Does salinity mediate the toxicity of perfluorooctanesulfonic acid (PFOS) in an estuarine fish?

Perfluorooctanesulfonic acid (PFOS) is detected in estuarine environments, where salinity levels fluctuate regularly. We investigated the effects of salinity on the toxicity of PFOS in embryos and larvae of Cyprinodon variegatus. We crossed six PFOS treatments (0, 1-10,000 µg/L) with two salinities (10, 30 ppt). Larvae exposed to the highest concentration of PFOS under high salinity accumulated over twice the amount of PFOS compared to larvae maintained under low salinity. Embryonic survival was unaffected by PFOS, salinity, or their interaction. PFOS delayed time to hatch and increased salinity reduced time to hatch regardless of PFOS treatment; however, no salinity by PFOS interactions were observed. Conversely, PFOS and salinity interacted in the larval stage, with decreased survival at 30 ppt salinity. This is one of the first studies evaluating interactive effects of PFOS and high salinity and highlights the importance of assessing PFAS toxicity across life stages.

Assessing the Combined Effects of Host and Parasite Exposure to Forever Chemicals in an Amphibian-Echinostome System.

Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants of growing concern due to their potential negative effects on wildlife and human health. Per- and polyfluoroalkyl substances have been shown to alter immune function in various taxa, which could influence the outcomes of host-parasite interactions. To date, studies have focused on the effects of PFAS on host susceptibility to parasites, but no studies have addressed the effects of PFAS on parasites. To address this knowledge gap, we independently manipulated exposure of larval northern leopard frogs (Rana pipiens) and parasites (flatworms) via their snail intermediate host to environmentally relevant PFAS concentrations and then conducted trials to assess host susceptibility to infection, parasite infectivity, and parasite longevity after emergence from the host. We found that PFAS exposure to only the host led to no significant change in parasite load, whereas exposure of parasites to a 10-µg/L mixture of PFAS led to a significant reduction in parasite load in hosts that were not exposed to PFAS. We found that when both host and parasite were exposed to PFAS there was no difference in parasite load. In addition, we found significant differences in parasite longevity post emergence following exposure to PFAS. Although some PFAS-exposed parasites had greater longevity, this did not necessarily translate into increased infection success, possibly because of impaired movement of the parasite. Our results indicate that exposure to PFAS can potentially impact host-parasite interactions. Environ Toxicol Chem 2024;00:1-10. © 2024 SETAC.

Differential Developmental Neurotoxicity and Tissue Uptake of the Per- and Polyfluoroalkyl Substance Alternatives, GenX and PFBS.

Per- and polyfluoroalkyl substances (PFAS) are a class of synthetic chemicals with several applications. Multiple adverse health effects are reported for longer carbon chain (≤C8) PFAS. Shorter carbon chain PFAS, [e.g., hexafluoropropylene oxide dimer acid (HFPO-DA; GenX) and perfluorobutanesulfonic acid (PFBS)] were introduced as alternatives. Past studies indicate that longer-chain PFAS are neurotoxic targeting the dopamine pathway, but it is not known if shorter-chain PFAS act similarly. This study aimed to evaluate developmental neurotoxicity and tissue uptake of GenX and PFBS using the zebrafish (Danio rerio). First, acute toxicity was assessed by measuring LC50 at 120 h postfertilization (hpf). Body burden was determined after embryonic exposure (1-72 hpf) to sublethal concentrations of GenX or PFBS by LC-ESI-MS/MS. Locomotor activity using a visual motor response assay at 120 hpf and dopamine levels at 72 hpf was assessed after embryonic exposure. PFBS was more acutely toxic and bioaccumulative than GenX. GenX and PFBS caused hyperactivity at 120 hpf, but stronger behavioral alterations were observed for PFBS. An increase in whole organism dopamine occurred at 40 ppb of GenX, while a decrease was observed at 400 ppb of PFBS. Differences detected in dopamine for these two PFAS indicate differential mechanisms of developmental neurotoxicity.

Optimized quantification of intra-host viral diversity in SARS-CoV-2 and influenza virus sequence data.

High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant-calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller and use of replicate sequencing have the most significant impact on single-nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false-negative rates. When replicates are not available, using a combination of multiple callers with more stringent cutoffs is recommended. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intra-host viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intra-host variation, viral diversity, and viral evolution. IMPORTANCE When viruses replicate inside a host cell, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus nor strongly beneficial can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in the inclusion of false-positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant-calling tools. We used simulated and synthetic data to test their performance against a true set of variants and then used these studies to inform variant identification in data from SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.

A battery-less wireless implant for the continuous monitoring of vascular pressure, flow rate and temperature.

Devices for monitoring blood haemodynamics can guide the perioperative management of patients with cardiovascular disease. Current technologies for this purpose are constrained by wired connections to external electronics, and wireless alternatives are restricted to monitoring of either blood pressure or blood flow. Here we report the design aspects and performance parameters of an integrated wireless sensor capable of implantation in the heart or in a blood vessel for simultaneous measurements of pressure, flow rate and temperature in real time. The sensor is controlled via long-range communication through a subcutaneously implanted and wirelessly powered Bluetooth Low Energy system-on-a-chip. The device can be delivered via a minimally invasive transcatheter procedure or it can be mounted on a passive medical device such as a stent, as we show for the case of the pulmonary artery in a pig model and the aorta and left ventricle in a sheep model, where the device performs comparably to clinical tools for monitoring of blood flow and pressure. Battery-less and wireless devices such as these that integrate capabilities for flow, pressure and temperature sensing offer the potential for continuous monitoring of blood haemodynamics in patients.

Soft skin-interfaced mechano-acoustic sensors for real-time monitoring and patient feedback on respiratory and swallowing biomechanics.

Swallowing is a complex neuromuscular activity regulated by the autonomic nervous system. Millions of adults suffer from dysphagia (impaired or difficulty swallowing), including patients with neurological disorders, head and neck cancer, gastrointestinal diseases, and respiratory disorders. Therapeutic treatments for dysphagia include interventions by speech-language pathologists designed to improve the physiology of the swallowing mechanism by training patients to initiate swallows with sufficient frequency and during the expiratory phase of the breathing cycle. These therapeutic treatments require bulky, expensive equipment to synchronously record swallows and respirations, confined to use in clinical settings. This paper introduces a wireless, wearable technology that enables continuous, mechanoacoustic tracking of respiratory activities and swallows through movements and vibratory processes monitored at the skin surface. Validation studies in healthy adults (n = 67) and patients with dysphagia (n = 4) establish measurement equivalency to existing clinical standard equipment. Additional studies using a differential mode of operation reveal similar performance even during routine daily activities and vigorous exercise. A graphical user interface with real-time data analytics and a separate, optional wireless module support both visual and haptic forms of feedback to facilitate the treatment of patients with dysphagia.

Acute Toxicity of Eight Aqueous Film-Forming Foams to 14 Aquatic Species.

Researchers have developed numerous per- and polyfluoroalkyl substances (PFAS)-free aqueous film-forming foam (AFFF) formulations to replace PFAS-containing AFFF used for fire suppression. As part of the Department of Defense's Strategic Environmental Research and Development Program (SERDP), we examined the direct lethal effects of seven PFAS-free AFFF and a PFAS-containing AFFF on 14 aquatic species using a series of lethal concentration (LC50) tests. We assessed the LC10, LC50, and LC90 values using log-logistic and logit analyses. Across all aquatic species tested, we discovered that exposure to at least one PFAS-free AFFF was more or as toxic as exposure to the PFAS-containing AFFF. For most cases, National Foam Avio F3 Green KHC 3% and Buckeye Platinum Plus C6MILSPEC 3% were the most and least toxic formulations, respectively. Moreover, we found consistency among results from multiple experiments using the same minnow species (Pimephales promelas) and among closely related taxa (e.g., daphnids, amphibians). Lastly, the LC50 values for AFFF formulations trended lower for tested marine species as compared to those of freshwater species. These results dramatically increase the current knowledge on the potentially toxic effects of AFFF but also highlight the need for additional research and the development of new PFAS-free AFFF that are more "ecologically friendly" than those containing persistent PFAS.

Efficacy of high-flow nasal oxygenation compared with tracheal intubation for oxygenation during laryngeal microsurgery: a randomised non-inferiority study.

BACKGROUND: Oxygenation via a high-flow nasal cannula (HFNC) can be an alternative to tracheal intubation during short apnoeic procedures. This randomised, non-inferiority study assessed the efficacy of HFNC compared with tracheal intubation in laryngeal microsurgery. METHODS: Patients (≥20 yr old) undergoing laryngeal microsurgery under general anaesthesia and neuromuscular blockade were randomised to either the HFNC or tracheal intubation groups. The primary endpoint was lowest pulse oxygen saturation (SpO2) during the first 30 min of surgery. Secondary endpoints included incidence of desaturation (SpO2 <95%), hypercarbia (transcutaneous carbon dioxide [CO2] ≥8.7 kPa), and rescue intervention. RESULTS: Amongst 130 patients randomised, 118 were included in the analysis. The lowest SpO2 was 100 (98-100)% in the HFNC group (n=56) and 100 (100-100)% in the tracheal intubation group (n=62), with a mean difference of -1.4% (95% confidence interval: -2.4% and -0.3%), failing to confirm non-inferiority with a non-inferiority margin of 2%. The peak transcutaneous CO2 and end-tidal CO2 at the end of surgery were higher in the HFNC group compared with the tracheal intubation group. Incidences of desaturation, hypercarbia, and rescue intervention were more frequent in patients receiving HFNC compared with tracheal intubation. CONCLUSIONS: HFNC oxygenation was not non-inferior to tracheal intubation for maintaining oxygen saturation during laryngeal microsurgery. Considering more frequent desaturation, hypercarbia, and requirement for rescue intervention compared with tracheal intubation, HFNC should be used with cautious monitoring even for short duration airway surgery. CLINICAL TRIAL REGISTRATION: NCT03629353.

Optimized Quantification of Intrahost Viral Diversity in SARS-CoV-2 and Influenza Virus Sequence Data.

High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller, and use of replicate sequencing have the most significant impact on single nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false negative rates. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intrahost viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intrahost variation, viral diversity, and viral evolution. IMPORTANCE: When viruses replicate inside a host, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus, nor strongly beneficial, can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in inclusion of false positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant calling tools. We used simulated and synthetic data to test their performance against a true set of variants, and then used these studies to inform variant identification in data from clinical SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.

Miniaturized wireless, skin-integrated sensor networks for quantifying full-body movement behaviors and vital signs in infants.

Early identification of atypical infant movement behaviors consistent with underlying neuromotor pathologies can expedite timely enrollment in therapeutic interventions that exploit inherent neuroplasticity to promote recovery. Traditional neuromotor assessments rely on qualitative evaluations performed by specially trained personnel, mostly available in tertiary medical centers or specialized facilities. Such approaches are high in cost, require geographic proximity to advanced healthcare resources, and yield mostly qualitative insight. This paper introduces a simple, low-cost alternative in the form of a technology customized for quantitatively capturing continuous, full-body kinematics of infants during free living conditions at home or in clinical settings while simultaneously recording essential vital signs data. The system consists of a wireless network of small, flexible inertial sensors placed at strategic locations across the body and operated in a wide-bandwidth and time-synchronized fashion. The data serve as the basis for reconstructing three-dimensional motions in avatar form without the need for video recordings and associated privacy concerns, for remote visual assessments by experts. These quantitative measurements can also be presented in graphical format and analyzed with machine-learning techniques, with potential to automate and systematize traditional motor assessments. Clinical implementations with infants at low and at elevated risks for atypical neuromotor development illustrates application of this system in quantitative and semiquantitative assessments of patterns of gross motor skills, along with body temperature, heart rate, and respiratory rate, from long-term and follow-up measurements over a 3-mo period following birth. The engineering aspects are compatible for scaled deployment, with the potential to improve health outcomes for children worldwide via early, pragmatic detection methods.

Integration of statistical inferences and machine learning algorithms for prediction of metritis cure in dairy cows.

The study's objectives were to identify cow-level and environmental factors associated with metritis cure to predict metritis cure using traditional statistics and machine learning algorithms. The data set used was from a previous study comparing the efficacy of different therapies and self-cure for metritis. Metritis was defined as fetid, watery, reddish-brownish discharge, with or without fever. Cure was defined as an absence of metritis signs 12 d after diagnosis. Cows were randomly allocated to receive a subcutaneous injection of 6.6 mg/kg of ceftiofur crystalline-free acid (Excede, Zoetis) at the day of diagnosis and 3 d later (n = 275); and no treatment at the time of metritis diagnosis (n = 275). The variables days in milk (DIM) at metritis diagnosis, treatment, season of the metritis diagnosis, month of metritis diagnostic, number of lactation, parity, calving score, dystocia, retained fetal membranes, body condition score at d 5 postpartum, vulvovaginal laceration score, the rectal temperature at the metritis diagnosis, fever at diagnosis, milk production from the day before to metritis diagnosis, and milk production slope up to 5, 7, and 9 DIM were offered to univariate logistic regression. Variables included in the multivariable logistic regression model were selected from the univariate analysis according to P-value. Variables were offered to the model to assess the association between these factors and metritis cure. Additionally, the univariate logistic regression variables were offered to a recursive feature elimination to find the optimal subset of features for a machine learning algorithms analysis. Cows without vulvovaginal laceration had 1.91 higher odds of curing of metritis than cows with vulvovaginal laceration. Cows that developed metritis at >7 DIM had 2.09 higher odds of being cured than cows that developed metritis at ≤7 DIM. For rectal temperature, each degree Celsius above 39.4°C led to lower odds to be cured than cows with rectal temperature ≤39.4°C. Furthermore, milk production slope and milk production difference from the day before to the metritis diagnosis were essential variables to predict metritis cure. Cows that had reduced milk production from the day before to the metritis diagnosis had lower odds to be cured than cows with moderate milk production increase. The results from the multivariable logistic regression and receiver operating characteristic analysis indicated that cows developing metritis at >7 DIM, with increase in milk production, and with a rectal temperature ≤39.40°C had increased likelihood of cure of metritis with an accuracy of 75%. The machine learning analysis showed that in addition to these variables, calving-related disorders, season, and month of metritis event were needed to predict whether the cow will cure or not from metritis with an accuracy ≥70% and F1 score (harmonic mean between precision and recall) ≥0.78. Although machine learning algorithms are acknowledged as powerful tools for predictive classification, the current study was unable to replicate its potential benefits. More research is needed to optimize predictive models of metritis cure.

In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

In vivo evolution of an emerging zoonotic bacterial pathogen in an immunocompromised human host.

Zoonotic transfer of animal pathogens to human hosts can generate novel agents, but the genetic events following such host jumps are not well studied. Here we characterize the mechanisms driving adaptive evolution of the emerging zoonotic pathogen Bordetella hinzii in a patient with interleukin-12 receptor ß1 deficiency. Genomic sequencing of 24 B. hinzii isolates cultured from blood and stool over 45 months revealed a clonal lineage that had undergone extensive within-host genetic and phenotypic diversification. Twenty of 24 isolates shared an E9G substitution in the DNA polymerase III ε-subunit active site, resulting in a proofreading deficiency. Within this proofreading-deficient clade, multiple lineages with mutations in DNA repair genes and altered mutational spectra emerged and dominated clinical cultures for more than 12 months. Multiple enzymes of the tricarboxylic acid cycle and gluconeogenesis pathways were repeatedly mutated, suggesting rapid metabolic adaptation to the human environment. Furthermore, an excess of G:C > T:A transversions suggested that oxidative stress shaped genetic diversification during adaptation. We propose that inactivation of DNA proofreading activity in combination with prolonged, but sub-lethal, oxidative attack resulting from the underlying host immunodeficiency facilitated rapid genomic adaptation. These findings suggest a fundamental role for host immune phenotype in shaping pathogen evolution following zoonotic infection.

Differential cardiopulmonary monitoring system for artifact-canceled physiological tracking of athletes, workers, and COVID-19 patients.

Soft, skin-integrated electronic sensors can provide continuous measurements of diverse physiological parameters, with broad relevance to the future of human health care. Motion artifacts can, however, corrupt the recorded signals, particularly those associated with mechanical signatures of cardiopulmonary processes. Design strategies introduced here address this limitation through differential operation of a matched, time-synchronized pair of high-bandwidth accelerometers located on parts of the anatomy that exhibit strong spatial gradients in motion characteristics. When mounted at a location that spans the suprasternal notch and the sternal manubrium, these dual-sensing devices allow measurements of heart rate and sounds, respiratory activities, body temperature, body orientation, and activity level, along with swallowing, coughing, talking, and related processes, without sensitivity to ambient conditions during routine daily activities, vigorous exercises, intense manual labor, and even swimming. Deployments on patients with COVID-19 allow clinical-grade ambulatory monitoring of the key symptoms of the disease even during rehabilitation protocols.

A skin-conformable wireless sensor to objectively quantify symptoms of pruritus.

Itch is a common clinical symptom and major driver of disease-related morbidity across a wide range of medical conditions. A substantial unmet need is for objective, accurate measurements of itch. In this article, we present a noninvasive technology to objectively quantify scratching behavior via a soft, flexible, and wireless sensor that captures the acousto-mechanic signatures of scratching from the dorsum of the hand. A machine learning algorithm validated on data collected from healthy subjects (n = 10) indicates excellent performance relative to smartwatch-based approaches. Clinical validation in a cohort of predominately pediatric patients (n = 11) with moderate to severe atopic dermatitis included 46 sleep-nights totaling 378.4 hours. The data indicate an accuracy of 99.0% (84.3% sensitivity, 99.3% specificity) against visual observation. This work suggests broad capabilities relevant to applications ranging from assessing the efficacy of drugs for conditions that cause itch to monitoring disease severity and treatment response.

Automated, multiparametric monitoring of respiratory biomarkers and vital signs in clinical and home settings for COVID-19 patients.

Capabilities in continuous monitoring of key physiological parameters of disease have never been more important than in the context of the global COVID-19 pandemic. Soft, skin-mounted electronics that incorporate high-bandwidth, miniaturized motion sensors enable digital, wireless measurements of mechanoacoustic (MA) signatures of both core vital signs (heart rate, respiratory rate, and temperature) and underexplored biomarkers (coughing count) with high fidelity and immunity to ambient noises. This paper summarizes an effort that integrates such MA sensors with a cloud data infrastructure and a set of analytics approaches based on digital filtering and convolutional neural networks for monitoring of COVID-19 infections in sick and healthy individuals in the hospital and the home. Unique features are in quantitative measurements of coughing and other vocal events, as indicators of both disease and infectiousness. Systematic imaging studies demonstrate correlations between the time and intensity of coughing, speaking, and laughing and the total droplet production, as an approximate indicator of the probability for disease spread. The sensors, deployed on COVID-19 patients along with healthy controls in both inpatient and home settings, record coughing frequency and intensity continuously, along with a collection of other biometrics. The results indicate a decaying trend of coughing frequency and intensity through the course of disease recovery, but with wide variations across patient populations. The methodology creates opportunities to study patterns in biometrics across individuals and among different demographic groups.

Wireless, skin-interfaced sensors for compression therapy.

Therapeutic compression garments (TCGs) are key tools for the management of a wide range of vascular lower extremity conditions. Proper use of TCGs involves application of a minimum and consistent pressure across the lower extremities for extended periods of time. Slight changes in the characteristics of the fabric and the mechanical properties of the tissues lead to requirements for frequent measurements and corresponding adjustments of the applied pressure. Existing sensors are not sufficiently small, thin, or flexible for practical use in this context, and they also demand cumbersome, hard-wired interfaces for data acquisition. Here, we introduce a flexible, wireless monitoring system for tracking both temperature and pressure at the interface between the skin and the TCGs. Detailed studies of the materials and engineering aspects of these devices, together with clinical pilot trials on a range of patients with different pathologies, establish the technical foundations and measurement capabilities.

Parity and the risk of incident dementia: a COSMIC study.

AIMS: To investigate the association between parity and the risk of incident dementia in women. METHODS: We pooled baseline and follow-up data for community-dwelling women aged 60 or older from six population-based, prospective cohort studies from four European and two Asian countries. We investigated the association between parity and incident dementia using Cox proportional hazards regression models adjusted for age, educational level, hypertension, diabetes mellitus and cohort, with additional analysis by dementia subtype (Alzheimer dementia (AD) and non-Alzheimer dementia (NAD)). RESULTS: Of 9756 women dementia-free at baseline, 7010 completed one or more follow-up assessments. The mean follow-up duration was 5.4 ± 3.1 years and dementia developed in 550 participants. The number of parities was associated with the risk of incident dementia (hazard ratio (HR) = 1.07, 95% confidence interval (CI) = 1.02-1.13). Grand multiparity (five or more parities) increased the risk of dementia by 30% compared to 1-4 parities (HR = 1.30, 95% CI = 1.02-1.67). The risk of NAD increased by 12% for every parity (HR = 1.12, 95% CI = 1.02-1.23) and by 60% for grand multiparity (HR = 1.60, 95% CI = 1.00-2.55), but the risk of AD was not significantly associated with parity. CONCLUSIONS: Grand multiparity is a significant risk factor for dementia in women. This may have particularly important implications for women in low and middle-income countries where the fertility rate and prevalence of grand multiparity are high.

Varying the Interpentacene Electronic Coupling to Tune Singlet Fission.

We have designed and used four different spacers, denoted A-D, to connect two pentacenes and to probe the impact of intramolecular forces on the modulation of pentacene-pentacene interactions and, in turn, on the key steps in singlet fission (SF), that is, the 1(S1S0)-to-1(T1T1) as well as 1(T1T1)-to-5(T1T1) transitions by means of transient absorption and electron paramagnetic resonance measurements. In terms of the 1(S1S0)-to-1(T1T1) transition, a superexchange mechanism, that is, coupling to a higher-lying CT state to generate a virtual intermediate, enables rapid SF in A-D. Sizeable electronic coupling in A and B opens, on one hand, an additional pathway, that is, the population of a real intermediate, and changes, on the other hand, the mechanism to that of hopping. In turn, A and B feature much higher 1(T1T1) quantum yields than C and D, with a maximum value of 162% for A. In terms of the 1(T1T1)-to-5(T1T1) transition, the sizable electronic coupling in A and B is counterproductive, and C and D give rise to higher 5(T1T1)-to-(T1 + T1) quantum yields than A and B, with a maximum value of 85% for D.

Protracted course of disseminated adenovirus disease with necrotizing granulomas in the liver.

A 52- year-old male with chronic lymphocytic leukemia was hospitalized with disseminated adenovirus disease. More than a month following recovery, hepatic necrotizing granulomas secondary to adenovirus were found. This case illustrates the protracted course that adenovirus disease may take and emphasizes an unusual presentation with hepatic necrotizing granulomas.