Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

Sex differences in heat stress vulnerability among middle-aged and older adults (PSU HEAT project).

Individuals over the age of 65 are the most vulnerable population during severe environmental heat events, experiencing worse health outcomes than any other age cohort. The risk is greater in older women than in age-matched men; however, whether that reflects a greater susceptibility to heat in women or simply population sex proportionality is unclear. Seventy-two participants (29 M/43 F) aged 40-92 yrs were exposed to progressive heat stress at a metabolic rate designed to reflect activities of daily living. Experiments were conducted in both hot-dry (HD; up to 53°C; ≤25% rh) and warm-humid (WH; ~35°C; ≥50% rh) environments. After determining critical limits for each condition, forward stepwise multiple linear regression analyses were conducted with net metabolic rate (Mnet) and age entered into the model first, followed by sex, body mass (mb), V̇o2max, body surface area, and LDL cholesterol. After accounting for Mnet and age, sex further improved the regression model in the HD environment (R2adj = 0.34, p < 0.001) and WH environment (R2 adj = 0.36, P < 0.005). Sex explained approximately 15% of the variance in critical environmental limits in HD conditions and 12% in WH conditions. Heat compensability curves were shifted leftward for older women indicating age and sex-dependent heat vulnerability compared to middle-aged women and older men in WH (p=0.007, p=0.03) and HD (p=0.001, p=0.01) environments. This reflects the heterogeneity of thermal-balance thresholds associated with aging relative to those seen in young adults and suggests that older females are more vulnerable than their age-matched male counterparts.

A Novel Conceptual Model for Human Heat Tolerance.

Human "heat tolerance" has no accepted definition or physiological underpinnings; rather, it is almost always discussed in relative or comparative terms. We propose to use environmental limits to heat balance accounting for metabolic rate and clothing, that is, the environments for which heat stress becomes uncompensable for a specified metabolic rate and clothing, as a novel metric for quantifying heat tolerance.

Sex differences in thermophysiological responses of elderly to low-intensity exercise during uncompensable heat strain.

PURPOSE: The rising frequency of extreme heat events poses an escalating threat of heat-related illnesses and fatalities, placing an additional strain on global healthcare systems. Whether the risk of heat-related issues is sex specific, particularly among the elderly, remains uncertain. METHODS: 16 men and 15 women of similar age (69 ± 5 years) were exposed to an air temperature of 39.1 ± 0.3 °C and a relative humidity (RH) of 25.1 ± 1.9%, during 20 min of seated rest and at least 40 min of low-intensity (10 W) cycling exercise. RH was gradually increased by 2% every 5 min starting at minute 30. We measured sweat rate, heart rate, thermal sensation, and the rise in gastrointestinal temperature (Tgi) and skin temperature (Tsk). RESULTS: Tgi consistently increased from minute 30 to 60, with no significant difference between females and males (0.012 ± 0.004 °C/min vs. 0.011 ± 0.005 °C/min; p = 0.64). Similarly, Tsk increase did not differ between females and males (0.044 ± 0.007 °C/min vs. 0.038 ± 0.011 °C/min; p = 0.07). Females exhibited lower sweat rates than males (0.29 ± 0.06 vs. 0.45 ± 0.14 mg/m2/min; p < 0.001) in particular at relative humidities exceeding 30%. No sex differences in heart rate and thermal sensation were observed. CONCLUSION: Elderly females exhibit significantly lower sweat rates than their male counterparts during low-intensity exercise at ambient temperatures of 39 °C when humidity exceeds 30%. However, both elderly males and females demonstrate a comparable rise in core temperature, skin temperature, and mean body temperature, indicating similar health-related risks associated with heat exposure.

Responsive neurostimulation in pediatric epilepsy: a systematic review and individual patient meta-analysis supplemented by a single institution case series in 105 aggregated patients.

PURPOSE: To assess responsive neurostimulation (RNS) efficacy in pediatric patients with drug-resistant epilepsy, comparing response (≥ 50% reduction in seizure frequency) rates between patients with two or fewer seizure foci and those with multifocal or generalized epilepsy. This study seeks to address the gap in knowledge regarding RNS effectiveness in pediatric populations. METHODS: A systematic review and meta-analysis included data from PubMed, Embase, and Web of Science through November 2023, including 17 retrospective studies and a case series of 24 patients from our practice for a total of 105 aggregated patients. The inclusion criteria of patients were age ≤ 18 and diagnosis of DRE. Exclusion criteria were nonhuman subjects and cases where RNS was not utilized to treat DRE. Study inclusion criteria were detailing the use of RNS and comparing patients with ≤ 2 foci with other focalities. Study exclusion criteria were failure to specify RNS lead placement or type of epilepsy. The risk of bias was assessed using the ROBINS-I tool for all non-randomized studies. Effect sizes and variances were aggregated to provide a comprehensive measure of RNS efficacy, and heterogeneity among the studies was assessed using I2 statistics and Cochran's Q test to evaluate the consistency of the findings. Statistical analyses were conducted using IBM SPSS. We analyzed demographics, epilepsy history, treatment outcomes, and RNS details using descriptive and inferential statistics, including Wilcoxon-Mann-Whitney, Fisher's exact, and chi-squared tests. This systematic review was not registered. RESULTS: Seventeen retrospective studies and a single-institution case series, encompassing 105 pediatric patients, were analyzed. Effect sizes and confidence intervals were calculated to quantify treatment effects. Analyses revealed that RNS reduces seizure frequency across a spectrum of pediatric epilepsy syndromes, irrespective of the seizures' focal, multifocal, or generalized origins. The effectiveness of RNS was not influenced by the patient's sex, age at epilepsy onset, or presence of neurological and psychiatric comorbidities. Prior vagus nerve stimulation surgery and the presence of an epileptic syndrome were factors associated with a lower likelihood of near-complete seizure remission with RNS, underscoring the complexities of treating patients with generalized epilepsies or previous interventional failures. The necessity of further research into individualized surgical strategies for patients was underscored by the mixed results of comparisons of electrode characteristics with responder rates. Limitations of our study include its reliance on retrospective studies, which introduces potential bias and limits the ability to infer causality. DISCUSSION: RNS is a safe and effective treatment in pediatric patients with DRE across demographic, comorbidity, and focality variability. FDA age and focality restrictions, along with patient and physician hesitancy, may be limiting the potential for effective treatment of pediatric DRE with RNS. Prospective randomized trials are recommended to validate these findings.

Sunscreen does not alter sweating responses or critical environmental limits in young adults (PSU HEAT project).

Outdoor athletes often eschew using sunscreen due to perceived performance impairments, which many attribute in part to the potential for reduced thermoregulatory heat loss. Past studies examining the impact of sunscreen on thermoregulation are equivocal. The purpose of this study was to determine the effects of mineral and chemical-based sunscreens on sweating responses and critical environmental limits in hot-dry (HD) and warm-humid (WH) environments. Nine subjects (3 M/6 F; 25 ± 2 yr) were tested with 1) no sunscreen (control), 2) chemical-, and 3) mineral-based sunscreen. Subjects were exposed to progressive heat stress with either 1) constant dry-bulb temperature (Tdb) at 34°C and increasing water vapor pressure (Pa) (WH trials) or 2) constant Pa at 12 mmHg and increasing Tdb (HD trials). Subjects walked at 4.9 ± 0.5 metabolic equivalents (METs) until an upward inflection in gastrointestinal temperature was observed (i.e., the critical environmental limit). Compared with control (39.9 ± 3.0°C), critical Tdb was not different in mineral (39.2 ± 3.5°C, P = 0.39) or chemical (39.7 ± 3.0°C, P = 0.98) sunscreen trials in HD environments. Compared with control (18.8 ± 4.0 mmHg), critical Pa was not different in mineral (18.9 ± 4.8 mmHg, P = 0.81) or chemical (19.5 ± 4.6 mmHg, P = 0.81) sunscreen trials in WH environments. Sweating rates, evaporative heat loss, skin wettedness, and sweating efficiency were not different among the three trials in the WH (all P ≥ 0.48) or HD (all P ≥ 0.87) environments. Critical environmental limits are unaffected by sunscreen application, suggesting sunscreen does not alter integrative thermoregulatory responses during exercise in the heat.NEW & NOTEWORTHY Our findings demonstrate that neither sweating nor critical environmental limits were affected by mineral-based and chemical-based sunscreen applications. The rates of change in core temperature during compensable and uncompensable heat stress were not changed by wearing sunscreen. Evaporative heat loss, efficiency of sweat evaporation, skin wettedness, and sweating rates were unaffected by sunscreen. Sunscreen did not alter integrative thermoregulatory responses during exercise in the heat.

Critical environmental core temperature limits and heart rate thresholds across the adult age span (PSU HEAT Project).

The frequency, duration, and severity of extreme heat events have increased and are projected to continue to increase throughout the next century. As a result, there is an increased risk of excessive heat- and cardiovascular-related morbidity and mortality during these extreme heat events. Therefore, the purposes of this investigation were to establish 1) critical environmental core temperature (Tc) limits for middle-aged adults (MA), 2) environmental thresholds that cause heart rate (HR) to progressively rise in MA and older (O) adults, and 3) examine critical environmental Tc limits and HR environmental thresholds across the adult age span. Thirty-three young (Y) (15 F; 23 ± 3 yr), 28 MA (17 F; 51 ± 6 yr), and 31 O (16 F; 70 ± 3 yr) subjects were exposed to progressive heat stress in an environmental chamber in a warm-humid (WH, 34-36°C, 50-90% rh) and a hot-dry (HD, 38°C-52°C, <30% rh) environment while exercising at a low metabolic rate reflecting activities of daily living (∼1.8 METs). In both environments, there was a main effect of age on the critical environmental Tc limit and environmental HR thresholds (main effect of age all P < 0.001). Across the lifespan, critical environmental Tc and HR thresholds decline linearly with age in HD environments (R2 ≥ 0.3) and curvilinearly in WH environments (R2 ≥ 0.4). These data support an age-associated shift in critical environmental Tc limits and HR thresholds toward lower environmental conditions and can be used to develop evidence-based safety guidelines to minimize future heat-related morbidity and mortality across the adult age span.NEW & NOTEWORTHY This study is the first to identify critical environmental core temperature and heart rate thresholds across the adult age spectrum. In addition, our data demonstrate that the rate of decline in Tc and HR limits with age is environmental-dependent. These findings provide strong empirical data for the development of safety guidelines and policy decisions to mitigate excessive heat- and cardiovascular-related morbidity and mortality for impending heat events.

Critical Environmental Limits for Human Thermoregulation in the Context of a Changing Climate.

Human-caused climate change has increased the average temperature of the Earth by over 1°C since the 19th century with larger increases expected by 2100 due to continued human influence. This change in mean ambient temperature has had nonlinear effects, resulting in more high temperature extremes, i.e., heat waves, that have increased in frequency, duration, and magnitude. Additional occurrences of humid heatwaves have significantly affected human health due to the physiological strain associated with a relative inability for evaporative cooling. Inability to efficaciously cool the body, whether during passive heat exposure or physical activity, not only leads to elevated core temperatures but also places strain on the cardiovascular system, often exacerbating age-related co-morbidities. As part of the PSU HEAT (Pennsylvania State University - Human Environmental Age Thresholds) Project, a progressive environmental strain protocol has been developed to determine critical environmental limits - combinations of ambient temperature and humidity -- associated with uncompensable heat stress and intractable rises in core temperature (Tc). These human heat balance thresholds, well below those originally theorized by climatologists, have been surpassed in recent heatwaves and be exceeded on a more regular basis in the future, providing additional impetus to the urgency of adaptative measures and climate change mitigation.

Heat stress vulnerability and critical environmental limits for older adults.

The present study examined heat stress vulnerability of apparently healthy older vs. young adults and characterized critical environmental limits for older adults in an indoor setting at rest (Rest) and during minimal activity associated with activities of daily living. Critical environmental limits are combinations of ambient temperature and humidity above which heat balance cannot be maintained (i.e., becomes uncompensable) for a given metabolic heat production. Here we exposed fifty-one young (23±4 yrs) and 49 older (71±6 yrs) adults to progressive heat stress across a wide range of environments in an environmental chamber during Minimal Activity (young and older subjects) and Rest (older adults only). Heat compensability curves were shifted leftward for older adults indicating age-dependent heat vulnerablity (p < 0.01). During Minimal Activity, critical environmental limits were lower in older compared to young adults (p < 0.0001) and lower than those at Rest (p < 0.0001). These data document heat vulnerability of apparently healthy older adults and to define critical environmental limits for indoor settings in older adults at rest and during activities of daily living, and can be used to develop evidence-based recommendations to minimize the deleterious impacts of extreme heat events in this population.

Anatomical characters of the phyllode and stem of Acacia podalyriifolia A. Cunn. ex G. Don (Fabaceae)

The Acacia genus has presented various secondary metabolites, such as tannins, flavonoids, alkaloids and gums. Preparations from different species have been applied for diabetes, gastrointestinal disorders and inflammatory diseases in the traditional medicine and have demonstrated cytotoxic, antimicrobial and antiparasitic activities. Acacia podalyriifolia A. Cunn. ex G. Don (Fabaceae) is a small wood, indigenous to Australia and cultivated worldwide for its ornamental feature. This work aimed to characterize the anatomy of the phyllode and stem, in order to contribute to the species identification. The botanical material was fixed, sectioned and prepared according to usual light and scanning microtechniques. The epidermal cells, in surface view, are polygonal and coated with striate and thick cuticle, and filaments of epicuticular wax. Paracytic stomata and unicellular non-glandular trichomes are seen. Palisade and ground parenchymas, and minor collateral bundles with xylem directed alternately to upper and lower sides occur in the blade. The midrib shows two collateral bundles facing each other. The stem, in incipient secondary growth, exhibits epidermis, annular collenchyma, sclerenchymatic sheath and collateral vascular organization. Cells containing phenolic compounds and prisms of calcium oxalate are observed.