Recent Exposure Research Articles

An absorption model of volatile organic compound by plant leaf: The most influential site in the absorption pathway

Plant leaves absorb some kinds of volatile organic compounds (VOCs) and can contribute to air purification, as revealed by recent exposure experiments conducted at environmentally realistic concentrations in ppb (v/v). However, the mechanisms underlying VOC absorption by plants remain unclear. In this study, we applied Fick's first law of diffusion to a VOC absorption model for plant leaves to account for the VOC diffusion process via stomata, air-liquid partitioning, partitioning into the plasma membrane, and metabolic conversion of the VOC in plant cells. The resistance and concentration of VOCs at individual sites were determined using previously reported absorption data for aliphatic aldehydes and ketones in three plant species and the leaf morphology parameters obtained from leaf cross-section micrographs. The highest resistance occurred at the metabolic site (rmet), suggesting that VOC metabolic capacity is the most influential factor in VOC absorption. The resistance of stomata (rs) or plasma membrane (rpl) was the second highest, depending on compound family. Using the absorption rate data of Q. acutissima, it is revealed that metabolic site resistance rmet for methyl vinyl ketone is affected by light intensity. Thus, our VOC absorption model can determine the most influential site in the absorption pathway both for different VOCs and plant species. Our model can contribute to the development of plant-based strategies for controlling air pollution.

Expanding Understanding of Urban Rift Valley Fever Risk and Associated Vector Ecology at Slaughterhouses in Kisumu, Kenya.

Rift Valley fever virus (RVFV) is an adaptable arbovirus that can be transmitted by a wide variety of arthropods. Widespread urban transmission of RVFV has not yet occurred, but peri-urban outbreaks of RVFV have recently been documented in East Africa. We previously reported low-level exposure in urban communities and highlighted the risk of introduction via live animal influx. We deployed a slaughtered animal testing framework in response to an early warning system at two urban slaughterhouses and tested animals entering the meat value chain for anti-RVFV IgG and IgM antibodies. We simultaneously trapped mosquitoes for RVFV and bloodmeal testing. Out of 923 animals tested, an 8.5% IgG seroprevalence was identified but no evidence of recent livestock exposure was detected. Mosquito species abundance varied greatly by slaughterhouse site, which explained 52% of the variance in blood meals. We captured many Culex spp., a known RVFV amplifying vector, at one of the sites (p < 0.001), and this species had the most diverse blood meals. No mosquito pools tested positive for RVFV antigen using a rapid VecTOR test. These results expand understanding of potential RVF urban disease ecology, and highlight that slaughterhouses are key locations for future surveillance, modelling, and monitoring efforts.

An epidemiological study of multisystem inflammatory syndrome in children (MIS-C) and young adults among COVID-19-positive patients - data from National Inpatient Sample database.

During the pandemic of COVID-19, a novel atypical set of clinical findings was seen among several children with recent or current exposure to the virus. It was termed the "multisystem inflammatory syndrome in children" (MIS-C). Our study used the 2021 National Inpatient Sample to study the associations of sex, race, and age with the incidence of MIS-C among COVID-19-positive children. Out of 69,440 COVID-19-positive children, 2,790 (4.0%) reported MIS-C. The incidence of MIS-C was highest among those aged 8 years old (17,130 MIS-C cases per 100,000 COVID-19 patients), Asian or Pacific Islanders (API) (5,346 MIS-C per 100,000 COVID-19 cases), and males (4,734 cases per 100,000 COVID-19 cases). Furthermore, 7.9% of MIS-C cases met the classification of Kawasaki disease.

Cohort profile: longitudinal and population comparison of children who are HIV-exposed uninfected and children who are HIV unexposed in Kenya (HOPE study)

PurposeGlobally, the number of children/adolescents exposed to HIV but uninfected (HIV-exposed uninfected, HEU) is growing. The HEU outcomes: population-evaluation and screening strategies study was designed to provide population-level evidence of...

Oropouche Virus Exposure in Febrile Patients during Chikungunya Virus Introduction in the State of Amapá, Amazon Region, Brazil.

Oropouche orthobunyavirus (OROV) is an arbovirus transmitted by midges that has been involved in outbreaks throughout Central and South America. In Brazil, human cases have been historically concentrated in the northern region of the country. Oropouche fever in humans range from mild clinical signs to rare neurological events, and is considered a neglected tropical disease in Brazil. Due to the clinical similarities to other arboviruses, such as chikungunya and dengue viruses, OROV infections are likely to be underreported. Chikungunya virus (CHIKV) cases in Brazil were first recognized in 2014 in the states of Amapá and Bahia in the north and northeast regions, respectively. Both OROV and CHIKV cause nonspecific symptoms, making clinical diagnosis difficult in a scenario of arbovirus cocirculation. Aiming to investigate OROV transmission during the CHIKV introduction in the state of Amapá located in the Brazilian Amazon, we conducted a retrospective molecular (RT-qPCR) and serological investigation in febrile cases (N = 166) collected between August 2014 and May 2015. All acute serum samples were negative for OROV RNA using RT-qPCR. However, neutralizing antibodies for OROV were detected using a plaque reduction neutralization test (PRNT90) in 10.24% (17/166) of the patients, with neutralizing antibody titers ranging from 20 to ≥640, suggesting the previous exposure of patients to OROV. Regarding CHIKV, recent exposure was confirmed by the detection of CHIKV RNA in 20.25% (33/163) of the patients and by the detection of anti-CHIKV IgM in 28.57% (44/154) of the patients. The additional detection of anti-CHIKV IgG in 12.58% (19/151) of the febrile patients suggests that some individuals had been previously exposed to CHIKV. Whether the OROV exposure reported here occurred prior or during the CHIKV circulation in Amapá, is unknown, but because those arboviral infections share similar clinical signs and symptoms, a silent circulation of enzootic arboviruses during the introduction of exotic arboviruses may occur, and highlights the importance of syndromic cases' surveillance to arboviruses in Brazil.

Two biases in incubation time estimation related to exposure

BackgroundEstimation of the SARS-CoV-2 incubation time distribution is hampered by incomplete data about infection. We discuss two biases that may result from incorrect handling of such data. Notified cases may recall recent exposures more precisely (differential recall). This creates bias if the analysis is restricted to observations with well-defined exposures, as longer incubation times are more likely to be excluded. Another bias occurred in the initial estimates based on data concerning travellers from Wuhan. Only individuals who developed symptoms after their departure were included, leading to under-representation of cases with shorter incubation times (left truncation). This issue was not addressed in the analyses performed in the literature.MethodsWe performed simulations and provide a literature review to investigate the amount of bias in estimated percentiles of the SARS-CoV-2 incubation time distribution.ResultsDepending on the rate of differential recall, restricting the analysis to a subset of narrow exposure windows resulted in underestimation in the median and even more in the 95th percentile. Failing to account for left truncation led to an overestimation of multiple days in both the median and the 95th percentile.ConclusionWe examined two overlooked sources of bias concerning exposure information that the researcher engaged in incubation time estimation needs to be aware of.

Phase I/II trial of healthy donor fecal microbiota transplant (hdFMT) in PD-1 relapsed/refractory (R/R) non-small cell lung cancer (NSCLC).

TPS8648 Background: A significant portion of patients (pts) with advanced NSCLC either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy administered alone or in combination with platinum chemotherapy. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1. In mice, gut microbiota modulate therapeutic activity of anti-PD-1 ICI, and administration of gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key bacterial species are associated with favorable response, although limited concordance among the identified species has been reported across studies. We and others have previously demonstrated that microbiome modulation reversed anti-PD-1 resistance in anti-PD-1 R/R melanoma, and augmented benefit of anti-PD-1 monotherapy in ICI-naïve melanoma. We hypothesize that intestinal dysbiosis mediates anti-PD-1 resistance in anti-PD-1 R/R NSCLC, and that hdFMT may resensitize NSCLC to PD-1 blockade. Methods: This is an investigator-initiated, phase II trial of hdFMT with pembrolizumab (P) in pts with R/R NSCLC progressed on prior anti-PD-1 based therapy alone or in combination with platinum chemotherapy. Pts must have measurable disease per RECIST v1.1, no untreated CNS metastases, and no contraindications to FMT administration. hdFMT is derived from non-obese, healthy, adults aged ≥18 to &lt;70, with no chronic diseases, and no recent antibiotic exposure. Donors are screened broadly for transmissible agents including SARS-CoV-2 using bookend screening. hdFMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts receive P 200mg every 3 weeks (Q3W). hdFMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo tumor biopsies at baseline and at W8, with optional post-progression biopsy. Primary endpoint: overall response rate (ORR) assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 5% will be tested versus a 1-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design (type I error 0.04, power 0.9, when true response rate is 0.25). PFS and OS will be estimated via Kaplan-Meier method. Enrollment has commenced. Clinical trial information: NCT05669846 .

Skin cancer risk behaviors in sexual minority men: A mixed methods approach.

Sexual minority men experience disproportionately elevated rates of skin cancers, likely driven by excess ultraviolet radiation exposure-namely through tanning behaviors. However, limited integrated theoretical models exist to explain sexual minority men's elevated skin cancer risk. The aim of the current study is to further test and refine an integrated theory of skin cancer risk behaviors among sexual minority men by incorporating minority stress into the integrated health behavior model of tanning. The study employed a parallel mixed methods design, with a Phase 1 qualitative stage (N = 30) and a Phase 2 quantitative stage (Model 1: N = 320; Model 2: N = 319). In both phases, participants were sexual minority men, equally stratified as those with versus without recent tanning exposure and were recruited from across the United States. Qualitative and quantitative data supported the overall integrated model, with some quantitative paths varying depending on the tanning behavior outcome. Overall, appearance-related motives to tan and beliefs that tanning regulates affect emerged as the most consistent proximal predictors. Minority stress significantly predicted holding more positive attitudes toward tanning as an effective affect regulation strategy. The results from this mixed methods study support the inclusion of minority stressors into the adapted integrative health behavior model of tanning. Replication within prospective designs would strengthen the evidence for this model, which may be helpful in guiding future skin cancer prevention programs tailored to sexual minority men. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Randomized phase II trial of pembrolizumab/lenvatinib (P+L) +/- responder fecal microbiota transplant (R-FMT) in PD-1 relapsed/refractory (R/R) cutaneous melanoma (MEL).

TPS9607 Background: A significant portion of patients (pts) with advanced MEL develop resistance to immune checkpoint inhibitors (ICI). The gut microbiome is a major tumor-extrinsic regulator of ICI response. In mice, gut microbiota modulate therapeutic activity of ICI, and administration of certain gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy in melanoma-bearing mice. In the LEAP-004 trial, P+L produced 21% ORR in PD-1 R/R MEL with Gr3+ TRAE 45.6%. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key species including Actinobacteria and Firmicutes are associated with favorable response. We and others have previously demonstrated that microbiome modulation using R-FMT reversed PD-1 non-response in PD-1 R/R MEL. In PD-1 naïve MEL, healthy donor FMT (hdFMT) augments benefit of PD-1 monotherapy. We hypothesized that intestinal dysbiosis mediates PD-1 resistance in PD-1 R/R MEL, microbiome modulation may reverse TKI toxicity, and that R-FMT may resensitize MEL to PD-1 blockade. Methods: This is an investigator-initiated, randomized, phase II trial of P+L vs. P+L+R-FMT in PD-1 R/R MEL. Pts must have measurable disease per RECIST v1.1, no active CNS metastases (or if present, previously treated and stable on repeat imaging), and no contraindications to FMT administration. R-FMT is derived from non-obese, advanced MEL with durable response (mPFS ≥24 months) following prior PD-1 ICI, with no recent (≤1 month) antibiotic exposure. Donors are screened broadly for infectious agents including SARS-CoV-2 using bookend screening. R-FMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts are randomized 1:1 to either P+L [P 200mg every 3 weeks (Q3W) along with L 20mg orally once daily] or P+L+R-FMT. R-FMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo biopsies at baseline and W8, with optional biopsy at progression. Primary endpoint: ORR assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 20% will be tested versus a one-sided alternative hypothesis of ≥50%. This design has a type I error rate 0.10 and power 0.8 when the true response rate is 0.25. Enrollment has commenced. Clinical trial information: NCT06030037 .

Response-contingent cocaine increases the reinforcing effectiveness of social contact.

Epidemiological studies report a high concordance rate of drug use within groups, suggesting an interplay between drug reinforcement and social cohesion. Preclinical studies reveal that (a) contingent access to a social partner increases cocaine intake and (b) experimenter-delivered cocaine increases the reinforcing effects of social contact. The purpose of this study was to determine if response-contingent cocaine increases the reinforcing effectiveness of social contact. Male rats were implanted with intravenous catheters and trained on a fixed ratio (FR1) schedule for 30-s access to a social partner. The reinforcing effectiveness of social contact was then determined using a progressive ratio (PR) schedule. After the PR test, rats were divided into two groups in which each response on an FR1 schedule produced social access and either response-contingent cocaine (0.5 mg/kg/infusion) or saline. After 9 days, the reinforcing effectiveness of social contact in the absence of infusions was determined again on the PR schedule. The cocaine and saline reinforcers were then switched between groups and the latter procedures were repeated. Recent exposure to response-contingent cocaine increased the reinforcing effectiveness of social contact on the PR schedule. This effect was transient, and the reinforcing effectiveness of social contact returned to baseline levels once response-contingent cocaine was replaced with saline. These data indicate that recent exposure to response-contingent cocaine transiently increases the reinforcing effectiveness of social contact and suggest that cocaine use may strengthen social cohesion by increasing the reinforcing effects of social contact with other individuals. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Lead exposure and source attribution for a mammalian scavenger before and after a culling program

Lead-based ammunition is a significant source of environmental lead and threatens species that scavenge lead-shot carcasses, particularly in areas with intensive shooting. With the impacts of lead on avian scavengers well established, there is increasing focus on the effects of lead on mammalian scavengers. We investigated lead exposure in a morphologically specialized mammalian scavenger, the Tasmanian devil (Sarcophilus harrisii), by analyzing their blood lead levels (BLLs) before and after a marsupial culling program using linear mixed effects models. We compared lead isotope signatures in devil blood to those in the culling ammunition to inform potential source attributions. We sampled 23 devils before culling and 15 after culling, finding no significant difference in mean BLLs pre and post-culling. However, devils captured closer to forestry coupes where culling had occurred had higher BLLs, and a greater proportion of devils displayed elevated BLLs post-culling (33 % compared to 18 % pre-culling). The highest BLL (7.93 μg/dL) was found in a devil post-culling and this individual had lead isotope signatures that matched the ammunition samples analyzed, suggesting the individual was exposed to lead from scavenging on culled carcasses. While 18 % of the devil blood lead samples had isotope signatures consistent with the ammunition samples, most were measurably different, indicating other sources of lead in the landscape. BLLs in our study landscape were similar to published BLLs for wild devils across Tasmania. That said, lead isotope signatures in the blood of individual devils sampled both before and after culling shifted closer to those of ammunition samples post-culling. Our results indicate that while some individual devils may have been exposed to lead from culling, most devils in the landscape did not show evidence of recent exposure. However, even low lead levels can adversely impact wildlife health and immunity, a particular concern for devils, a species endangered by disease.

A randomized, multicenter, open-label phase III trial of hyperthermic intraperitoneal chemotherapy in platinum-resistant recurrent ovarian cancer (KOV-HIPEC-02).

TPS5635 Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) during cytoreductive surgery has emerged to achieve a higher concentration of chemotherapeutic agents and treat micro-metastases on peritoneal surfaces. At advanced staged ovarian cancer treated with neoadjuvant chemotherapy, HIPEC during interval cytoreductive surgery with cisplatin 75-100mg/m2 increases progression-free survival and overall survival (OV-HIPEC-01 and KOV-HIPEC-01). In chemotherapy-naïve ovarian cancer patients, survival benefit is not identified with HIPEC (KOV-HIPEC-01). And the meta-analysis revealed the survival benefit after recent exposure of chemotherapy. In ovarian cancer, HIPEC is thought to overcome chemotherapy resistance. Methods: This trial (KOV-02) is currently actively enrolling, a multicenter, open-label, 1:1 randomized, phase III trial that will enroll 140 patients in platinum-resistant recurrent epithelial ovarian cancer. The trial is registered on ClinicalTrials.gov (NCT05316181). Institutional review board approval was obtained. The first patient was enrolled on April 07, 2022. The experimental arm will receive cytoreductive surgery and HIPEC (Doxorubicin 35mg/m2 and mitomycin 15mg/m2, 41.5-42.0°C) followed by physician-choice chemotherapy, and the control arm will receive physician-choice chemotherapy until disease progression or intolerable toxicity. The primary objective of the trial is to evaluate progression-free survival (PFS) between the HIPEC group and the control group. Secondary objectives are overall survival (OS), cancer-specific survival, safety, and quality of life. Assuming that the enrollment period is three years and the follow-up period is two years, the total number of events required is 121. Based on the log-rank test, the total number of subjects required to prove HR 0.6 with a two-sided alpha of 0.05 and 80% power is 126. Considering 10% drop-out, 140 patients are finally studied. Clinical trial information: NCT05316181 .

P.066 A 65 year-old male with subacute asymmetric, proximal more than distal upper extremity weakness with associated paresthesias and pain

Background: Neuroborreliosis affects approximately 10-15% of people with untreated Lyme disease and typically declares itself 2-18 weeks after infection. North American neuroborreliosis often manifests with cranial nerve palsy, meningitis, and/or radiculoneuritis. Methods: Here we describe a case of North American neuroborreliosis and also highlight some of the rare manifestations of systemic Lyme disease. A 65-year old male presented with a subacute history of progressive upper extremity weakness, neck pain, and headache. This occurred in the context of a recent tick exposure. Results: MRI of the brachial plexus, serology and CSF studies, and EMG/NCS were consistent with a diagnosis of polyradicular neuroborreliosis. However, whole body imaging identified some concerning features suggestive of lymphoma: specifically a large necrotic mediastinal lymph node and a number of vascular abnormalities. In light of these findings, the differential also included neurolymphomatosis and a PET scan was conducted. Reassuringly, there was no increase in FDG avidity in the distribution of his affected nerves. Moreover, his neurologic symptoms exhibited clinical improvement following treatment of his neuroborreliosis. Conclusions: This case provides an excellent example of the clinical features of neuroborreliosis, but more importantly also highlights some of the rarer potential manifestations, which warrant further investigation.

Risk of hypersensitivity pneumonitis and other interstitial lung diseases following organic dust exposure

BackgroundOrganic dust is associated with hypersensitivity pneumonitis, and associations with other types of interstitial lung disease (ILD) have been suggested. We examined the association between occupational organic dust exposure and...

Association between recent exposure to continuous glucose monitoring-recorded hypoglycaemia and counterregulatory and symptom responses to subsequent controlled hypoglycaemia in people with type 1 diabetes.

Experimental hypoglycaemia blunts the counterregulatory hormone and symptom responses to a subsequent episode of hypoglycaemia. In this study, we aimed to assess the associations between antecedent exposure and continuous glucose monitoring (CGM)-recorded hypoglycaemia during a 1-week period and the counterregulatory responses to subsequent experimental hypoglycaemia in people with type 1 diabetes. Forty-two people with type 1 diabetes (20 females, mean ± SD glycated haemoglobin 7.8% ± 1.0%, diabetes duration median (interquartile range) 22.0 (10.5-34.9) years, 29 CGM users, and 19 with impaired awareness of hypoglycaemia) wore an open intermittently scanned CGM for 1 week to detect hypoglycaemic exposure before a standardized hyperinsulinaemic-hypoglycaemic [2.8 ± 0.1 mmol/L (50.2 ± 2.3 mg/dl)] glucose clamp. Symptom responses and counterregulatory hormones were measured during the clamp. The study is part of the HypoRESOLVE project. CGM-recorded hypoglycaemia in the week before the clamp was negatively associated with adrenaline response [β -0.09, 95% CI (-0.16, -0.02) nmol/L, p = .014], after adjusting for CGM use, awareness of hypoglycaemia, glycated haemoglobin and total daily insulin dose. This was driven by level 2 hypoglycaemia [<3.0 mmol/L (54 mg/dl)] [β -0.21, 95% CI (-0.41, -0.01) nmol/L, p = .034]. CGM-recorded hypoglycaemia was negatively associated with total, autonomic, and neuroglycopenic symptom responses, but these associations were lost after adjusting for potential confounders. Recent exposure to CGM-detected hypoglycaemia was independently associated with an attenuated adrenaline response to experimental hypoglycaemia in people with type 1 diabetes.

Universal Sexual Violence Intervention Effects in a Cluster-Randomized Trial: Moderation by Sexual Orientation.

Sexual minority (e.g., gay/lesbian, bisexual, and queer) students are more likely than their heterosexual peers to experience sexual violence (SV) during college. Interventions that prevent SV and improve SV care-seeking behaviors for sexual minority students are lacking. Giving Information for Trauma Support and Safety (GIFTSS) is an evidence-based universal SV intervention implemented by providers during college health and counseling visits. Compared to controls, GIFTSS participants reported greater self-efficacy to use SV harm reduction strategies and SV disclosure during clinical visits. However, GIFTSS' effectiveness for sexual minority participants is unknown. The current study examines whether sexual orientation moderates GIFTSS' effects on numerous SV-related outcomes (i.e., to test whether intervention effects at 4 and 12 months differed based on sexual orientation). Across 28 college campuses in Pennsylvania and West Virginia, 2,291 students participated in a two-arm cluster-randomized controlled trial. We used mixed models with two- and three-way interaction terms to test whether sexual orientation modified GIFTSS' effects at 4- and 12-month follow-up on participants': SV recognition; knowledge of and self-efficacy to enact SV harm reduction strategies; intentions to intervene; knowledge of and self-efficacy to use SV-related services; SV disclosure during visits; and recent SV exposure. Overall, 22.1% of participants were sexual minorities (n = 507). Sexual orientation moderated GIFTSS effectiveness as indicated by significant three-way interaction (p = .01) at 12-month follow-up, and knowledge of SV services decreased for heterosexual participants (β = -.23) but increased for sexual minority participants (β = .23). Our study indicates that universal provider-based education may promote greater knowledge of SV services among sexual minority than heterosexual participants, and population-specific interventions are needed that reduce sexual minority students' SV exposure, service utilization, and other critical aspects of SV prevention on university campuses.Clinical Trial Registration: Registry name: College Health Center-based Alcohol and Sexual Violence Intervention (GIFTSS), Registration number: NCT02355470, Web link: https://clinicaltrials.gov/ct2/show/NCT02355470, Deidentified individual participant data will not be made available.

IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer

Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P= 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Informing the Need for a SARS-CoV-2 Booster Based on the Immune Responses Among Young Healthy Adults to Variants Circulating in Late 2023.

COVID-19 remains a global public health challenge due to new immune-evasive SARS-CoV-2 variants and heterogeneous immunity. In this cross-sectional study, we evaluated the adaptive immune responses in US active duty personnel who completed a COVID-19 primary vaccine series and had heterogenous SARS-CoV-2 vaccination and infection histories to 3 previously dominant variants (ancestral, Delta, BA.5) and 3 circulating variants (XBB.1.5, EG.5, and BA.2.86) in late 2023. Analyses were based on the most recent exposure in terms of timing (within or beyond 12 months) and type (vaccine or infection). Significant reduction was observed in binding antibodies, neutralization antibodies, memory B cells, and CD8+ T cells against circulating variants when compared with previous variants. The reduction in antibody response was more pronounced in those whose most recent exposure was >12 months from enrollment. In contrast, the CD4+ T-cell response was largely consistent across all tested variants. The type of most recent exposure was not a significant factor in determining the magnitude of current immune responses. Administration of the XBB.1.5-based booster is likely to enhance cross-reactive humoral responses against SARS-CoV-2 circulating lineages. Ongoing surveillance of immune responses to emerging variants is needed for informing vaccine composition and timing.

Pigs in southern Italy are exposed to three ruminant pathogens: an analysis of seroprevalence and risk factors analysis study

BackgroundPigs are susceptible to several ruminant pathogens, including Coxiella burnetti, Schmallenberg virus (SBV) and bovine viral diarrhea virus (BVDV). These pathogens have already been described in the pig population, although the dynamics of the infection and the impact on pig farms are currently unclear. The aim of this work was to evaluate the presence of these infections in the pig population of the Campania region, southern Italy, and to evaluate the risk factors associated with a greater risk of exposure.ResultsA total of 414 serum samples belonging to 32 herds were tested for the presence of antibodies against SBV, Coxiella, and BVD using commercial multispecies ELISA kits. SBV (5.3%) was the most prevalent pathogen, followed by Coxiella (4.1%) and BVD (3%). The risk factors included in the study (age, sex, province, farming system, ruminant density and major ruminant species) had no influence on the probability of being exposed to BVD and Coxiella, except for the location, in fact more pigs seropositive to Coxiella were found in the province of Caserta. However, the univariate analysis highlighted the influence of age, location, and sex on exposure to SBV. The subsequent multivariate analysis statistically confirmed the importance of these factors. The presence of neutralizing antibodies for SBV and BVDV, or antibodies directed towards a specific phase of infection for Coxiella was further confirmed with virus-neutralization assays and phase-specific ELISAs in a large proportion of positive samples. The presence of high neutralizing antibody titers (especially for SBV) could indicate recent exposures. Twelve of the 17 positive samples tested positive for antibodies against Coxiella phase I or II antigens, indicating the presence of both acute and chronic infections (one animal tested positive for both phases antibodies).ConclusionsOur study indicates a non-negligible exposure of pigs from southern Italy to the above pathogens. Further studies are necessary to fully understand the dynamics of these infections in pigs, the impact on productivity, and the public health consequences in the case of Coxiella.

The biological embedding of social adversity: How adolescent housing insecurity impacts inflammation over time

Background & PurposeAdolescent housing insecurity is a dynamic form of social adversity that impacts child health outcomes worldwide. However, the means by which adolescent housing insecurity may become biologically embedded to influence health outcomes over the life course remain unclear. Therefore, we aimed to utilize life course perspectives and advanced causal inference methods to evaluate the potential for inflammation to contribute to the biological embedding of adolescent housing insecurity. Materials and methodsUsing prospective data from the Great Smoky Mountains Study, we investigated the relationship between adolescent housing insecurity and whole-blood spot samples assayed for C-reactive protein (CRP). Adolescent housing insecurity was created based on annual measures of frequent residential moves, reduced standard of living, forced separation from the home, and foster care. Annual measures of CRP ranged from 0.001 mg/L to 13.6 mg/L (median = 0.427 mg/L) and were log10 transformed to account for positively skewed values. We used g-estimation of structural nested mean models to estimate a series of conditional average causal effects of adolescent housing insecurity on CRP levels from ages 11 to 16 years and interpreted the results within life course frameworks of accumulation, recency, and sensitive periods. Principal ResultsOf the 1,334 participants, 427 [44.3 %] were female. Based on the conditional average causal effect, one exposure to adolescent housing insecurity from ages 11 to 16 years led to a 6.4 % (95 % CI = 0.69 – 12.4) increase in later CRP levels. Exposure at 14 years of age led to a 27.9 % increase in CRP levels at age 15 (95 % CI = 6.5 – 53.5). Recent exposures to adolescent housing insecurity (<3 years) suggested stronger associations with CRP levels than distant exposures (>3 years), but limited statistical power prevented causal conclusions regarding recency effects at the risk of a Type II Error. Major ConclusionsThese findings highlight inflammation—as indicated by increased CRP levels—as one potential mechanism for the biological embedding of adolescent housing insecurity. The results also suggest that adolescent housing insecurity—particularly recent, repeated, and mid-adolescent exposures—may increase the risk of poor health outcomes and should be considered a key intervention target.