Citations

AbstractBackgroundManagement of multidrug‐resistant (MDR) and rifampin‐resistant (RR) tuberculosis is challenging. Data on transplant recipients is limited. We reviewed published literature to examine treatment choices, outcomes, and adverse effects from MDR‐TB/RR‐TB treatment in transplant recipients.MethodsMultiple databases from inception to 12/2022 were reviewed using the keywords “drug‐resistant TB” or “drug‐resistant tuberculosis” or “multidrug‐resistant TB” or “multidrug‐resistant tuberculosis”. MDR‐TB was defined as resistance to isoniazid (H) and rifampin (R), and RR if resistant to rifampin alone. Cases without patient‐level data and reports which did not describe treatment and/or outcomes for MDR‐TB were excluded.ResultsA total of 12 patients (10 solid organ transplants and two hematopoietic cell transplants) were included. Of these, 11 were MDR‐TB and one was RR‐TB. Seven recipients were male. The median age was 41.5 (range 16–60) years. Pre‐transplant evaluation for the majority (8/12, 66.7%) did not reveal a prior history of TB or TB treatment, but 9/12 were from TB intermediate or high‐burden countries. Seven patients were initially treated with the quadruple first‐line anti‐TB regimen. Those who had early RR confirmation (5/12) via Xpert MTB/RIF assay were initiated on alternative therapies. Final regimens were individualized based on susceptibility profiles and tolerability. Adverse events were reported in seven recipients, including acute kidney injury (n = 3), cytopenias (n = 3), and jaundice (n = 2). Four recipients died, with two deaths attributable to TB. The remaining eight patients who survived had functioning allografts at the last follow‐up.ConclusionsMDR‐TB treatment in transplant recipients is associated with many complications. Xpert MTB/RIF detected RR early and guided early empiric therapy. image

AbstractNeutralizing antispike monoclonal antibody (mAb) therapies were highly efficacious in preventing coronavirus disease 2019 (COVID‐19) hospitalization. While severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) variants may harbor spike protein mutations conferring reduced in vitro susceptibility to these antibodies, the effect of these mutations on clinical outcomes is not well characterized. We conducted a case–control study of solid organ transplant recipients who received an antispike mAb for treatment of mild‐to‐moderate COVID‐19 and had an available sample from initial COVID‐19 diagnosis for genotypic sequencing. Patients whose SARS‐CoV‐2 isolate had at least one spike codon mutation conferring at least fivefold decreased in vitro susceptibility were classified as resistant. Overall, 9 of 41 patients (22%) had at least one spike codon mutation that confers reduced susceptibility to the antispike mAb used for treatment. Specifically, 9 of 12 patients who received sotrovimab had S371L mutation that was predicted to confer a 9.7‐fold reduced susceptibility. However, among 22 patients who required hospitalization, 5 had virus with resistance mutation. In contrast, among 19 control patients who did not require hospitalization, 4 also had virus‐containing resistance mutations (p > 0.99). In conclusion, spike codon mutations were common, though mutations that conferred a 9.7‐fold reduced susceptibility did not predict subsequent hospitalization after treatment with antispike mAb.

AbstractIn this phase 1/2 study, carfilzomib was added to high‐dose melphalan conditioning prior to autologous stem cell transplantation (ASCT) in patients with multiple myeloma that had been treated with ≤2 prior lines of therapy. Carfilzomib was escalated at doses of 27, 36, 45, and 56 mg/m2 on days −6, −5, −2, and −1 before ASCT in the phase 1 component of the study. In addition, all the patients received melphalan 100 mg/m2 on days −4 and −3. The primary endpoint of the phase 1 component was to identify the maximum tolerated dose, and the primary endpoint of the phase 2 component was the rates of complete response (≥CR) at 1 year after ASCT. The phase 1 dose escalation cohort included 14 patients, and 35 patients were included in the phase 2 cohort. The maximum tested dose was 56 mg/m2 (MTD). The median time from diagnosis to study enrollment was 5.8 (range 3.4–88.4) months, and 16% of patients had obtained a ≥CR prior to ASCT. The best response within 1 year after ASCT was a ≥ CR rate in 22% for the entire cohort, and 22% for patients treated at the MTD. The ≥VGPR rates improved from 41% before ASCT to 77% by 1 year after ASCT. One patient had a grade 3 renal adverse event, and renal function returned to baseline with supportive care. The rate of grade 3–4 cardiovascular toxicity was 16%. The addition of carfilzomib to melphalan conditioning was safe and resulted in deep responses after ASCT.

Objective: We sought to evaluate symptomatic adverse event (AE) rates among patients with pancreatic cancer receiving neoadjuvant therapy on clinical trial (A021501) using the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). Background: To date, pancreatic cancer clinical trials have measured AEs using standard physician reporting [Common Terminology Criteria for Adverse Events (CTCAE)]. Patient-reported symptomatic AEs have been incompletely characterized. Methods: A021501 (December 31, 2016–January 1, 2019) randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX+hypofractionated radiotherapy (Arm 2), followed by pancreatectomy and adjuvant FOLFOX6. Patients completed PRO-CTCAE assessments at baseline, on day 1 of each chemotherapy cycle, and daily during radiotherapy. Results: Of 126 patients, 96 (76%) initiated treatment and completed a baseline plus at least 1 postbaseline PRO-CTCAE assessment. Diarrhea and fatigue were the only symptomatic grade 3 or higher AEs identified in at least 10% of patients using CTCAE. At least 10% of all patients reported an adjusted PRO-CTCAE composite grade 3 AE during neoadjuvant treatment for 10 of 15 items: anxiety (10%), bloating of abdomen (16%), decreased appetite (18%), diarrhea (13%), dry mouth (21%), fatigue (36%), nausea (18%), generalized pain (16%), abdominal pain (21%), and problems tasting (32%). Decreased appetite was higher in Arm 2 than in Arm 1 (P=0.0497); no other differences between study arms were observed. Conclusion: Symptomatic AEs during neoadjuvant therapy were common and were reported more frequently by patients using PRO-CTCAE than were recorded by clinicians using standard CTCAE.

Introduction: Acrocyanosis and erythema pernio are 2 dermatologic manifestations of vasospastic changes. Primary care providers should consider that these conditions can occur as primary or idiopathic conditions and as secondary conditions related to another disease or medication. Herein we describe a case of acrocyanosis and erythema pernio attributed to vincristine therapy. Case Description: A 22-year-old man was evaluated for discomfort and red lesions involving the toes of both feet for several weeks. He had completed chemotherapy 1 month earlier for Ewing sarcoma in the right femur. Local control for the primary tumor included wide local excision and reconstruction with a vascularized fibular allograft from the right fibula. On examination, his right foot was dark blue and cool. Toes on both feet had nonpainful erythematous papules. After the case was discussed with the patient’s oncology team, the diagnosis was medication-induced acrocyanosis of the right foot and bilateral erythema pernio. Treatment consisted of supportive care to keep the feet warm and promote circulation to the feet. At 2-week follow-up, the patient’s symptoms and the appearance of his feet had markedly improved. Discussion: Primary care clinicians should be able to recognize dermatologic manifestations of vasospastic changes, including acrocyanosis and erythema pernio, and rule out possible secondary causes, such as pharmacologic agents. This patient’s history of therapy for Ewing sarcoma prompted consideration of medication-induced vasospastic changes most likely related to the adverse vasospastic effects of vincristine. Symptoms should improve with cessation of the offending medication.

Maximal aerobic exercise capacity [maximal oxygen consumption (V̇o 2max )] is one of the strongest predictors of morbidity and mortality. Aerobic exercise training can increase V̇o 2max , but inter-individual variability is marked and unexplained physiologically. The mechanisms underlying this variability have major clinical implications for extending human healthspan. Here, we report a novel transcriptome signature related to ΔV̇o 2max with exercise training detected in whole blood RNA. We used RNA-Seq to characterize transcriptomic signatures of ΔV̇o 2max in healthy women who completed a 16-wk randomized controlled trial comparing supervised, higher versus lower aerobic exercise training volume and intensity (4 training groups, fully crossed). We found significant baseline gene expression differences in subjects who responded to aerobic exercise training with robust versus little/no ΔV̇o 2max , and differentially expressed genes/transcripts were mostly related to inflammatory signaling and mitochondrial function/protein translation. Baseline gene expression signatures associated with robust versus little/no ΔV̇o 2max were also modulated by exercise training in a dose-dependent manner, and they predicted ΔV̇o 2max in this and a separate dataset. Collectively, our data demonstrate the potential utility of using whole blood transcriptomics to study the biology of inter-individual variability in responsiveness to the same exercise training stimulus.

AbstractDespite the known benefits of supportive work environments for promoting patient quality and safety and healthcare worker retention, there is no clear mandate for improving work environments within Learning Health Systems (LHS) nor an LHS wellness competency. Striking rises in burnout levels among healthcare workers provide urgency for this topic.MethodsWe brought three experts on moral injury, burnout prevention, and ethics to a recurring, interactive LHS training program “Design Shop” session, harnessing scholars’ ideas prior to the meeting. Generally following SQUIRE 2.0 guidelines, we evaluated the prework and discussion via informal content analysis to develop a set of pathways for developing moral injury and burnout prevention programs. Along these lines, we developed a new competency for moral injury and burnout prevention within LHS training programs.ResultsIn preparation for the session, scholars differentiated moral injury from burnout, highlighted the profound impact of COVID‐19 on moral injury, and proposed testable interventions to reduce injury. Scholar and expert input was then merged into developing the new competency in moral injury and burnout prevention. In particular, the competency focuses on preparing scholars to (1) demonstrate knowledge of moral injury and burnout, (2) measure burnout, moral injury, and their remediable predictors, (3) use methods for improving burnout, (4) structure training programs with supportive work environments, and (5) embed burnout and moral injury prevention into LHS structures.ConclusionsBurnout and moral injury prevention have been largely omitted in LHS training. A competency related to burnout and moral injury reduction can potentially bring sustainable work lives for scholars and their colleagues, better incorporation of their science into clinical practice, and better outcomes for patients.