Effectiveness of 13-valent pneumococcal conjugate vaccine for prevention of invasive pneumococcal disease among children in the United States between 2010 and 2019: An indirect cohort study.

BACKGROUND: A U.S. case-control study (2010-2014) demonstrated vaccine effectiveness (VE) for ≥ 1 dose of the thirteen-valent pneumococcal conjugate vaccine (PCV13) against vaccine-type (VT) invasive pneumococcal disease (IPD) at 86 %; however, it lacked statistical power to examine VE by number of doses and against individual serotypes. METHODS: We used the indirect cohort method to estimate PCV13 VE against VT-IPD among children aged < 5 years in the United States from May 1, 2010 through December 31, 2019 using cases from CDC's Active Bacterial Core surveillance, including cases enrolled in a matched case-control study (2010-2014). Cases and controls were defined as individuals with VT-IPD and non-PCV13-type-IPD (NVT-IPD), respectively. We estimated absolute VE using the adjusted odds ratio of prior PCV13 receipt (1-aOR x 100 %). RESULTS: Among 1,161 IPD cases, 223 (19.2 %) were VT cases and 938 (80.8 %) were NVT controls. Of those, 108 cases (48.4 %; 108/223) and 600 controls (64.0 %; 600/938) had received > 3 PCV13 doses; 23 cases (17.6 %) and 15 controls (2.4 %) had received no PCV doses. VE ≥ 3 PCV13 doses against VT-IPD was 90.2 % (95 % Confidence Interval75.4-96.1 %), respectively. Among the most commonly circulating VT-IPD serotypes, VE of ≥ 3 PCV13 doses was 86.8 % (73.7-93.3 %), 50.2 % (28.4-80.5 %), and 93.8 % (69.8-98.8 %) against serotypes 19A, 3, and 19F, respectively. CONCLUSIONS: At least three doses of PCV13 continue to be effective in preventing VT-IPD among children aged < 5 years in the US. PCV13 was protective against serotypes 19A and 19F IPD; protection against serotype 3 IPD did not reach statistical significance.

International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world. Here, we provide expert consensus clinical practice guidelines for the use of bispecific antibodies for the treatment of myeloma. The International Myeloma Working Group is also involved in the collection of prospective real-time data of patients treated with such immunotherapies, with the aim of learning continuously and adapting clinical practices to optimise the management of patients receiving immunotherapies.

D-TERMINED, a phase 1 trial in newly diagnosed high-grade glioma with temozolomide, radiation, and minocycline followed by adjuvant minocycline/temozolomide.

Background: Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas. Methods: Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry. Results: The MTD of minocycline was 150 mg twice per day (N = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1. Conclusions: Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.

Human IL-6 fosters long-term engraftment of patient-derived disease-driving myeloma cells in immunodeficient mice.

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned human IL-6-transgenic (hIL-6-transgenic) NSG (NSG+hIL6) mice reliably support the engraftment of malignant and premalignant human plasma cells, including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and postrelapse myeloma, plasma cell leukemia, and amyloid light chain amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single-cell RNA sequencing showed nonmalignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma-engrafted mice given CAR T cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient-derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

Paraproteinemic neuropathies.

The diagnostic evaluation of a peripheral neuropathy includes testing for the presence of monoclonal gammopathy, which can be found in about 10% of patients with peripheral neuropathy. Our role, as physicians, is to determine whether the neuropathy is directly related to the gammopathy or whether the co-occurrence of these two disorders is purely coincidental. The evaluating physician needs to be familiar with the different types of neuropathies associated with monoclonal gammopathies, their clinical and electrodiagnostic characteristics, and their appropriate diagnostic evaluation and management. Testing for monoclonal protein disorders includes serum protein electrophoresis (SPEP) and immunofixation of blood, and in some cases of urine, as well as measurement of free light chains and quantitative immunoglobulins. Specific antibody testing is directed by paraprotein type and neuropathy phenotype. Patients with abnormal free light chains in association with sensory and autonomic neuropathy should be evaluated for AL amyloidosis. When a lambda monoclonal protein is identified together with a clinical phenotype of chronic inflammatory demyelinating neuropathy (CIDP), a diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome should be considered. Patients with IgM paraprotein associated neuropathy should be assessed for distal acquired demyelinating sensorimotor (DADS) neuropathy, with or without anti myelin associated glycoprotein (MAG) antibody or CANOMAD syndrome. In many cases, a monoclonal gammopathy of uncertain significance (MGUS) is incidental and unrelated to the neuropathy. Collaboration with oncology is critical in evaluating patients with monoclonal proteins to assess for underlying plasma cell neoplasms or B cell lymphomas.

Ether lipids influence cancer cell fate by modulating iron uptake.

Cancer cell fate has been widely ascribed to mutational changes within protein-coding genes associated with tumor suppressors and oncogenes. In contrast, the mechanisms through which the biophysical properties of membrane lipids influence cancer cell survival, dedifferentiation and metastasis have received little scrutiny. Here, we report that cancer cells endowed with a high metastatic ability and cancer stem cell-like traits employ ether lipids to maintain low membrane tension and high membrane fluidity. Using genetic approaches and lipid reconstitution assays, we show that these ether lipid-regulated biophysical properties permit non-clathrin-mediated iron endocytosis via CD44, leading directly to significant increases in intracellular redox-active iron and enhanced ferroptosis susceptibility. Using a combination of in vitro three-dimensional microvascular network systems and in vivo animal models, we show that loss of ether lipids also strongly attenuates extravasation, metastatic burden and cancer stemness. These findings illuminate a mechanism whereby ether lipids in carcinoma cells serve as key regulators of malignant progression while conferring a unique vulnerability that can be exploited for therapeutic intervention.

Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators.

Microbial rhodopsin-derived genetically encoded voltage indicators (GEVIs) are powerful tools for mapping bioelectrical dynamics in cell culture and in live animals. Förster resonance energy transfer (FRET)-opsin GEVIs use voltage-dependent changes in opsin absorption to modulate the fluorescence of an attached fluorophore, achieving high brightness, speed, and voltage sensitivity. However, the voltage sensitivity of most FRET-opsin GEVIs has been reported to decrease or vanish under two-photon (2P) excitation. Here we investigated the photophysics of the FRET-opsin GEVIs Voltron1 and 2. We found that the voltage sensitivity came from a photocycle intermediate, not from the opsin ground state. The voltage sensitivities of both GEVIs were nonlinear functions of illumination intensity; for Voltron1, the sensitivity reversed sign under low-intensity illumination. Using photocycle-optimized 2P illumination protocols, we demonstrate 2P voltage imaging with Voltron2 in barrel cortex of a live mouse. These results open the door to high-speed 2P voltage imaging of FRET-opsin GEVIs in vivo.

Practical Aspects of Immunotherapy: A Report from the 20th International Myeloma Society (IMS) Annual Meeting.

Immunotherapeutic strategies, specifically T-cell-redirected therapies, have been transformative in the context of multiple myeloma (MM). With the approval of two chimeric antigen receptor T-cell (CAR-T) drug products and three bispecific antibodies/T-cell engagers (bsAbs/TCEs) in relapsed/refractory MM (RRMM), the 20th annual IMS meeting dedicated a session to the practical aspects of these therapies. Here, we highlight the discussion during this session, including the role of CAR-T and bsAb therapies in frontline MM treatment, management of acute toxicities, prevention and management of infections, and finally treatment sequencing of T-cell redirected therapies.

Optogenetic control of Nodal signaling patterns.

A crucial step in early embryogenesis is the establishment of spatial patterns of signaling activity. Tools to perturb morphogen signals with high resolution in space and time can help reveal how embryonic cells decode these signals to make appropriate fate decisions. Here, we present new optogenetic reagents and an experimental pipeline for creaHng designer Nodal signaling patterns in live zebrafish embryos. Nodal receptors were fused to the light-sensitive heterodimerizing pair Cry2/CIB1N, and the Type II receptor was sequestered to the cytosol. The improved optoNodal2 reagents eliminate dark activity and improve response kinetics, without sacrificing dynamic range. We adapted an ultra-widefield microscopy platform for parallel light patterning in up to 36 embryos and demonstrated precise spatial control over Nodal signaling activity and downstream gene expression. Patterned Nodal activation drove precisely controlled internalization of endodermal precursors. Further, we used patterned illumination to generate synthetic signaling patterns in Nodal signaling mutants, rescuing several characteristic developmental defects. This study establishes an experimental toolkit for systematic exploration of Nodal signaling patterns in live embryos.

Bladder Stones in Renal Transplant Patients: Presentation, Management, and Follow-up.

INTRODUCTION: The study aim was to analyze the presentation, management, and follow-up of renal transplant patients developing bladder calculi. METHODS: Patients who underwent renal transplant with postoperative follow-up at our institution were retrospectively analyzed (1984-2023) to assess for the development of post-transplant bladder stones. All bladder stones were identified by computerized tomography (CT) imaging and stone size was measured using this imaging modality. RESULTS: The prevalence of bladder calculi post-renal transplantation during the study window was 0.22% (N=20/8835) with a median time to bladder stone diagnosis of 13 years post-transplant. Of all bladder stone patients, 6 (30%) received deceased donor and 14 (70%) living donor transplants. There were 11 patients with known bladder stone composition available; the most common being calcium oxalate (N=6). Eleven (55%) patients had clinical signs or symptoms (most commonly microhematuria). Fourteen of the bladder stone cohort patients (70%) underwent treatment including cystolitholapaxy in 12 subjects. Of these 14 patients, 9 (64%) were found to have non-absorbable suture used for their ureteroneocystotomy closure. CONCLUSIONS: The prevalence of bladder stones post-renal transplant is low. The utilization of non-absorbable suture for ureteral implantation was the main risk factor identified in our series. This technique is no longer used at our institution. Other factors contributing to bladder stone formation in this population warrant identification.

Outpatient visits and antibiotic use due to higher valency pneumococcal vaccine serotypes.

BACKGROUND: In 2022-2023, 15- and 20-valent pneumococcal conjugate vaccines (PCV15/PCV20) were recommended for infants. We aimed to estimate the incidence of outpatient visits and antibiotic prescriptions in U.S. children (≤17 years) from 2016-2019 for acute otitis media, pneumonia, and sinusitis associated with PCV15- and PCV20-additional (non-PCV13) serotypes to quantify PCV15/20 potential impacts. METHODS: We estimated the incidence of PCV15/20-additional serotype-attributable visits and antibiotic prescriptions as the product of all-cause incidence rates, derived from national healthcare surveys and MarketScan databases, and PCV15/20-additional serotype-attributable fractions. We estimated serotype-specific attributable fractions using modified vaccine-probe approaches incorporating incidence changes post-PCV13 and ratios of PCV13 versus PCV15/20 serotype frequencies, estimated through meta-analyses. RESULTS: Per 1000 children annually, PCV15-additional serotypes accounted for an estimated 2.7 (95% confidence interval 1.8-3.9) visits and 2.4 (1.6-3.4) antibiotic prescriptions. PCV20-additional serotypes resulted in 15.0 (11.2-20.4) visits and 13.2 (9.9-18.0) antibiotic prescriptions annually per 1,000 children. PCV15/20-additional serotypes account for 0.4% (0.2-0.6%) and 2.1% (1.5-3.0%) of pediatric outpatient antibiotic use. CONCLUSIONS: Compared with PCV15-additional serotypes, PCV20-additional serotypes account for >5 times the burden of visits and antibiotic prescriptions. Higher-valency PCVs, especially PCV20, may contribute to preventing pediatric pneumococcal respiratory infections and antibiotic use.

Human hypoxia models in aerospace medicine: Potential applications for human pharmacological research.

Aerospace medicine required controlled terrestrial models to investigate influences of altered atmosphere conditions, such as hypoxia, on human health and performance. These models could potentially be expanded to encompass disease conditions or treatment targets regulated through hypoxia or hypercapnia. Hypoxia, a condition in which the body is deprived of adequate oxygen supply, profoundly affects human physiology at multiple levels and contributes to the pathogenesis of various diseases. Experimental exposure to hypoxic conditions has gained recognition as a model for studying diseases such as pulmonary hypertension, chronic obstructive pulmonary disease, obstructive sleep apnoea, migraine and kidney disease. This approach may be particularly useful in mechanism-oriented early-stage clinical studies. This review discusses the ability of hypoxia models from space medicine research to mimic or induce these conditions in a controlled laboratory setting as a tool for testing the efficacy and safety of new pharmaceutical interventions.

Deep learning approach for automated segmentation of myocardium using bone scintigraphy single-photon emission computed tomography/computed tomography in patients with suspected cardiac amyloidosis.

BACKGROUND: We employed deep learning to automatically detect myocardial bone-seeking uptake as a marker of transthyretin cardiac amyloid cardiomyopathy (ATTR-CM) in patients undergoing 99mTc-pyrophosphate (PYP) or hydroxydiphosphonate (HDP) single-photon emission computed tomography (SPECT)/computed tomography (CT). METHODS: We identified a primary cohort of 77 subjects at Brigham and Women's Hospital and a validation cohort of 93 consecutive patients imaged at the University of Pennsylvania who underwent SPECT/CT with PYP and HDP, respectively, for evaluation of ATTR-CM. Global heart regions of interest (ROIs) were traced on CT axial slices from the apex of the ventricle to the carina. Myocardial images were visually scored as grade 0 (no uptake), 1 (uptakeribs). A 2D U-net architecture was used to develop whole-heart segmentations for CT scans. Uptake was determined by calculating a heart-to-blood pool (HBP) ratio between the maximal counts value of the total heart region and the maximal counts value of the most superior ROI. RESULTS: Deep learning and ground truth segmentations were comparable (p=0.63). A total of 42 (55%) patients had abnormal myocardial uptake on visual assessment. Automated quantification of the mean HBP ratio in the primary cohort was 3.1±1.4 versus 1.4±0.2 (p<0.01) for patients with positive and negative cardiac uptake, respectively. The model had 100% accuracy in the primary cohort and 98% in the validation cohort. CONCLUSION: We have developed a highly accurate diagnostic tool for automatically segmenting and identifying myocardial uptake suggestive of ATTR-CM.

Mapping uterine calcium dynamics during the ovulatory cycle in live mice.

Uterine contraction patterns vary during the ovulatory cycle and throughout pregnancy but prior measurements have produced limited and conflicting information on these patterns. We combined a virally delivered genetically encoded calcium reporter (GCaMP8m) and ultra-widefield imaging in live nonpregnant mice to characterize uterine calcium dynamics at organ scale throughout the estrous cycle. Prior to ovulation (proestrus and estrus) uterine excitations primarily initiated in a region near the oviduct, but after ovulation (metestrus and diestrus), excitations initiated at loci homogeneously distributed throughout the organ. The frequency of excitation events was lowest in proestrus and estrus, higher in metestrus and highest in diestrus. These results establish a platform for mapping uterine activity, and show that the question of whether there is an anatomically localized trigger for uterine excitations depends on the estrous cycle phase.

Results From a Pilot Study of an Automated Directly Observed Therapy Intervention Using Artificial Intelligence With Conditional Economic Incentives Among Young Adults With HIV.

BACKGROUND: Despite improvements in antiretroviral therapy (ART) availability, suboptimal adherence is common among youth with HIV (YWH) and can increase drug resistance and poor clinical outcomes. Our study examined an innovative mobile app-based intervention that used automated directly observed therapy (aDOT) using artificial intelligence, along with conditional economic incentives (CEIs) to improve ART adherence and enhance viral suppression among YWH. SETTING: We conducted a pilot study of the aDOT-CEI intervention, informed by the operant framework of Key Principles in Contingency Management Implementation, to improve ART adherence among YWH (18-29) in California and Florida who had an unsuppressed HIV viral load. METHODS: We recruited 28 virally unsuppressed YWH from AIDS Healthcare Foundation clinics, who used the aDOT platform for 3 months. Study outcomes included feasibility and acceptability, self-reported ART adherence, and HIV viral load. RESULTS: Participants reported high satisfaction with the app (91%), and 82% said that it helped them take their medication. Comfort with the security and privacy of the app was moderate (55%), and 59% indicated the incentives helped improve daily adherence. CONCLUSIONS: Acceptability and feasibility of the aDOT-CEI intervention were high with potential to improve viral suppression, although some a priori metrics were not met. Pilot results suggest refinements which may improve intervention outcomes, including increased incentive amounts, provision of additional information, and reassurance about app privacy and security. Additional research is recommended to test the efficacy of the aDOT-CEI intervention to improve viral suppression in a larger sample.

Human IL-6 fosters long-term engraftment of patient derived disease-driving myeloma cells in immunodeficient mice.

Multiple myeloma is a largely incurable and life-threatening malignancy of antibody-secreting plasma cells. An effective and widely available animal model that recapitulates human myeloma and related plasma cell disorders is lacking. We show that busulfan-conditioned hIL-6 transgenic NSG mice (NSG+hIL6) reliably support the engraftment of malignant and pre-malignant human plasma cells including from patients diagnosed with monoclonal gammopathy of undetermined significance, pre- and post-relapse myeloma, plasma cell leukemia, and AL amyloidosis. Consistent with human disease, NSG+hIL6 mice engrafted with patient-derived myeloma cells, developed serum M spikes, and a majority developed anemia, hypercalcemia, and/or bone lesions. Single cell RNA sequencing showed non-malignant and malignant cell engraftment, the latter expressing a wide array of mRNAs associated with myeloma cell survival and proliferation. Myeloma engrafted mice given CAR T-cells targeting plasma cells or bortezomib experienced reduced tumor burden. Our results establish NSG+hIL6 mice as an effective patient derived xenograft model for study and preclinical drug development of multiple myeloma and related plasma cell disorders.

T cell lymphoma and secondary primary malignancy risk after commercial CAR T cell therapy.

We report a T cell lymphoma (TCL) occurring 3 months after anti-CD19 chimeric antigen receptor (CAR) T cell immunotherapy for non-Hodgkin B cell lymphoma. The TCL was diagnosed from a thoracic lymph node upon surgery for lung cancer. The TCL exhibited CD8+ cytotoxic phenotype and a JAK3 variant, while the CAR transgene was very low. The T cell clone was identified at low levels in the blood before CAR T infusion and in lung cancer. To assess the overall risk of secondary primary malignancy after commercial CAR T (CD19, BCMA), we analyzed 449 patients treated at the University of Pennsylvania. At a median follow-up of 10.3 months, 16 patients (3.6%) had a secondary primary malignancy. The median onset time was 26.4 and 9.7 months for solid and hematological malignancies, respectively. The projected 5-year cumulative incidence is 15.2% for solid and 2.3% for hematological malignancies. Overall, one case of TCL was observed, suggesting a low risk of TCL after CAR T.