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 yrs), 28 MA (17F; 51±6 yrs), and 31 O (16F; 70±3 yrs) 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 life span, 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.

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.

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.

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.

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.

Core temperature and heart rate at the upper limit of the prescriptive zone.

The expressed goal of limiting workplace heat stress exposures to a core temperature (Tc ) of 38°C traces back to a 1969 World Health Organization Technical Report (WHO Series 412). The actual goal was to limit exposures to the upper limit of the prescriptive zone (ULPZ). To explore the physiological strain at the ULPZ, progressive heat stress protocol data from Penn State University (PSU) and University of South Florida (USF) below and at the ULPZ were used to articulate the relation of Tc and heart rate (HR) to metabolic rate (MR) with consideration of acclimatization state, clothing, exposure condition (PreULPZ vs. ULPZ), and sex. Regression models demonstrated the association of MR and sex with Tc and HR. At the ULPZ, women had systematically higher values of Tc and HR than men at the same MR likely due to higher relative demands. There was no effect for acclimatization state and clothing. As expected for individuals, Tc was practically constant below the ULPZ and HR exhibited increasing values approaching the ULPZ. At 490 W, the high MR cited in the WHO document, the mean Tc for men was near the 38°C limit with systematically lower Tc at lower MRs.

Craniectomy size and decompression of the temporal base using the altered posterior question-mark incision for decompressive hemicraniectomy.

The altered posterior question-mark incision for decompressive hemicraniectomy (DHC) was proposed to reduce the risk of intraoperative injury of the superficial temporal artery (STA) and demonstrated a reduced rate of wound-healing disorders after cranioplasty. However, decompression size during DHC is essential and it remains unclear if the new incision type allows for an equally effective decompression. Therefore, this study evaluated the efficacy of the altered posterior question-mark incision for craniectomy size and decompression of the temporal base and assessed intraoperative complications compared to a modified standard reversed question-mark incision. The authors retrospectively identified 69 patients who underwent DHC from 2019 to 2022. Decompression and preservation of the STA was assessed on postoperative CT scans and CT or MR angiography. Forty-two patients underwent DHC with the standard reversed and 27 patients with the altered posterior question-mark incision. The distance of the margin of the craniectomy to the temporal base was 6.9 mm in the modified standard reversed and 7.2 mm in the altered posterior question-mark group (p = 0.77). There was no difference between the craniectomy sizes of 158.8 mm and 158.2 mm, respectively (p = 0.45), and there was no difference in the rate of accidental opening of the mastoid air cells. In both groups, no transverse/sigmoid sinus was injured. Twenty-four out of 42 patients in the modified standard and 22/27 patients in the altered posterior question-mark group had a postoperative angiography, and the STA was preserved in all cases in both groups. Twelve (29%) and 5 (19%) patients underwent revision due to wound-healing disorders after DHC, respectively (p = 0.34). There was no difference in duration of surgery. Thus, the altered posterior question-mark incision demonstrated technically equivalent and allows for an equally effective craniectomy size and decompression of the temporal base without increasing risks of intraoperative complications. Previously described reduction in wound-healing complications and cranioplasty failures needs to be confirmed in prospective studies to demonstrate the superiority of the altered posterior question-mark incision.

Distribution of upper limit of the prescriptive zone values for acclimatized and unacclimatized individuals.

Heat stress has an adverse impact on worker health and well-being, and the effects will increase with more frequent and severe heat events associated with global warming. Acclimatization to heat stress is widely considered to be a critical mitigation strategy and wet bulb globe temperature- (WBGT-) based occupational standards and guidelines contain adjustments for acclimatization. The purpose here was to 1) compare the mean values for the upper limit of the prescriptive zone (ULPZ, below which the rise in core temperature is minimal) between unacclimatized and acclimatized men and women; 2) demonstrate that the change in the occupational exposure limit (ΔOEL) due to acclimatization is independent of metabolic rate; 3) examine the relation between ΔOEL and body surface area (BSA); and 4) compare the exposure-response curves between unacclimatized and acclimatized populations. Empirically derived ULPZ data for unacclimatized participants from Pennsylvania State University (PSU) and acclimatized participants from University of South Florida (USF) were used to explore the difference between unacclimatized and acclimatized heat exposure limits. The findings provide support for a constant 3°C WBGT OEL decrease to account for unacclimatized workers. Body surface area explained part of the difference in ULPZ values between men and women. In addition, the pooled PSU and USF data provide insight into the distribution of individual values for the ULPZ among young, healthy unacclimatized and acclimatized populations in support of occupational heat stress guidelines.NEW & NOTEWORTHY Occupational exposure limit guidelines using wet bulb globe temperature (WBGT) distinguish between acclimatized and unacclimatized workers with about a 3°C difference between them. For the first time, empirical data from two laboratories provide support for acclimatization state adjustments. Using a constant difference rather than increasing differences with metabolic rate better describes the limit for unacclimatized participants. Furthermore, the lower upper limit of the prescriptive zone (ULPZ) values set forth for women do not relate to fitness level but are partly explained by their smaller body surface area (BSA). An examination of individual ULPZ values suggests that many unacclimatized individuals should be able to sustain safe work at the exposure limit for acclimatized workers.

Nitric oxide-mediated cutaneous microvascular function is not altered in middle-aged-to-older adults following mild SARS-CoV-2 infection: A pilot study.

We tested the hypothesis that post-COVID-19 adults (PC) would have impaired cutaneous nitric oxide (NO)-mediated vasodilation compared to controls (CON). We performed a cross-sectional study including 10 (10 F/0 M, 69 ± 7 years) CON and 7 (2 F/5 M, 66 ± 8 years) PC (223 ± 154 days post-diagnosis). COVID-19 symptoms severity (survey) was assessed (0-100 scale for 18 common symptoms). NO-dependent cutaneous vasodilation was induced by a standardized 42°C local heating protocol and quantified via perfusion of 15 mM NG-nitro-L-arginine methyl ester during the plateau of the heating response (intradermal microdialysis). Red blood cell flux was measured with laser-Doppler flowmetry. Cutaneous vascular conductance (CVC = flux/mm Hg) was presented as a percentage of maximum (28 mM sodium nitroprusside +43°C). All data are means ± SD. The local heating plateau (CON: 71 ± 23% CVCmax vs. PC: 81 ± 16% CVCmax , p = 0.77) and NO-dependent vasodilation (CON: 56 ± 23% vs. PC: 60 ± 22%, p = 0.77) were not different between groups. In the PC group neither time since diagnosis nor peak symptom severity (46 ± 18 AU) correlated with NO-dependent vasodilation (r < 0.01, p = 0.99 and r = 0.42, p = 0.35, respectively). In conclusion, middle-aged and older adults who have had COVID-19 did not have impaired NO-dependent cutaneous vasodilation. Additionally, in this cohort of PC, neither time since diagnosis nor symptomology were related to microvascular function.

Onset of cardiovascular drift during progressive heat stress in young adults (PSU HEAT project).

With climate change, humans are at a greater risk for heat-related morbidity and mortality, often secondary to increased cardiovascular strain associated with an elevated core temperature (Tc). Critical environmental limits (i.e., the upper limits of compensable heat stress) have been established based on Tc responses for healthy, young individuals. However, specific environmental limits for the maintenance of cardiovascular homeostasis have not been investigated in the context of thermal strain during light activity. Therefore, the purposes of this study were to 1) identify the specific environmental conditions (combinations of ambient temperature and water vapor pressure) at which cardiovascular drift [i.e., a continuous rise in heart rate (HR)] began to occur and 2) compare those environments to the environmental limits for the maintenance of heat balance. Fifty-one subjects (27 F; 23 ± 4 yr) were exposed to progressive heat stress across a wide range of environmental conditions in an environmental chamber at two low metabolic rates reflecting minimal activity (MinAct; 159 ± 34 W) or light ambulation (LightAmb; 260 ± 55 W). Whether systematically increasing ambient temperature or humidity, the onset of cardiovascular drift occurred at lower environmental conditions compared with Tc inflection points at both intensities (P < 0.05). Furthermore, the time at which cardiovascular drift began preceded the time of Tc inflection (MinAct P = 0.01; LightAmb P = 0.0002), and the difference in time between HR and Tc inflection points did not differ (MinAct P = 0.08; LightAmb P = 0.06) across environmental conditions for either exercise intensity. These data suggest that even in young adults, increases in cardiovascular strain precede the point at which heat stress becomes uncompensable during light activity.NEW & NOTEWORTHY To our knowledge, this study is the first to 1) identify the specific combinations of temperature and humidity at which an increase in cardiovascular strain (cardiovascular drift) occurs and 2) compare those environments to the critical environmental limits for the maintenance of heat balance. We additionally examined the difference in time between the onset of increased cardiovascular strain and uncompensable heat stress. We show that an increase in cardiovascular strain systematically precedes sustained heat storage in young adults.

Within-limb variation in skin pigmentation does not influence cutaneous vasodilation.

Ultraviolet radiation (UVR) exposure acutely reduces nitric oxide (NO)-dependent cutaneous vasodilation. In addition, increased constitutive skin melanin is associated with attenuated NO-dependent cutaneous vasodilation. However, the impact of within-limb variation in skin melanization, associated with seasonal UVR exposure, on NO-dependent cutaneous vasodilation is unknown. We investigated the effect of within-limb variation in skin melanin on NO-dependent cutaneous vasodilation. Intradermal microdialysis fibers were placed in the inner-upper arm, ventral forearm, and dorsal forearm of seven adults (33 ± 14 yr; 4 M/3 F) with constitutively light skin pigmentation. Melanin-index (M-index; an index of skin pigmentation), measured via reflectance spectrophotometry, confirmed differences in sun exposure among sites. A standardized local heating (42°C) protocol induced cutaneous vasodilation. After attaining a stable elevated blood flow plateau, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) was infused to quantify the NO contribution. Laser-Doppler flowmetry (LDF) measured red cell flux and cutaneous vascular conductance (CVC = LDF/mean arterial pressure) and was normalized to maximal (%CVCmax; 28 mM sodium nitroprusside + 43°C local heating). Dorsal forearm M-index was higher [50.5 ± 11.8 au (arbitrary units)] compared with the ventral forearm (37.5 ± 7.4 au; P ≤ 0.03) and upper arm (30.0 ± 4.0 au; P ≤ 0.001) M-index. Cutaneous vasodilation responses to local heating were not different among sites (P ≥ 0.12). Importantly, neither the magnitude of the local heating plateau (dorsal: 85 ± 21%; ventral: 70 ± 21%; upper: 87 ± 15%; P ≥ 0.16) nor the NO-mediated component of that response (dorsal: 59 ± 15%; ventral: 54 ± 13%; upper: 55 ± 11%; P ≥ 0.79) was different among sites. These data suggest that within-limb differences in skin pigmentation secondary to seasonal UVR exposure do not alter NO-dependent cutaneous vasodilation.NEW & NOTEWORTHY Locally derived endothelial nitric oxide (NO) contributes to the full expression of cutaneous vasodilation responses. Acute ultraviolet radiation (UVR) exposure attenuates NO-mediated vasodilation of the cutaneous microvasculature. Our findings suggest that in constitutively lightly pigmented skin, variation in skin melanin due to seasonal exposure to UVR does not alter the NO contribution to cutaneous vasodilation. Seasonal UVR exposure does not impact the NO-mediated cutaneous microvascular function.

Relatively minor influence of individual characteristics on critical wet-bulb globe temperature (WBGT) limits during light activity in young adults (PSU HEAT Project).

Critical environmental limits are temperature-humidity thresholds above which heat balance cannot be maintained for a given metabolic heat production. This study examined the association between individual characteristics [sex, body surface area (AD), aerobic capacity (V̇o2max), and body mass (mb)] and critical environmental limits in young adults at low metabolic rates. Forty-four (20 M/24 F; 23 ± 4 yr) subjects were exposed to progressive heat stress in an environmental chamber at two low net metabolic rates (Mnet); minimal activity (MinAct; Mnet = ∼160 W) and light ambulation (LightAmb; Mnet = ∼260 W). In two hot-dry (HD; ≤25% rh) environments, ambient water vapor pressure (Pa = 12 or 16 mmHg) was held constant and dry-bulb temperature (Tdb) was systematically increased. In two warm-humid (WH; ≥50% rh) environments, Tdb was held constant at 34°C or 36°C, and Pa was systematically increased. The critical wet-bulb globe temperature (WBGTcrit) was determined for each condition. During MinAct, after entry of Mnet into the forward stepwise linear regression model, no individual characteristics were entered into the model for WH (R2adj = 0.01, P = 0.27) or HD environments (R2adj = -0.01, P = 0.44). During LightAmb, only mb was entered into the model for WH environments (R2adj = 0.44, P < 0.001), whereas only V̇o2max was entered for HD environments (R2adj = 0.22; P = 0.002). These data demonstrate negligible importance of individual characteristics on WBGTcrit during low-intensity nonweight-bearing (MinAct) activity with a modest impact of mb and V̇o2max during weight-bearing (LightAmb) activity in extreme thermal environments.NEW & NOTEWORTHY Our laboratory has recently published a series of papers establishing the upper ambient temperature-humidity thresholds for maintaining heat balance, termed critical environmental limits, in young adults. However, no studies have investigated the relative influence of individual characteristics, such as sex, body size, and aerobic fitness, on those environmental limits. Here, we demonstrate the contributions of sex, body mass, body surface area, and maximal aerobic capacity on critical wet-bulb globe temperature (WBGT) limits in young adults.

Adverse heat-health outcomes and critical environmental limits (Pennsylvania State University Human Environmental Age Thresholds project).

BACKGROUND: The earth's climate is warming and the frequency, duration, and severity of heat waves are increasing. Meanwhile, the world's population is rapidly aging. Epidemiological data demonstrate exponentially greater increases in morbidity and mortality during heat waves in adults ≥65 years. Laboratory data substantiate the mechanistic underpinnings of age-associated differences in thermoregulatory function. However, the specific combinations of environmental conditions (i.e., ambient temperature and absolute/relative humidity) above which older adults are at increased risk of heat-related morbidity and mortality are less clear. METHODS: This review was conducted to (1) examine the recent (past 3 years) literature regarding heat-related morbidity and mortality in the elderly and discuss projections of future heat-related morbidity and mortality based on climate model data, and (2) detail the background and unique methodology of our ongoing laboratory-based projects aimed toward identifying the specific environmental conditions that result in elevated risk of heat illness in older adults, and the implications of using the data toward the development of evidence-based safety interventions in a continually-warming climate (PSU HEAT; Human Environmental Age Thresholds). RESULTS: The recent literature demonstrates that extreme heat continues to be increasingly detrimental to the health of the elderly and that this is apparent across the world, although the specific environmental conditions above which older adults are at increased risk of heat-related morbidity and mortality remain unclear. CONCLUSION: Characterizing the environmental conditions above which risk of heat-related illnesses increase remains critical to enact policy decisions and mitigation efforts to protect vulnerable people during extreme heat events.

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.

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.

COGNITION: a prospective precision oncology trial for patients with early breast cancer at high risk following neoadjuvant chemotherapy.

BACKGROUND: COGNITION (Comprehensive assessment of clinical features, genomics and further molecular markers to identify patients with early breast cancer for enrolment on marker driven trials) is a diagnostic registry trial that employs genomic and transcriptomic profiling to identify biomarkers in patients with early breast cancer with a high risk for relapse after standard neoadjuvant chemotherapy (NACT) to guide genomics-driven targeted post-neoadjuvant therapy. PATIENTS AND METHODS: At National Center for Tumor Diseases Heidelberg patients were biopsied before starting NACT, and for patients with residual tumors after NACT additional biopsy material was collected. Whole-genome/exome and transcriptome sequencing were applied on tumor and corresponding blood samples. RESULTS: In the pilot phase 255 patients were enrolled, among which 213 were assessable: thereof 48.8% were identified to be at a high risk for relapse following NACT; 86.4% of 81 patients discussed in the molecular tumor board were eligible for a targeted therapy within the interventional multiarm phase II trial COGNITION-GUIDE (Genomics-guided targeted post neoadjuvant therapy in patients with early breast cancer) starting enrolment in Q4/2022. An in-depth longitudinal analysis at baseline and in residual tumor tissue of 16 patients revealed some cases with clonal evolution but largely stable genetic alterations, suggesting restricted selective pressure of broad-acting cytotoxic neoadjuvant chemotherapies. CONCLUSIONS: While most precision oncology initiatives focus on metastatic disease, the presented concept offers the opportunity to empower novel therapy options for patients with high-risk early breast cancer in the post-neoadjuvant setting within a biomarker-driven trial and provides the basis to test the value of precision oncology in a curative setting with the overarching goal to increase cure rates.

Core temperature responses to compensable versus uncompensable heat stress in young adults (PSU HEAT Project).

With global warming, much attention has been paid to the upper limits of human adaptability. However, the time to reach a generally accepted core temperature criterion (40.2°C) associated with heat-related illness above (uncompensable heat stress) and just below (compensable heat stress) the upper limits for heat balance remains unclear. Forty-eight (22 men/26 women; 23 ± 4 yr) subjects were exposed to progressive heat stress in an environmental chamber during minimal activity (MinAct, 159 ± 34 W) and light ambulation (LightAmb, 260 ± 55 W) in warm-humid (WH; ∼35°C, >60% RH) and hot-dry (HD; 43°C-48°C, <25% RH) environments until heat stress became uncompensable. For each condition, we compared heat storage (S) and the change in gastrointestinal temperature (ΔTgi) over time during compensable and uncompensable heat stress. In addition, we examined whether individual characteristics or seasonality were associated with the rate of increase in Tgi. During compensable heat stress, S was higher in HD than in WH environments (P < 0.05) resulting in a greater but more variable ΔTgi (P ≥ 0.06) for both metabolic rates. There were no differences among conditions during uncompensable heat stress (all P > 0.05). There was no influence of sex, aerobic fitness, or seasonality, but a larger body size was associated with a greater ΔTgi during LightAmb in WH (P = 0.003). The slopes of the Tgi response during compensable (WH: MinAct, 0.06, LightAmb, 0.09; HD: MinAct, 0.12, LightAmb, 0.15°C/h) and uncompensable (WH: MinAct, 0.74, LightAmb, 0.87; HD: MinAct, 0.71, LightAmb, 0.93°C/h) heat stress can be used to estimate the time to reach a target core temperature from any given starting value.NEW & NOTEWORTHY This study is the first to examine heat storage and the rate of change in core temperature above (uncompensable heat stress) and just below (compensable heat stress) critical environmental limits to human heat balance. Furthermore, we examine the influence of individual subject characteristics and seasonality on the change in core temperature in warm-humid versus hot-dry environments. We provide the rate of change in core temperature, enabling projections to be made to and from any hypothetical core temperature.