 70 %, P < 0.001), %CVCmax at 39 °C was reduced (-16 ± 10 %, P < 0.001) following NO3- ingestion. A greater reduction in %CVCmax was weakly to moderately associated with higher body fat% (r = 0.45 [0.05-0.72], P = 0.029), central adiposity% (r = 0.50 [0.13-0.75], P = 0.012), neutrophil% (r = 0.42 [0.02-0.70], P = 0.041), and higher neutrophil to lymphocyte ratio (r = 0.49 [0.11-0.75], P = 0.016). These findings demonstrate a single dose of dietary NO3- does not promote CVC responses to local heating in sedentary older women with overweight and obesity. Correlation with multiple biomarkers suggest systemic inflammation may be involved.

The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.

The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.

Analysis of Polyfunctionality for Enhanced CAR T-Cell Therapy for Hematologic Malignancies.

Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising immunotherapeutic strategy for eradicating human cancers. Their therapeutic success and durability of clinical responses hinges, in large part, on their functional capacity, including the ability of these engineered cells to simultaneously expand and persist after infusion into patients. CD19 CAR T-cell polyfunctionality, assessing the simultaneous functions of cytokine production, proliferation, and cytotoxicity has been reported to correlate with clinical outcomes. Assay optimization is potentially limited by the heterogeneous nature of CAR T-cell infusion products and target specificity. We optimized a single-cell platform for polyfunctionality using CAR T cell products manufactured from healthy donors, engineered against a novel target, BAFF-R, and validated the protocol using CD19 CAR T cells. We observed distinct qualitative differences between BAFF-R and CD19 CAR T cells relative to the proportions of stimulatory vs. effector cytokines, based on target antigen density, and generally, CD19 CAR T cells exhibited lower indices of polyfunctionality. Finally, we applied our assay to the autologous BAFF-R CAR T-cell product generated from the first NHL patient treated on an ongoing clinical trial who had progressed after prior CD19 CAR T-cell therapy. We observed robust indicators of polyfunctionality, which correlated with successful CAR T cell expansion after infusion and achievement of durable complete remission ongoing after 18 months. The precise identification of factors determining the role of BAFF-R CAR T-cell fitness on toxicity and clinical outcome will require the application of this robust assay in the analysis of additional treated patients.

Mapping the Geographical Distribution of the Mucosa-Associated Gut Microbiome in GI-Symptomatic Children with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by cognitive, behavioral, and communication impairments. In the last few years, it has been proposed that alterations in the gut microbiota may contribute to an aberrant communication between the gut and brain in children with ASD. Consistent with this notion, several studies have demonstrated that children with ASD have an altered fecal microbiota compared to typically developing (TD) children. However, it is unclear where along the length of the gastrointestinal (GI) tract these alterations in microbial communities occur. Additionally, the variation between specific mucosa-associated communities remains unknown. To address this gap in knowledge of the microbiome associated with ASD, biopsies from the antrum, duodenum, ileum, ascending colon, and rectum of children with ASD and age- and sex-matched TD children were examined by 16s rRNA sequencing. We observed an overall elevated abundance of Bacillota and Bacteroidota and decreased abundance of Pseudomonadota in all GI tract regions of both male and female ASD children compared to TD children. Further analysis at the genera level revealed unique differences in the microbiome in the different regions of the GI tract in ASD children compared to TD children. We also observed sex-specific differences in the gut microbiota composition in children with ASD. These data indicate that the microbiota of ASD children is altered at multiple regions of the GI tract and that different anatomic locations have unique alterations in mucosa-associated bacterial genera.

Fulfilling the Promise of Breathomics: Considerations for the Discovery and Validation of Exhaled Volatile Biomarkers.

The exhaled breath represents an ideal matrix for non-invasive biomarker discovery, and exhaled metabolomics have the potential to be clinically useful in the era of precision medicine. In this concise translational review we will specifically address volatile organic compounds in the breath, with a view towards fulfilling the promise of these as actionable biomarkers, in particular for lung diseases. We review the literature paying attention to seminal work linked to key milestones in breath research; discuss potential applications for breath biomarkers across disease areas and healthcare systems, including the perspectives of industry; and outline critical aspects of study design that will need to be considered for any pivotal research going forward, if breath analysis is to provide robust validated biomarkers that meet the requirements for future clinical implementation.