Assessment of CD8+ T-cell mediated immunity in an influenza A(H3N2) human challenge model in Belgium: a single centre, randomised, double-blind phase 2 study.

BACKGROUND: Protection afforded by inactivated influenza vaccines can theoretically be improved by inducing T-cell responses to conserved internal influenza A antigens. We assessed whether, in an influenza controlled human infection challenge, susceptible individuals receiving a vaccine boosting T-cell responses would exhibit lower viral load and decreased symptoms compared with placebo recipients. METHODS: In this single centre, randomised, double-blind phase 2 study, healthy adult (aged 18-55 years) volunteers with microneutralisation titres of less than 20 to the influenza A(H3N2) challenge strain were enrolled at an SGS quarantine facility in Antwerp, Belgium. Participants were randomly assigned double-blind using a permuted-block list with a 3:2 allocation ratio to receive 0·5 mL intramuscular injections of modified vaccinia Ankara (MVA) expressing H3N2 nucleoprotein (NP) and matrix protein 1 (M1) at 1·5 × 108 plaque forming units (4·3 × 108 50% tissue culture infectious dose [TCID50]; MVA-NP+M1 group) or saline placebo (placebo group). At least 6 weeks later, participants were challenged intranasally with 0·5 mL of a 1 × 106 TCID50/mL dose of influenza A/Belgium/4217/2015 (H3N2). Nasal swabs were collected twice daily from day 2 until day 11 for viral PCR, and symptoms of influenza were recorded from day 2 until day 11. The primary outcome was to determine the efficacy of MVA-NP+M1 vaccine to reduce the degree of nasopharyngeal viral shedding as measured by the cumulative viral area under the curve using a log-transformed quantitative PCR. This study is registered with ClinicalTrials.gov, NCT03883113. FINDINGS: Between May 2 and Oct 24, 2019, 145 volunteers were enrolled and randomly assigned to the MVA-NP+M1 group (n=87) or the placebo group (n=58). Of these, 118 volunteers entered the challenge period (71 in the MVA-NP+M1 group and 47 in the placebo group) and 117 participants completed the study (71 in the MVA-NP+M1 group and 46 in the placebo group). 78 (54%) of the 145 volunteers were female and 67 (46%) were male. The primary outcome, overall viral load as determined by quantitative PCR, did not show a statistically significant difference between the MVA-NP+M1 (mean 649·7 [95% CI 552·7-746·7) and placebo groups (mean 726·1 [604·0-848·2]; p=0·17). All reported treatment emergent adverse events (TEAEs; 11 in the vaccination phase and 51 in the challenge phase) were grade 1 and 2, except for two grade 3 TEAEs in the placebo group in the challenge phase. A grade 4 second trimester fetal death, considered possibly related to the MVA-NP+M1 vaccination, and an acute psychosis reported in a placebo participant during the challenge phase were reported. INTERPRETATION: The use of an MVA vaccine to expand CD4+ or CD8+ T cells to conserved influenza A antigens in peripheral blood did not affect nasopharyngeal viral load in an influenza H3N2 challenge model in seronegative, healthy adults. FUNDING: Department of Health and Human Services; Administration for Strategic Preparedness and Response; Biomedical Advanced Research and Development Authority; and Barinthus Biotherapeutics.

Regional impact assessment of air quality improvement: The air quality lifecourse assessment tool (AQ-LAT) for the West Midlands combined authority (WMCA).

Poor air quality is the largest environmental health risk in England. In the West Midlands, UK, ∼2.9 million people are affected by air pollution with an average loss in life expectancy of up to 6 months. The 2021 Environment Act established a legal framework for local authorities in England to develop regional air quality plans, generating a policy need for predictive environmental impact assessment tools. In this context, we developed a novel Air Quality Lifecourse Assessment Tool (AQ-LAT) to estimate electoral ward-level impacts of PM2.5 and NO2 exposure on outcomes of interest to local authorities, namely morbidity (asthma, coronary heart disease (CHD), stroke, lung cancer), mortality, and associated healthcare costs. We apply the Tool to assess the health economic burden of air pollutant exposure and estimate benefits that would be generated by meeting WHO 2021 Global Air Quality Guidelines (AQGs) (annual average concentrations) for NO2 (10 µg/m3) and PM2.5 (5 µg/m3) in the West Midlands Combined Authority Area. All West Midlands residents live in areas which exceed WHO AQGs, with 2070 deaths, 2070 asthma diagnoses, 770 CHD diagnoses, 170 lung cancers and 650 strokes attributable to air pollution exposure annually. Reducing PM2.5 and NO2 concentrations to WHO AQGs would save 10,700 lives reducing regional mortality by 1.8%, gaining 92,000 quality-adjusted life years (QALYs), and preventing 20,500 asthma, 7400 CHD, 1400 lung cancer, and 5700 stroke diagnoses, with economic benefits of £3.2 billion over 20 years. Significantly, we estimate 30% of QALY gains relate to reduced disease burden. The AQ-LAT has major potential to be replicated across local authorities in England and applied to inform regional investment decisions.

Patient-initiated follow-up in gynaecology: Patient and clinician views.

OBJECTIVES: Follow-up appointments in the UK National Health Service account for up to two thirds of outpatient activity, but there is a significant resource impact in providing time fixed follow-up appointments. Increasingly patient initiated follow-up is being used, to make follow-up appointments work better for patients both in terms of timing and necessity, and to reduce unnecessary outpatient activity. The objective of this study was to use a modified questionnaire to evaluate patient and clinician views regarding Patient-Initiated Follow-Up (PIFU) in gynaecology services and identify subgroups suited to this pathway of care. STUDY DESIGN: Participants including both patients and clinicians were recruited from a gynaecology outpatient department. Patients who have poorer access healthcare (with disabilities and black and ethnic minority background) were purposively targeted so their experiences could be included. Value and burden scores were evaluated using patient and clinician surveys based on a modified QQ-10 questionnaire which assessed perceived value and burden of patient initiated follow-up in gynaecology. Free text comments regarding PIFU were also collected. RESULTS: 305 patients and 30 clinicians were surveyed. Overall response to patient initiated follow-up was positive. Patients and clinicians attributed high value (77.4 % and 81.4 %) and low burden scores (37.5 % and 44.7 %) to PIFU. Patient autonomy was cited as a reason for this by 84.6 % of patients and 93.3 % of clinicians. Patients attending benign gynaecological sub-specialties including endometriosis (84.2), general gynaecology (82.5) and vulval clinics (81.4) attributed the highest value scores. Gynaecology oncology patients attributed the lowest value (64.0) and highest burden score (51.3) of all subgroups. Younger adults (<60) were more likely to express a preference for PIFU (52.9 %) than older adults (≥60) (28.6 %). CONCLUSIONS: In this study, both patients and clinicians are in favour of selected use of PIFU in gynaecology services. Both questionnaires found younger patients with benign gynaecological conditions were perceived as best suited PIFU. We recommend offering PIFU to select patients who are confident in self-monitoring, factoring patient choice so patients are not disadvantaged by this system. Further evaluation of PIFU in practice is needed before widespread implementation.

Dispersion Analysis of Perpendicular Modes Using a Hybrid Two-Trace Two-Dimensional (2T2D) Smart Error Sum.

Using linear dichroism theory, one would assume that a z-cut of a uniaxial crystal is equivalent to an x-cut to determine the perpendicular component of the dielectric tensor and the corresponding oscillator parameters. However, Fresnel's equations show that the effect of interfaces in the form of the continuity relations of the different components of the electric field must be considered. A consequence of the continuity relations is that perpendicular modes increase less significantly in strength with increasing angle of incidence than expected. This is a consequence of the fact that it is the inverse of the perpendicular component of the dielectric function that increasingly becomes important with a growing angle of incidence. An inverse dielectric function, however, has typically much smaller values than the dielectric function. An additional consequence is that perpendicular modes are blueshifted and coupled in such a way that oscillator strength is transferred to the higher wavenumber mode. Thus, the spectral signatures of perpendicular modes are often weak and masked by the parallel modes when two modes overlap. Accordingly, to enable dispersion analysis, it is suggested to use a hybrid of the conventional residual sum of squares and the two-trace two-dimensional (2T2D) smart error sum, which can correct systematic multiplicable errors in the experimental spectrum. As demonstrated for fresnoite (Ba2TiSi2O8), this is an important step toward determining the perpendicular component of the dielectric tensor and the corresponding oscillator parameters using dispersion analysis, since asynchronous 2T2D correlation spectra are, in particular, sensitive to perpendicular modes.

Intermittent hypoxia-induced enhancements in corticospinal excitability predict gains in motor learning and metabolic efficiency.

Acute intermittent hypoxia (AIH) enhances human motor function after incomplete spinal cord injury. Although the underlying mechanisms in humans are unknown, emerging evidence indicates that AIH facilitates corticospinal excitability to the upper limb. However, the functional relevance of this plasticity remains unexplored, and it is unclear whether similar plasticity can be induced for lower limb motor areas. We recently demonstrated that AIH improves motor learning and metabolic efficiency during split-belt walking. Thus, we hypothesized that AIH increases lower limb excitability and that these enhancements would predict the magnitude of motor learning and the corresponding reductions in net metabolic power. We assessed tibialis anterior (TA) excitability using transcranial magnetic stimulation and quantified changes in spatiotemporal asymmetries and net metabolic power in response to split-belt speed perturbations. We show that AIH enhances TA excitability and that the magnitude of this facilitation positively correlates with greater spatiotemporal adaptation. Notably, we demonstrate a novel association between increased excitability and reduced net metabolic power during motor learning and savings. Together, our results suggest that AIH-induced gains in excitability predict both the magnitude of motor learning and the associated metabolic efficiency. Determining indices of AIH-induced improvements in motor performance is critical for optimizing its therapeutic reach.

Countering Calcium Blooming With Personalized Contrast Media Injection Protocols: The 1-2-3 Rule for Photon-Counting Detector CCTA.

OBJECTIVE: Photon-counting detector computed tomography (PCD-CT) enables spectral data acquisition of CT angiographies allowing for reconstruction of virtual monoenergetic images (VMIs) in routine practice. Specifically, it has potential to reduce the blooming artifacts associated with densely calcified plaques. However, calcium blooming and iodine attenuation are inversely affected by energy level (keV) of the VMIs, creating a challenge for contrast media (CM) injection protocol optimization. A pragmatic and simple rule for calcium-dependent CM injection protocols is investigated and proposed for VMI-based coronary CT angiography with PCD-CT. MATERIALS AND METHODS: A physiological circulation phantom with coronary vessels including calcified lesions (maximum CT value >700 HU) with a 50% diameter stenosis was injected into at iodine delivery rates (IDRs) of 0.3, 0.5, 0.7, 1.0, 1.5, 2.0, 2.5, and 3.0 g I/s. Images were acquired using a first-generation dual-source PCD-CT and reconstructed at various VMI levels (between 45 and 190 keV). Iodine attenuation in the coronaries was measured at each IDR for each keV, and blooming artifacts from the calcified lesions were assessed including stenosis grading error (as % overestimation vs true lumen). The IDR to achieve 300 HU at each VMI level was then calculated and compared with stenosis grading accuracy to establish a general rule for CM injection protocols. RESULTS: Plaque blooming artifacts and intraluminal iodine attenuation decreased with increasing keV. Fixed windowing (representing absolute worst case) resulted in stenosis overestimation from 77% ± 4% at 45 keV to 5% ± 2% at 190 keV, whereas optimized windowing resulted in overestimation from 29% ± 3% at 45 keV to 4% ± 1% at 190 keV. The required IDR to achieve 300 HU showed a strong linear correlation to VMI energy (R2 = 0.98). Comparison of this linear plot versus stenosis grading error and blooming artifact demonstrated that multipliers of 1, 2, and 3 times the reference IDR for theoretical clinical regimes of no, moderate, and severe calcification density, respectively, can be proposed as a general rule. CONCLUSIONS: This study provides a proof-of-concept in an anthropomorphic phantom for a simple pragmatic adaptation of CM injection protocols in coronary CT angiography with PCD-CT. The 1-2-3 rule demonstrates the potential for reducing the effects of calcium blooming artifacts on overall image quality.

Ebola Virus Disease Outbreaks: Lessons Learned From Past and Facing Future Challenges.

INTRODUCTION: The purpose of this review is to examine African Ebola outbreaks from their first discovery to the present, to determine how the medical and public health response has changed and identify the causes for those changes. We sought to describe what is now known about the epidemiology and spread of Ebola virus disease (EVD) from the significant outbreaks that have occurred and outbreak control methods applied under often challenging circumstances. Given the substantial role that the U.S. Government and the U.S. DoD have played in the 2014 to 2016 West African Ebola outbreak, the role of the DoD and the U.S. African Command in controlling EVD is described. MATERIALS AND METHODS: A descriptive method design was used to collect and analyze all available Ebola outbreak literature using the PubMed database. An initial literature search was conducted by searching for, obtaining, and reading original source articles on all major global Ebola outbreaks. To conduct a focused search, we used initial search terms "Ebola outbreak," "Ebola virus disease," "Ebola response," "Ebola countermeasures," and also included each country's name where Ebola cases are known to have occurred. From the 4,673 unique articles obtained from this search and subsequent article title review, 307 articles were identified for potential inclusion. Following abstract and article review, 45 original source articles were used to compile the history of significant Ebola outbreaks. From this compilation, articles focused on each respective subsection of this review to delineate and describe the history of EVD and response, identifying fundamental changes, were obtained and incorporated. RESULTS: We present known Ebola virus and disease attributes, including a general description, seasonality and location, transmission capacity, clinical symptoms, surveillance, virology, historical EVD outbreaks and response, international support for Ebola outbreak response, U.S. DoD support, medical countermeasures supporting outbreak response, remaining gaps to include policy limitations, regional instability, climate change, migration, and urbanization, public health education and infrastructure, and virus persistence and public awareness. CONCLUSIONS: The health and societal impacts of EVD on Africa has been far-reaching, with about 35,000 cases and over 15,000 deaths, with small numbers of cases spreading globally. However, the history of combatting EVD reveals that there is considerable hope for African nations to quickly and successfully respond to Ebola outbreaks, through use of endemic resources including Africa CDC and African Partner Outbreak Response Alliance and the U.S. African Command with greater DoD reachback. Although there remains much to be learned about the Ebola virus and EVD including whether the potential for novel strains to become deadly emerging infections, invaluable vaccines, antivirals, and public health measures are now part of the resources that can be used to combat this disease.

mTORC1 regulates cell survival under glucose starvation through 4EBP1/2-mediated translational reprogramming of fatty acid metabolism.

Energetic stress compels cells to evolve adaptive mechanisms to adjust their metabolism. Inhibition of mTOR kinase complex 1 (mTORC1) is essential for cell survival during glucose starvation. How mTORC1 controls cell viability during glucose starvation is not well understood. Here we show that the mTORC1 effectors eukaryotic initiation factor 4E binding proteins 1/2 (4EBP1/2) confer protection to mammalian cells and budding yeast under glucose starvation. Mechanistically, 4EBP1/2 promote NADPH homeostasis by preventing NADPH-consuming fatty acid synthesis via translational repression of Acetyl-CoA Carboxylase 1 (ACC1), thereby mitigating oxidative stress. This has important relevance for cancer, as oncogene-transformed cells and glioma cells exploit the 4EBP1/2 regulation of ACC1 expression and redox balance to combat energetic stress, thereby supporting transformation and tumorigenicity in vitro and in vivo. Clinically, high EIF4EBP1 expression is associated with poor outcomes in several cancer types. Our data reveal that the mTORC1-4EBP1/2 axis provokes a metabolic switch essential for survival during glucose starvation which is exploited by transformed and tumor cells.

Metabolism-driven in vitro/in vivo disconnect of an oral ERɑ VHL-PROTAC.

Targeting the estrogen receptor alpha (ERα) pathway is validated in the clinic as an effective means to treat ER+ breast cancers. Here we present the development of a VHL-targeting and orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of ERα. In vitro studies with this PROTAC demonstrate excellent ERα degradation and ER antagonism in ER+ breast cancer cell lines. However, upon dosing the compound in vivo we observe an in vitro-in vivo disconnect. ERα degradation is lower in vivo than expected based on the in vitro data. Investigation into potential causes for the reduced maximal degradation reveals that metabolic instability of the PROTAC linker generates metabolites that compete for binding to ERα with the full PROTAC, limiting degradation. This observation highlights the requirement for metabolically stable PROTACs to ensure maximal efficacy and thus optimisation of the linker should be a key consideration when designing PROTACs.

Co-ordinated assembly of the multilayered cell envelope of Gram-negative bacteria.

Bacteria surround themselves with complex cell envelopes to maintain their integrity and protect against external insults. The envelope of Gram-negative organisms is multilayered, with two membranes sandwiching the periplasmic space that contains the peptidoglycan cell wall. Understanding how this complicated surface architecture is assembled during cell growth and division is a major fundamental problem in microbiology. Additionally, because the envelope is an important antibiotic target and determinant of intrinsic antibiotic resistance, understanding the mechanisms governing its assembly is relevant to therapeutic development. In the last several decades, most of the factors required to build the Gram-negative envelope have been identified. However, surprisingly, little is known about how the biogenesis of the different cell surface layers is co-ordinated. Here, we provide an overview of recent work that is beginning to uncover the links connecting the different envelope biosynthetic pathways and assembly machines to ensure uniform envelope growth.

Quantitation of propofol metabolites by LC-MS/MS demonstrating long detection window for urine drug monitoring.

Introduction: Chromatographic methods for analysis of propofol and its metabolites have been widely used in pharmacokinetic studies of propofol distribution, metabolism, and clearance. Application of chromatographic methods is also needed in clinical and forensic laboratories for detecting and monitoring propofol misuse. Objective: We report a method for sensitive analysis of propofol, propofol 1-glucuronide (PG), 4-hydroxypropofol 1-glucuronide (1-QG), 4-hydroxypropofol 4-glucuronide (4-QG) and 4-hydroxypropofol 4-sulfate (4-QS) in urine by LC-MS/MS analysis. The method employs a simple dilute-and-analyze sample preparation with stable isotope internal standardization. Results: Validation studies demonstrate a linear calibration model (100-10,000 ng/mL), with dilution integrity verified for the extended range of concentrations experienced in propofol use. Criteria-based validation was achieved, including an average coefficient of variation of 6.5 % and a percent bias of -4.2 ng/mL. The method was evaluated in 12 surgical patients, with monitoring periods lasting up to 30 days following intravenous propofol administrations of 100-3000 mg on the day of surgery. While the concentration ratio of PG to 4-hydroxy propofol metabolite decreased significantly in the days following surgery, PG maintained the highest concentration in all specimens. Both PG and 1-QG were detectable throughout the monitoring periods, including in a patient monitored for 30 days. Lower concentrations were determined for 4-QG and 4-QS, with evidence of detection up to 20 days. Propofol was not detectable in any urine specimens, thereby proving ineffective for identifying drug use. Conclusion: The validated method for quantifying propofol metabolites demonstrates its applicability for the sensitive detection of propofol misuse over a long window of drug-use detection.

Diagnostic accuracy of digital technologies compared with 12-lead ECG in the diagnosis of atrial fibrillation in adults: A protocol for a systematic review.

BACKGROUND: Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia in the world. AF increases the risk of stroke 5-fold, though the risk can be reduced with appropriate treatment. Therefore, early diagnosis is imperative but remains a global challenge. In low-and middle-income countries (LMICs), a lack of diagnostic equipment and under-resourced healthcare systems generate further barriers. The rapid development of digital technologies that are capable of diagnosing AF remotely and cost-effectively could prove beneficial for LMICs. However, evidence is lacking on what digital technologies exist and how they compare in regards to diagnostic accuracy. We aim to systematically review the diagnostic accuracy of all digital technologies capable of AF diagnosis. METHODS: MEDLINE, Embase and Web of Science will be searched for eligible studies. Free text terms will be combined with corresponding index terms where available and searches will not be limited by language nor time of publication. Cohort or cross-sectional studies comprising adult (≥18 years) participants will be included. Only studies that use a 12-lead ECG as the reference test (comparator) and report outcomes of sensitivity, specificity, the diagnostic odds ratio (DOR) or the positive and negative predictive value (PPV and NPV) will be included (or if they provide sufficient data to calculate these outcomes). Two reviewers will independently assess articles for inclusion, extract data using a piloted tool and assess risk of bias using the QUADAS-2 tool. The feasibility of a meta-analysis will be determined by assessing heterogeneity across the studies, grouped by index device, diagnostic threshold and setting. If a meta-analysis is feasible for any index device, pooled sensitivity and specificity will be calculated using a random effect model and presented in forest plots. DISCUSSION: The findings of our review will provide a comprehensive synthesis of the diagnostic accuracy of available digital technologies capable for diagnosing AF. Thus, this review will aid in the identification of which devices could be further trialed and implemented, particularly in a LMIC setting, to improve the early diagnosis of AF. TRIAL REGISTRATION: Systematic review registration: PROSPERO registration number is CRD42021290542. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021290542.

Epibulbar Complex Choristoma Containing Bone: A Case Report and Closer Look at Classifications.

Introduction: Epibulbar choristoma is a benign congenital lesion containing histologically normal-appearing tissue in an abnormal ectopic location. An epibulbar choristoma is classified as either epibulbar dermoid, dermolipoma, or complex choristoma based on histological examination. The case presented was a presumed epibulbar dermolipoma with no signs of ossification on imaging, examination, or intraoperatively until the specimen was examined histologically, clarifying the lesion as an epibulbar complex choristoma. Reassuringly, the presence of bone in such lesions should not change management. Case Presentation: A mother noticed a small fleshy mass on her 9-year-old daughter's superotemporal bulbar conjunctiva. The suspected epibulbar dermolipoma was confirmed with MRI and initially managed conservatively. Two years later, she was referred for apparent growth and cosmetic concerns, and she underwent surgical debulking. Conclusion: We present this case for its unusual presentation and histological findings. Orbital surgeons should be aware of the possibility of ossification of epibulbar choristomas and avoid confusion with alternative diagnoses. Clarification of the latest classification system for epibulbar choristomas is provided.

A structure-function analysis shows SARS-CoV-2 BA.2.86 balances antibody escape and ACE2 affinity.

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility.

Urinary concentrations of phthalate metabolites in relation to preeclampsia and other hypertensive disorders of pregnancy in the environmental influences on child health outcomes (ECHO) program.

BACKGROUND: Phthalate exposure may contribute to hypertensive disorders of pregnancy (HDP), including preeclampsia/eclampsia (PE/E), but epidemiologic studies are lacking. OBJECTIVES: To evaluate associations of pregnancy phthalate exposure with development of PE/E and HDP. METHODS: Using data from 3,430 participants in eight Environmental influences on Child Health Outcomes (ECHO) Program cohorts (enrolled from 1999 to 2019), we quantified concentrations of 13 phthalate metabolites (8 measured in all cohorts, 13 in a subset of four cohorts) in urine samples collected at least once during pregnancy. We operationalized outcomes as PE/E and composite HDP (PE/E and/or gestational hypertension). After correcting phthalate metabolite concentrations for urinary dilution, we evaluated covariate-adjusted associations of individual phthalates with odds of PE/E or composite HDP via generalized estimating equations, and the phthalate mixture via quantile-based g-computation. We also explored effect measure modification by fetal sex using stratified models. Effect estimates are reported as odds ratios (OR) with 95% confidence intervals (95% CIs). RESULTS: In adjusted analyses, a doubling of mono-benzyl phthalate (MBzP) and of mono (3-carboxypropyl) phthalate (MCPP) concentrations was associated with higher odds of PE/E as well as composite HDP, with somewhat larger associations for PE/E. For example, a doubling of MCPP was associated with 1.12 times the odds of PE/E (95%CI 1.00, 1.24) and 1.02 times the odds of composite HDP (95%CI 1.00, 1.05). A quartile increase in the phthalate mixture was associated with 1.27 times the odds of PE/E (95%CI 0.94, 1.70). A doubling of mono-carboxy isononyl phthalate (MCiNP) and of mono-carboxy isooctyl phthalate (MCiOP) concentrations were associated with 1.08 (95%CI 1.00, 1.17) and 1.11 (95%CI 1.03, 1.19) times the odds of PE/E. Effect estimates for PE/E were generally larger among pregnancies carrying female fetuses. DISCUSSION: In this study, multiple phthalates were associated with higher odds of PE/E and HDP. Estimates were precise and some were low in magnitude. Interventions to reduce phthalate exposures during pregnancy may help mitigate risk of these conditions.

Cilta-cel, a BCMA-targeting CAR-T therapy for patients with multiple myeloma.

INTRODUCTION: Ciltacabtagene autoleucel (cilta-cel), a BCMA-targeting CAR-T therapy, is approved in the United States and Europe for patients with relapsed/refractory multiple myeloma (RRMM) and ≥1 prior line of therapy (LOT), including a proteasome inhibitor and an immunomodulatory drug, and are lenalidomide refractory. AREAS COVERED: We examine recent long-term data in heavily pretreated RRMM (LEGEND-2, CARTITUDE-1) and earlier LOTs (CARTITUDE-4) compared with standard therapy and discuss the rationale for investigating cilta-cel as frontline therapy for transplant-eligible and transplant-ineligible patients (CARTITUDE-5, CARTITUDE-6). EXPERT OPINION: CAR-T therapies can improve outcomes for patients with MM across different LOTs. CARTITUDE-1 and CARTITUDE-4 have set a new bar for efficacy, with median PFS of 34.9 months in heavily pretreated patients (CARTITUDE-1) and a 74% relative risk reduction for progression/death versus standard care in patients with 1-3 prior LOTs (CARTITUDE-4), with manageable safety. Response rates were consistent between the two studies: 98% in CARTITUDE-1 and approaching 100% for infused patients in CARTITUDE-4. Cilta-cel could be a key treatment choice for patients with RRMM after first LOT. Clinical trials investigating frontline cilta-cel therapy will provide valuable insights into optimizing treatment pathways with the aim to potentially cure MM.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).

Over 25 Years of Hope: Development of Lymphatic Filariasis Patient Support Groups in Haiti.

Support groups can create environments that are conducive to healing and well-being, particularly for persons with stigmatizing chronic diseases. In 1998, the support group concept was adapted in Haiti for persons with disabling lymphedema caused by lymphatic filariasis (LF). The project was developed with the expectation that the support group model conceived in the developed world be interpreted and modified by persons affected with lymphedema in the Haitian setting. Initiated with modest financial support within a research initiative to eliminate LF, a total of 50 "Hope Clubs" were formed from 1998 to 2023 across seven communes (districts) located in 3 of Haiti's 10 regional Departments. Documented benefits of the support groups included improved limb self-care, decreased incidence of inflammatory episodes (adenolymphangitis), enhanced self-efficacy, economic benefit through microenterprise, and improved quality of life. Despite challenges of funding shortfalls, natural disasters, and political insecurity, persistence of LF support groups in Haiti highlights the crucial role of group ownership by affected persons and the freedom to reinvent the support group concept in light of local social, cultural, and economic conditions.