Benefits of an expanded use of plasma exchange for anti-neutrophil cytoplasmic antibody-associated vasculitis within a dedicated clinical service.

BACKGROUND: Current recommendations for ANCA-associated vasculitis (AAV) support its management within a dedicated clinical service. Therapies for AAV are imperfect with many patients failing to achieve disease control and others experiencing disease relapse. Plasma exchange (PEX) may be beneficial especially when the kidney is involved. METHODS: Within a new, dedicated service we retrospectively assessed, over a 6-year period, the benefits of PEX in two patient cohorts, discriminated by PEX treatment alone. Patients received PEX alongside standard of care if they fulfilled any of the following criteria: 1. serum creatinine >500 µmol/l or dialysis-requiring renal failure, 2. alveolar haemorrhage, 3. renal biopsy showing ≥30 % focal and necrotising lesions ± cellular crescents. Outcome measures included disease remission and relapse, cumulative immunosuppression, and morbidity and mortality. RESULTS: Of 104 new patients, 58 patients received PEX at presentation, 46 did not. Cyclophosphamide and/or rituximab dosing was similar for both groups. Although patients receiving PEX had poorer renal function, a higher C-reactive protein and disease activity score at presentation disease remission rate was similar in both groups (no PEX vs. PEX: 96 % vs. 98 %). The PEX group entered remission quicker (no PEX vs. PEX: 3.9 ± 4.0 vs. 2.8 ± 1.3 months, p < 0.05), with a lower 3-month cumulative glucocorticoid dose (no PEX vs. PEX: 2.5 ± 0.4 vs. 2.3 ± 0.2 g, p < 0.001). Relapse was similar between groups but adverse events lower in the PEX group. CONCLUSIONS: PEX may be of benefit in AAV. Larger, longer randomised controlled trials are now needed.

A narrative synthesis of the effectiveness and acceptability of musculoskeletal first contact physiotherapy practitioner roles in primary care.

BACKGROUND: Musculoskeletal (MSK) First Contact Practitioners (FCP), diagnostic clinicians with expertise in the assessment and management of undifferentiated MSK conditions in primary care have been widely employed in the United Kingdom since 2020. The role aims to bring specialist clinical knowledge to patients at the first point of contact and reduce the burden on existing primary care services. Since the national adoption of the role, little has been published to support the effectiveness or acceptability of the role. This narrative synthesis review aims to highlight and summarise the current body of evidence. METHODOLOGY: An adapted systematic review was carried out to inform thematic reporting and narrative synthesis, under the sub-themes of clinical outcomes, patient satisfaction, acceptability and cost analysis. RESULTS: Eight publications were included in the review, reporting improvements in clinical outcomes in patients seen by MSK FCP, patient satisfaction and general acceptability of the role. However, all data were collected from observational studies and qualitative sources, some of which were found to be of low methodological quality. CONCLUSION: Although the review identified consistent positivity relating to effectiveness, satisfaction and acceptability across the reviewed publications, conclusions are limited due to the relatively recent introduction of the FCP role leading to limited availability of relevant publications.

Incidence of Pediatric Urinary Tract Infections Before and During the COVID-19 Pandemic.

IMPORTANCE: Urinary tract infection (UTI) is common in children, but the population incidence is largely unknown. Controversy surrounds the optimal diagnostic criteria and how to balance the risks of undertreatment and overtreatment. Changes in health care use during the COVID-19 pandemic created a natural experiment to examine health care use and UTI diagnosis and outcomes. OBJECTIVES: To examine the population incidence of UTI in children and assess the changes of the COVID-19 pandemic regarding UTI diagnoses and measures of UTI severity. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational cohort study used US commercial claims data from privately insured patients aged 0 to 17 years from January 1, 2016, to December 31, 2021. EXPOSURE: Time periods included prepandemic (January 1, 2016, to February 29, 2020), early pandemic (April 1 to June 30, 2020), and midpandemic (July 1, 2020, to December 31, 2021). MAIN OUTCOMES AND MEASURES: The primary outcome was the incidence of UTI, defined as having a UTI diagnosis code with an accompanying antibiotic prescription. Balancing measures included measures of UTI severity, including hospitalizations and intensive care unit admissions. Trends were evaluated using an interrupted time-series analysis. RESULTS: The cohort included 13 221 117 enrollees aged 0 to 17 years, with males representing 6 744 250 (51.0%) of the population. The mean incidence of UTI diagnoses was 1.300 (95% CI, 1.296-1.304) UTIs per 100 patient-years. The UTI incidence was 0.86 per 100 patient-years at age 0 to 1 year, 1.58 per 100 patient-years at 2 to 5 years, 1.24 per 100 patient-years at 6 to 11 years, and 1.37 per 100 patient-years at 12 to 17 years, and was higher in females vs males (2.48 [95% CI, 2.46-2.50] vs 0.180 [95% CI, 0.178-0.182] per 100 patient-years). Compared with prepandemic trends, UTIs decreased in the early pandemic: -33.1% (95% CI, -39.4% to -26.1%) for all children and -52.1% (95% CI, -62.1% to -39.5%) in a subgroup of infants aged 60 days or younger. However, all measures of UTI severity decreased or were not significantly different. The UTI incidence returned to near prepandemic rates (-4.3%; 95% CI, -32.0% to 34.6% for all children) after the first 3 months of the pandemic. CONCLUSIONS AND RELEVANCE: In this cohort study, UTI diagnosis decreased during the early pandemic period without an increase in measures of disease severity, suggesting that reduced overdiagnosis and/or reduced misdiagnosis may be an explanatory factor.

Phase 2 Trial of the Farnesyltransferase Inhibitor Tipifarnib for Relapsed/Refractory Peripheral T Cell Lymphoma.

A phase 2, international, open-label, non-randomized, single-arm trial was conducted to evaluate the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, as monotherapy for relapsed/refractory peripheral T-cell lymphoma (PTCL) and to evaluate tumor mutation profile as a biomarker of response. Adults with relapsed/refractory PTCL received tipifarnib 300 mg orally twice daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR); secondary endpoints included ORR, progression-free survival (PFS), duration of response (DOR), and adverse events (AEs) in specific subtypes. Sixty-five patients with PTCL were enrolled: n=38 angioimmunoblastic T-cell lymphoma (AITL), n=25 PTCL not otherwise specified (PTCL-NOS), and n=2 other T-cell lymphomas. The ORR was 39.7% (95% CI, 28.1-52.5) in all patients and 56.3% (95% CI, 39.3-71.8) for AITL. Median PFS was 3.5 months overall (954% CI, 2.1-4.4), and 3.6 months (95% CI, 1.9-8.3) for AITL. Median DOR was 3.7 months (95% CI, 2.0-15.3), and greatest in AITL patients (7.8 months; 95% CI, 2.0-16.3). The median overall survival was 32.8 months (95% CI, 14.4 to not applicable). Tipifarnib-related hematologic AEs were manageable and included: neutropenia (43.1%), thrombocytopenia (36.9%), and anemia (30.8%); other tipifarnib-related AEs included nausea (29.2%) and diarrhea (27.7%). One treatment-related death occurred. Mutations in RhoA, DNMT3A, and IDH2 were seen in 60%, 33%, and 27%, respectively, in the AITL tipifarnib responder group vs 36%, 9%, and 9% in the non-responder group. Tipifarnib monotherapy demonstrated encouraging clinical activity in heavily pre-treated relapsed/refractory PTCL, especially in AITL, with a manageable safety profile. ClinicalTrials.gov NCT02464228.

Setup Uncertainty of Pediatric Brain Tumor Patients Receiving Proton Therapy: A Prospective Study.

This study quantifies setup uncertainty in brain tumor patients who received image-guided proton therapy. Patients analyzed include 165 children, adolescents, and young adults (median age at radiotherapy: 9 years (range: 10 months to 24 years); 80 anesthetized and 85 awake) enrolled in a single-institution prospective study from 2020 to 2023. Cone-beam computed tomography (CBCT) was performed daily to calculate and correct manual setup errors, once per course after setup correction to measure residual errors, and weekly after treatments to assess intrafractional motion. Orthogonal radiographs were acquired consecutively with CBCT for paired comparisons of 40 patients. Translational and rotational errors were converted from 6 degrees of freedom to a scalar by a statistical approach that considers the distance from the target to the isocenter. The 95th percentile of setup uncertainty was reduced by daily CBCT from 10 mm (manual positioning) to 1-1.5 mm (after correction) and increased to 2 mm by the end of fractional treatment. A larger variation existed between the roll corrections reported by radiographs vs. CBCT than for pitch and yaw, while there was no statistically significant difference in translational variation. A quantile mixed regression model showed that the 95th percentile of intrafractional motion was 0.40 mm lower for anesthetized patients (p=0.0016). Considering additional uncertainty in radiation-imaging isocentricity, the commonly used total plan robustness of 3 mm against positional uncertainty would be appropriate for our study cohort.

Tipifarnib Potentiates the Antitumor Effects of PI3Kα Inhibition in PIK3CA- and HRAS-Dysregulated HNSCC via Convergent Inhibition of mTOR Activity.

Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor regression in vivo. On the basis of these findings, the KURRENT-HN trial was launched to evaluate the effectiveness of this combination in PIK3CA-mutant/amplified and/or HRAS-overexpressing R/M HNSCC. Preliminary evidence supports the clinical activity of this molecular biomarker-driven combination therapy. Combined alpelisib and tipifarnib has potential to benefit >45% of patients with R/M HNSCC. By blocking feedback reactivation of mTORC1, tipifarnib may prevent adaptive resistance to additional targeted therapies, enhancing their clinical utility. SIGNIFICANCE: The mechanistically designed, biomarker-matched strategy of combining alpelisib and tipifarnib is efficacious in PIK3CA- and HRAS-dysregulated head and neck squamous carcinoma and could improve outcomes for many patients with recurrent, metastatic disease. See related commentary by Lee et al., p. 3162.

Examining the Effect of the First Wave of the COVID-19 Pandemic on Home Care Recipients' Instrumental Activities of Daily Living Capacity.

OBJECTIVE: To examine the effect of the pandemic on, and factors associated with, change in home care (HC) recipients' capacity for instrumental activities of daily living. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: HC recipients in Ontario, Canada, between September 1, 2018, and August 31, 2020, who were not totally dependent on others and not severely cognitively impaired at baseline. METHODS: Data were collected with the interRAI Home Care assessment. Outcomes of interest were declines in instrumental activities of daily living. Factors hypothesized to be associated with declining function were entered as independent variables into multivariable generalized estimating equations, and results were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Those significant at P < .01 were retained in the final models. RESULTS: There were 6786 and 5019 HC recipients in the comparison and pandemic samples, respectively. Between baseline and follow-up for the 2 groups, 34.1% and 42.1% of HC recipients declined in shopping, whereas 25.2% and 30.5% declined in transportation capacity in the comparison and pandemic sample, respectively. For shopping, those with cognitive impairment (OR 0.83, 95% CI 0.76-0.89) and receiving formal care (OR 0.72, 95% CI 0.62-0.85) were less likely to decline, whereas those who were older (OR 1.91, 95% CI 1.69-2.16) and had unstable health (OR 1.31, 95% CI 1.16-1.48) were more likely. For transportation, those receiving informal (OR 0.71, 95% CI 0.61-0.81) or formal care (OR 0.56, 95% CI 0.47-0.67) were less likely to decline, whereas those who were older (OR 1.81, 95% CI 1.58-2.07) and had unstable health (OR 1.35, 95% CI 1.119-1.54) were more likely. CONCLUSIONS AND IMPLICATIONS: The pandemic was associated with a decline in HC recipients' capacity for shopping and transportation. HC recipients who are older and have unstable health may benefit from preventive strategies.

Safety, Antitumor Activity, and T-cell Responses in a Dose-Ranging Phase I Trial of the Oncolytic Peptide LTX-315 in Patients with Solid Tumors.

PURPOSE: LTX-315 is a first-in-class, 9-mer membranolytic peptide that has shown potent immunomodulatory properties in preclinical models. We conducted a phase I dose-escalating study of intratumoral LTX-315 administration in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-nine patients were enrolled, receiving LTX-315 injections into accessible tumors. The primary objective was to assess the safety and tolerability of this approach, with antitumor and immunomodulatory activity as secondary objectives. Tumor biopsies were collected at baseline and posttreatment for analysis of immunologic parameters. RESULTS: The most common treatment-related grade 1-2 adverse events were vascular disorders including transient hypotension (18 patients, 46%), flushing (11 patients, 28%), and injection site reactions in 38% of patients. The most common grade 3 LTX-315-related toxicities were hypersensitivity or anaphylaxis (4 patients, 10%). Analysis of immune endpoints in serial biopsies indicated that LTX-315 induces necrosis and CD8+ T-cell infiltration into the tumor microenvironment. Sequencing of the T-cell receptor repertoire in peripheral blood identified significant expansion of T-cell clones after treatment, of which 49% were present in available tumor biopsies after treatment, suggesting that they were tumor associated. Substantial volume reduction (≥30%) of injected tumors occurred in 29% of the patients, and 86% (12/14 biopsies) had an increase in intralesional CD8+ T cells posttreatment. No partial responses by immune-related response criteria were seen, but evidence of abscopal effect was demonstrated following treatment with LTX-315. CONCLUSIONS: LTX-315 has an acceptable safety profile, is clinically active, induces changes in the tumor microenvironment and contributes to immune-mediated anticancer activity.

Impaired intestinal iron absorption in Crohn's disease correlates with disease activity and markers of inflammation.

BACKGROUND: Anemia in patients with Crohn's disease (CD) is a common problem of multifactorial origin, including blood loss, malabsorption of iron, and anemia of inflammation. Anemia of inflammation is caused by the effects of inflammatory cytokines [predominantly interleukin-6 (IL-6)] on iron transport in enterocytes and macrophages. We sought to elucidate alterations in iron absorption in pediatric patients with active and inactive CD. METHODS: Nineteen subjects with CD (8 female, 11 male patients) were recruited between April 2003 and June 2004. After an overnight fast, serum iron and hemoglobin levels, serum markers of inflammation [IL-6, C-reactive protein (CRP), and erythrocyte sedimentation rate], and a urine sample for hepcidin assay were obtained at 8 am. Ferrous sulfate (1 mg/kg) was administered orally, followed by determination of serum iron concentrations hourly for 4 hours after the ingestion of iron. An area under the curve for iron absorption was calculated for each patient data set. RESULTS: There was a strong inverse correlation between the area under the curve and IL-6 (P = 0.002) and area under the curve and CRP levels (P = 0.04). Similarly, the difference between baseline and 2-hour serum iron level (Delta[Fe]2hr) correlated with IL-6 (P = 0.008) and CRP (P = 0.045). When cutoff values for IL-6 (>5 pg/mL) and CRP (>1.0 mg/dL) were used, urine hepcidin levels also positively correlated with IL-6 and CRP levels (P = 0.003 and 0.007, respectively). CONCLUSIONS: Subjects with active CD have impaired oral iron absorption and elevated IL-6 levels compared with subjects with inactive disease. These findings suggest that oral iron may be of limited benefit to these patients. Future study is needed to define the molecular basis for impaired iron absorption.

Diagnosis and treatment of tuberculosis among children at an HIV care program in Dar es Salaam, Tanzania.

Diagnosis and treatment of tuberculosis is challenging in children with human immunodeficiency virus (HIV) infection. We describe the clinical features, diagnostic testing results, tuberculosis and HIV treatment and clinical outcomes of 57 HIV-infected children diagnosed with tuberculosis at the DarDar Pediatric Program in Dar es Salaam, Tanzania. In this cohort, tuberculosis was common, microbiologic studies were frequently negative and mortality was high.

Fibrolipomas masquerading as abdominal hernias.

A 15-year-old Caucasian girl presented to her general practitioner with a tender, irreducible mass in the paraumbilical region. On examination, two small masses could be felt. She was referred to general surgery. Ultrasound imaging and MRI were unremarkable. However, clinical suspicion suggested multiple areas of abdominal wall herniation. The patient was admitted for elective surgery to exclude herniation. At operation, three subcutaneous masses were found but with no evidence of abdominal wall herniation. Histopathology results from the specimens showed mature adipose tissue mixed with fibrous deposits. There was no evidence of malignancy. A diagnosis of fibrolipoma was given.

Acadesine for patients with relapsed/refractory chronic lymphocytic leukemia (CLL): a multicenter phase I/II study.

PURPOSE: Acadesine has shown in vitro to selectively induce apoptosis in B cells from chronic lymphocytic leukemia (CLL) patients. We conducted a phase I/II open-label clinical study, to determine the safety and tolerability of acadesine given intravenously as a 4-h infusion to CLL patients. METHODS: Patient population included CLL patients with relapsed/refractory disease who had received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. Twenty-four patients were included: eighteen in Part I treated at single doses of 50-315 mg/kg, and six in Part II, three with two doses at 210 mg/kg and three with five doses at 210 mg/kg. RESULTS: A manageable and predictable safety profile was demonstrated for acadesine at single doses between 50 and 210 mg/kg; 210 mg/kg was the maximum tolerated dose (MTD) and optimal biological dose (OBD). Grade ≥2 hyperuricemia occurred commonly but was not clinically significant and resolved with the administration of prophylactic allopurinol. Other adverse events included transient anemia and/or thrombocytopenia (not clinically significant), renal impairment, and transient infusion-related hypotension (clinically significant). Trends of efficacy such as a reduction of peripheral CLL cells and reduction in lymphadenopathy were observed; however, the results were variable due to the small population and the range of doses tested. CONCLUSIONS: A MTD of 210 mg/kg was established with single acadesine dose. Multiple dose administrations at the OBD were tested with an acceptable safety profile, showing that acadesine might be a valuable agent for the treatment of relapsed/refractory CLL patients.

Substituent dependence of the reactions of [RuCl2(PPh3)3] with bulky aromatic thiols.

2,4,6-trialkylbenzenethiols react with [RuCl2(PPh3)3] to give Ru products with the alkyl substituents forming M-C sigma bonds, carbene, carbene with a S alpha-heteroatom, agostic hydrogen interaction or a simple tetrahedral Ru(II) species, depending on the substituent.

Hepatic glycogen synthase deficiency: an infrequently recognized cause of ketotic hypoglycemia.

The glycogen storage diseases comprise several inherited diseases caused by abnormalities of enzymes that regulate the synthesis or degradation of glycogen. In contrast to the classic hepatic glycogen storage diseases that are characterized by fasting hypoglycemia and hepatomegaly, the liver is not enlarged in GSD0. Patients with GSD0 typically have fasting ketotic hypoglycemia without prominent muscle symptoms. Most children are cognitively and developmentally normal. Short stature and osteopenia are common features, but other long-term complications, common in other types of GSD, have not been reported in GSD0. Until recently, the definitive diagnosis of GSD0 depended on the demonstration of decreased hepatic glycogen on a liver biopsy. The need for an invasive procedure may be one reason that this condition has been infrequently diagnosed. Mutation analysis of the GYS2 gene (12p12.2) is a non-invasive method for making this diagnosis in patients suspected to have this disorder. This mini-review discusses the pathophysiology of this disorder, use of mutation analysis to diagnose GSD0, and the clinical characteristics of all reported cases of GSD0.

40Ar/39Ar dates from the West Siberian Basin: Siberian flood basalt province doubled.

Widespread basaltic volcanism occurred in the region of the West Siberian Basin in central Russia during Permo-Triassic times. New 40Ar/39Ar age determinations on plagioclase grains from deep boreholes in the basin reveal that the basalts were erupted 249.4 +/- 0.5 million years ago. This is synchronous with the bulk of the Siberian Traps, erupted further east on the Siberian Platform. The age and geochemical data confirm that the West Siberian Basin basalts are part of the Siberian Traps and at least double the confirmed area of the volcanic province as a whole. The larger area of volcanism strengthens the link between the volcanism and the end-Permian mass extinction.