Heatwaves exacerbate pollen limitation through reductions in pollen production and pollen vigour.

Increasingly frequent heat waves threaten the reproduction of flowering plants; compromising the future persistence, adaptive capacity, and dispersal of wild plant populations, and also the yield of fruit-bearing crop plants. Heat damages the development of sensitive floral organs and gametes, which inhibits pollen germination, pollen tube growth, and fertilization. However, the role of heat has not been integrated into the framework of pollen quantity and quality limitation and how heat influences the success of cross and self-pollination. We exposed developing flowers to either controlled temperature (25 °C:20 °C) or extreme heat (35 °C:20 °C) over 72 h. We then hand-pollinated them with either crossed or self-derived pollen from the same temperature treatment to determine the direct and interactive effects of simulated heatwaves on pollen tube growth and resulting seed set. We also collected anthers from virgin flowers to measure heat impacts on pollen production. Under cooler control temperatures pollen tube survival of self-derived pollen was approximately 27% lower than that of crossed pollen. Pollen tube survival in heat-treated cross-pollinated and heat-treated self-pollinated flowers were 71% and 77% lower compared to flowers cross-pollinated at control temperatures. These differences in pollen tube survival rate between heat-treated cross-pollinated and heat-treated self-pollinated flowers were insignificant. Furthermore, extreme heat reduced seed set by 87%, regardless of pollen origin, and also reduced pollen production during flower development by approximately 20%. Our results suggest flowers that develop during heatwaves are likely to experience exacerbated pollen quantity and quality limitation driven by changes in pollen production and pollen vigour. Heatwave-induced pollen limitation will likely reduce crop yields in agricultural systems, and depress mating and reproduction in wild plant species, the latter of which may hinder the adaptive capacity of plants to a rapidly changing world.

Inhibition of EZH2 Reduces Aging-Related Decline in Interstitial Cells of Cajal of the Mouse Stomach.

BACKGROUND & AIMS: Restricted gastric motor functions contribute to aging-associated undernutrition, sarcopenia, and frailty. We previously identified a decline in interstitial cells of Cajal (ICC; gastrointestinal pacemaker and neuromodulator cells) and their stem cells (ICC-SC) as a key factor of gastric aging. Altered functionality of the histone methyltransferase enhancer of zeste homolog 2 (EZH2) is central to organismal aging. Here, we investigated the role of EZH2 in the aging-related loss of ICC/ICC-SC. METHODS: klotho mice, a model of accelerated aging, were treated with the most clinically advanced EZH2 inhibitor, EPZ6438 (tazemetostat; 160 mg/kg intraperitoneally twice a day for 3 weeks). Gastric ICC were analyzed by Western blotting and immunohistochemistry. ICC and ICC-SC were quantified by flow cytometry. Gastric slow wave activity was assessed by intracellular electrophysiology. Ezh2 was deactivated in ICC by treating KitcreERT2/+;Ezh2fl/fl mice with tamoxifen. TRP53, a key mediator of aging-related ICC loss, was induced with nutlin 3a in gastric muscle organotypic cultures and an ICC-SC line. RESULTS: In klotho mice, EPZ6438 treatment mitigated the decline in the ICC growth factor KIT ligand/stem cell factor and gastric ICC. EPZ6438 also improved gastric slow wave activity and mitigated the reduced food intake and impaired body weight gain characteristic of this strain. Conditional genomic deletion of Ezh2 in Kit-expressing cells also prevented ICC loss. In organotypic cultures and ICC-SC, EZH2 inhibition prevented the aging-like effects of TRP53 stabilization on ICC/ICC-SC. CONCLUSIONS: Inhibition of EZH2 with EPZ6438 mitigates aging-related ICC/ICC-SC loss and gastric motor dysfunction, improving slow wave activity and food intake in klotho mice.

Perspective of obstetric care-providers on being involved in cervical cancer screening during antenatal care in the Netherlands.

BACKGROUND: The aim of this study was to determine attitude of Dutch midwifes, gynecologists and general practitioners (GPs) towards involvement in antenatal cervical cancer screening (CCS) in the Netherlands. METHODS: In 2021, Dutch midwives, gynecologists, and GPs were offered a single digital questionnaire assessing perceived feasibility, benefits, and harms of antenatal CCS. RESULTS: A total of 6943 Questionnaires were send and response rate was 18% (N = 1260). Of all respondents, 78% considered antenatal CCS via obstetric care providers feasible. Most respondents (85%) agreed that offering CCS in person can increase motivation to attend. Most midwives (93%) considered that women would feel less encumbered if cervical sampling would be performed by obstetric care providers, rather than by GPs. CONCLUSION: Results indicate that introduction of antenatal CCS is considered feasible by a majority of Dutch midwifes, gynecologists, and GPs. Considered benefits include improved motivation to attend and reduced test related barriers.

Pathophysiological processes underlying hidden hearing loss revealed in Kcnt1/2 double knockout mice.

Presbycusis is a prevalent condition in older adults characterized by the progressive loss of hearing due to age-related changes in the cochlea, the auditory portion of the inner ear. Many adults also struggle with understanding speech in noise despite having normal auditory thresholds, a condition termed "hidden" hearing loss because it evades standard audiological assessments. Examination of animal models and postmortem human tissue suggests that hidden hearing loss is also associated with age-related changes in the cochlea and may, therefore, precede overt age-related hearing loss. Nevertheless, the pathological mechanisms underlying hidden hearing loss are not understood, which hinders the development of diagnostic biomarkers and effective treatments for age-related hearing loss. To fill these gaps in knowledge, we leveraged a combination of tools, including transcriptomic profiling and morphological and functional assessments, to identify these processes and examine the transition from hidden to overt hearing loss. As a novel approach, we took advantage of a recently characterized model of hidden hearing loss: Kcnt1/2 double knockout mice. Using this model, we find that even before observable morphological pathology, hidden hearing loss is associated with significant alteration in several processes, notably proteostasis, in the cochlear sensorineural structures, and increased susceptibility to overt hearing loss in response to noise exposure and aging. Our findings provide the first insight into the pathophysiology associated with the earliest and, therefore, most treatable stages of hearing loss and provide critical insight directing future investigation of pharmaceutical strategies to slow and possibly prevent overt age-related hearing loss.

Ketamine reduces seizure and interictal continuum activity in refractory status epilepticus: a multicenter in-person and teleneurocritical care study.

BACKGROUND: There is not a preferred medication for treating refractory status epilepticus (RSE) and intravenous ketamine is increasingly used. Ketamine efficacy, safety, dosage, and influence of other variables on seizure cessation while on ketamine infusions are not well studied. We aimed to characterize ketamine effect on RSE, including interictal activity on electroencephalogram (EEG) and when done by Teleneurocritical care (TNCC). METHODS: We conducted a multicenter, retrospective study from August 2017 to October 2022. Patients 18 years or older who had RSE and received ketamine were included. The primary outcome was effect of ketamine on RSE including interictal activity; secondary outcomes were effect of other variables on RSE, care by TNCC, ketamine infusion dynamics, adverse events, and discharge outcomes. Logistic regression was used. RESULTS: Fifty-one patients from five hospitals met inclusion criteria; 30 patients had RSE and interictal activity on EEG. Median age was 56.8 years (IQR 18.2) and 26% had previously diagnosed epilepsy. Sixteen (31%) patients were treated virtually by TNCC. In those with RSE on EEG, ketamine was added as the fourth antiseizure medication (mean 4.4, SD 1.6). An initial bolus of ketamine was used in 24% of patients (95 mg, IQR 47.5), the median infusion rate was 30.8 mcg/kg/min (IQR 40.4), and median infusion duration was 40 h (IQR 37). Ketamine was associated with 50% cessation of RSE and interictal activity at 24 h in 84% of patients, and complete seizure cessation in 43% of patients. In linear regression, ASMs prior to ketamine were associated with seizure cessation (OR 2.6, 95% CI 0.9-6.9, p = 0.05), while the inverse was seen with propofol infusions (OR 0.02, 95% CI 0.001-0.43, p = 0.01). RSE management by in-person NCC versus virtual by TNCC did not affect rates of seizure cessation. CONCLUSIONS: Ketamine infusions for RSE were associated with reduced seizure burden at 24 h, with 84% of patients having 50% seizure reduction. Similar efficacy and safety was observed irrespective of underlying RSE etiology or when done via TNCC vs in-person NCC.

Insecticides, more than herbicides, land use, and climate, are associated with declines in butterfly species richness and abundance in the American Midwest.

Mounting evidence shows overall insect abundances are in decline globally. Habitat loss, climate change, and pesticides have all been implicated, but their relative effects have never been evaluated in a comprehensive large-scale study. We harmonized 17 years of land use, climate, multiple classes of pesticides, and butterfly survey data across 81 counties in five states in the US Midwest. We find community-wide declines in total butterfly abundance and species richness to be most strongly associated with insecticides in general, and for butterfly species richness the use of neonicotinoid-treated seeds in particular. This included the abundance of the migratory monarch (Danaus plexippus), whose decline is the focus of intensive debate and public concern. Insect declines cannot be understood without comprehensive data on all putative drivers, and the 2015 cessation of neonicotinoid data releases in the US will impede future research.

The complementary dominance hypothesis: a model for remediating the 'good' hand in stroke survivors.

The complementary dominance hypothesis is a novel model of motor lateralization substantiated by decades of research examining interlimb differences in the control of upper extremity movements in neurotypical adults and hemisphere-specific motor deficits in stroke survivors. In contrast to earlier ideas that attribute handedness to the specialization of one hemisphere, our model proposes complementary motor control specializations in each hemisphere. The dominant hemisphere mediates optimal control of limb dynamics as required for smooth and efficient movements, whereas the non-dominant hemisphere mediates impedance control, important for countering unexpected mechanical conditions and achieving steady-state limb positions. Importantly, this model proposes that each hemisphere contributes its specialization to both arms (though with greater influence from either arm's contralateral hemisphere) and thus predicts that lesions to one hemisphere should produce hemisphere-specific motor deficits in not only the contralesional arm, but also the ipsilesional arm of stroke survivors - a powerful prediction now supported by a growing body of evidence. Such ipsilesional arm motor deficits vary with contralesional arm impairment, and thus individuals with little to no functional use of the contralesional arm experience both the greatest impairments in the ipsilesional arm, as well as the greatest reliance on it to serve as the main or sole manipulator for activities of daily living. Accordingly, we have proposed and tested a novel intervention that reduces hemisphere-specific ipsilesional arm deficits and thereby improves functional independence in stroke survivors with severe contralesional impairment.

Symmetry and synchrony of bimanual movements are not predicated on interlimb control coupling.

Previous studies suggest that bimanual coordination recruits neural mechanisms that explicitly couple control of the arms, resulting in symmetric kinematics. However, the higher symmetry for actions that require congruous joint motions compared with noncongruous joint motions calls into question the concept of control coupling as a general policy. An alternative view proposes that codependence might emerge from an optimal feedback controller that minimizes control effort and costs in task performance. Support for this view comes from studies comparing conditions in which both hands move a shared or independent virtual objects. Because these studies have mainly focused on congruous bimanual movements, it remains unclear if kinematic symmetry emerges from such control policies. We now examine movements with congruous or noncongruous joint motions (inertially symmetric or asymmetric, respectively) under shared or independent cursors conditions. We reasoned that if a control policy minimizes kinematic differences between limbs, spatiotemporal symmetry should remain relatively unaffected by inertial asymmetries. As shared tasks reportedly elicit greater interlimb codependence, these conditions should elicit higher bilateral covariance regardless of inertial asymmetries. Our results indicate a robust spatiotemporal symmetry only under inertially symmetric conditions, regardless of cursor condition. We simulated bimanual reaching using an optimal feedback controller with and without explicit costs of kinematic asymmetry, finding that only the latter mirrored our empirical data. Our findings support the hypothesis that bimanual control policies do not include kinematic asymmetry as a cost when it is not demanded by task constraints suggesting that kinematic symmetry depends critically on mechanical movement conditions.NEW & NOTEWORTHY Previously, the control coupling hypothesis and task-dependent control hypothesis have been shown to be robust in the bimanually symmetrical movement, but whether the same policy remains robust in the bimanually asymmetrical movement remains unclear. Here, with evidence from empirical and simulation data, we show that a spatiotemporal symmetry between the arms is not predicated on control coupling, but instead it is predicated on the symmetry of mechanical conditions (e.g. limb inertia) between the arms.

Poisson Modeling Predicts Acute Telestroke Patient Call Volume.

Background: Predicting the frequency of calls for telestroke and emergency teleneurology consultation is essential to prepare staffing for the immediate management of time-sensitive strokes. In this study, we evaluate Poisson distribution count data using a generalized linear model that predicts the volume of hourly telestroke calls over a 24-h period. Methods: We performed an Institutional Review Board approved retrospective cohort review of patients (January 2019-December 2022) from an institutional telestroke database at a large nonprofit multihospital system in the United States. All patients ≥18 years with a telestroke activation were included. Telestroke calls were quantified in frequency per day and analyzed by multiple time and date intervals. Poisson probability mass function (PMF) and cumulative distribution function (CDF) were used to predict call probabilities. A univariable Poisson regression model was fit to predict call volumes. Results: A total of 8,499 patients at 21 hospitals met inclusion criteria, the mean calls/day were 5.82 ± 2.54, and mean calls/day within each hour increment ranged from a minimum of 0.07 from 5 a.m. to 6 a.m. to a maximum of 0.45 from 7 p.m. to 8 p.m. The Poisson distribution was the most appropriate parametric probability model for these data, confirmed by the fit of the data to the expected distributions corresponding to the calculated means. The predicted probabilities of call frequencies by hour were calculated using the Poisson PMF and CDF; the probability of two or fewer calls/day by hour ranged from 98.9% to 99.9%. Univariable Poisson regression modeled an increase of future calls/day from 6.7 calls/day in July 2023 to 7.6 calls/day in October 2025. Conclusion: Poisson modeling closely fits telestroke call volumes, predicts the future volumes, and can be applied to any health system in which the mean call volume is known, which may inform the number of physicians needed to cover calls in real-time.

Economic evaluation of intensive home treatment in comparison to care as usual alongside a randomised controlled trial.

BACKGROUND: There is a dearth of research on the cost-effectiveness of intensive home treatment (IHT), an alternative to psychiatric hospitalisation for patients experiencing psychiatric crises. We therefore present a health economic evaluation alongside a pre-randomised controlled trial of IHT compared to care as usual (CAU). METHOD: Patients were pre-randomised to IHT or CAU using a double-consent open-label Zelen design. For the cost-utility analysis, the EuroQol 5-dimensional instrument was used. The cost-effectiveness was assessed using the Brief Psychiatric Rating Scale (BPRS). RESULTS: Data of 198 patients showed that each additional QALY gained from offering IHT instead of CAU was on average associated with an extra cost of €48,003. There is a 38% likelihood that IHT will lead to more QALYs at lower costs compared to CAU. An improvement of one additional point on the BPRS by offering IHT instead of CAU was associated with an extra cost of €19,203. There is a 38% likelihood that IHT will lead to higher BPRS score improvements at lower costs. Based on the NICE willingness-to-pay threshold of £30,000 (€35,000) per QALY, IHT could potentially be considered cost-effective with a likelihood of 55-60% when viewed from a societal perspective, and > 75% from a health care perspective. CONCLUSIONS: IHT appears slightly more attractive in terms of cost-utility and cost-effectiveness than CAU, although differences in both costs and effects are small especially when viewed from the societal costs perspective. From the health care sector costs perspective, IHT has a higher probability of being cost-effective compared to CAU. TRIALS REGISTRATION: Netherlands Trial Register: NTR6151.

Extended Window Thrombolytics for Ischemic Stroke: A Telestroke versus In-person Experience.

Background and Purpose: Telestroke evaluation of patients with acute ischemic stroke is supported by American Heart and Stroke Association Guidelines. However, there is no data on outcomes or safety of administering IV thrombolytic stroke therapy using extended window criteria (>4.5 h since onset of symptoms with a hyperacute MRI diffusion T2/FLAIR mismatch) via telestroke. Here, we report adverse events and outcomes of extended-window thrombolysis by telestroke vs in-person care. Methods: We performed a retrospective cohort review from 2020 to 2022 of prospectively collected multinstitutional databases from a large, not-for-profit health system with both in-person stroke and telestroke care. The primary outcome was frequency of symptomatic intracranial hemorrhage (sICH). Secondary outcomes were favorable functional outcome at hospital discharge (modified Rankin Scale, mRS, 0-3) and discharge disposition. Results: A total of 33 patients were treated with extended-window thrombolysis (n = 20 in-person, n = 13 telestroke). The median NIH stroke scale was 6, and time since last known normal was similar (median [95% CI]: in-person 13 h [11-15 h] vs telestroke 12 h [9-16 h], P = .33). The sICH frequency was low and occurred in one patient (4.8% in-person vs 0% by telestroke). Favorable outcome at discharge was not different between in-person and telestroke care (median mRS [95% CI]: 2 [1-3] vs 1 [0-2], OR .0 [.0-1.8], P = .27), and discharge deposition was also similar. Conclusions: In patients eligible for extended window acute stroke treatment with thrombolytics, there was no difference in adverse events between telestroke and in-person care.

Prescriptive factors for intensive home treatment in acute psychiatry: a secondary analysis of a randomised controlled trial.

BACKGROUND: Intensive home treatment (IHT) aims to prevent psychiatric hospitalisation. Although this intervention is well tested, it is still unknown for whom this intervention works best. Therefore, this study aims to explore prescriptive factors that moderate the effect of IHT compared to care as usual (CAU) on symptom severity. METHODS: Using data from a randomised controlled trial, 198 participants that experience an exacerbation of acute psychiatric symptoms were included in this secondary analysis. In order to maximise clinical relevance, generally available environmental and clinical baseline factors were included as tentative moderators: age, gender, employment status, domestic situation, psychiatric disorders, psychological symptoms, psychosocial functioning, alcohol and other substance use. The outcome variable symptom severity was measured using the Brief Psychiatric Rating Scale (BPRS) and collected at 26 and 52 weeks post-randomisation. Multiple regression analysis was used to examine which participants' characteristics moderate the effect of IHT on the total BPRS score. RESULTS: Our results suggest that being employed (B = 0.28, SE = 0.13, 95% CI = 0.03-0.53, p = 0.03) at baseline seems to have a moderation effect, which result in lower symptom severity scores at 26 weeks follow-up for patients who received IHT. This effect was not found at 52 weeks. CONCLUSIONS: On the basis of the number of factors tested, there is no evidence for robust outcome moderators of the effect of IHT versus CAU. Our conclusion is therefore that IHT can be offered to a diverse target population with comparable clinical results. TRIAL REGISTRATION: This trial is registered (date of registration: 2016-11-23) at the international clinical trials registry platform (NTR6151).

Milk recording data indicates the importance of fertility, including age at first calving, on the progression of first lactation cows to second lactation.

Dairy farmers do not recoup the rearing costs incurred from birth to first calving until second lactation but varying proportions of first lactation cows are removed from the herd before second calving. Herein, we used milk recording data to examine the outcomes and performance of first lactation cows to gain insight into farmer decisions to keep or remove them from the herd. An InterHerd+ dataset derived from 500 milk recording dairy herds in UK was used to examine first lactation cows which calved in 2020. Of 29,128 first lactation cows that calved in 2020, 82.6% remained within the herd and re-calved, 4.9% conceived but exited the herd before re-calving, 6.0% were served but exited the herd after failing to conceive and 6.6% exited the herd without being served. The fertility data on these cows support the logical conclusion that farmers retain cows that are served and conceive sooner, possibly in order to keep within a broadly seasonal calving pattern. Cows which were served but not conceived had a median AFC 16-20 days greater than the median AFC for those that conceived. Farmers may also be retaining cows with relatively high milk yields and lower somatic cell counts, or these parameters may be an indicator of a range of attributes affecting the farmer's decision. The data also suggest that farmers are rearing more replacements than required, because over one third of the cows removed in first lactation are never served, and 70% of these are sold within 120 days post-partum. These cows had a significantly older median age at first calving of 818 days, but their early removal without serving suggests there is an oversupply of replacements forcing farmers to dispose of these cows early in lactation. In order to develop a deeper understanding of herd turnover and replacement, future work could examine cow removals in lactation 2 onwards.

Enhanced U-Pb detrital zircon, Lu-Hf zircon, δ18O zircon, and Sm-Nd whole rock global databases.

High-quality global isotopic databases provide Earth scientists with robust means for developing and testing a variety of geological hypotheses. Database design establishes the range of questions that can be addressed, and validation techniques can enhance data quality. Here, six validated global isotopic databases provide extensive records of analyses from U-Pb in detrital zircon, Lu-Hf in zircon, Sm-Nd from whole rocks, and δ18O in zircon. The U-Pb detrital zircon records are segregated into three independently sampled databases. Independent samples are critical for testing the replicability of results, a key requisite for gaining confidence in the validity of a hypothesis. An advantage of our updated databases is that a hypothesis developed from one of the global detrital zircon databases can be immediately tested with the other two independent detrital zircon databases to assess the replicability of results. The independent εHf(t) and εNd(t) values provide similar means of testing for replicable results. This contribution discusses database design, data limitations, and validation techniques used to ensure the data are optimal for subsequent geological investigations.

The effect of chronic, non-pathogenic maternal immune activation on offspring postnatal muscle and immune outcomes.

The objective was to determine the effects of maternal inflammation on offspring muscle development and postnatal innate immune response. Sixteen first-parity gilts were randomly allotted to repeated intravenous injections with lipopolysaccharide (LPS; n = 8, treatment code INFLAM) or comparable volume of phosphate buffered saline (CON, n = 8). Injections took place every other day from gestational day (GD) 70 to GD 84 with an initial dose of 10 µg LPS/kg body weight (BW) increasing by 12% each time to prevent endotoxin tolerance. On GD 70, 76, and 84, blood was collected at 0 and 4 h postinjection via jugular or ear venipuncture to determine tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß concentrations. After farrowing, litter mortality was recorded, and the pig closest to litter BW average was used for dissection and muscle fiber characterization. On weaning (postnatal day [PND] 21), pigs were weighed individually and 2 barrows closest to litter BW average were selected for another study. The third barrow closest to litter BW average was selected for the postnatal LPS challenge. On PND 52, pigs were given 5 µg LPS/kg BW via intraperitoneal injection, and blood was collected at 0, 4, and 8 h postinjection to determine TNF-α concentration. INFLAM gilt TNF-α concentration increased (P < 0.01) 4 h postinjection compared to 0 h postinjection, while CON gilt TNF-α concentration did not differ between time points. INFLAM gilt IL-6 and IL-1ß concentrations increased (P = 0.03) 4 h postinjection compared to 0 h postinjection on GD 70, but did not differ between time points on GD 76 and 84. There were no differences between INFLAM and CON gilts litter mortality outcomes (P ≥ 0.13), but INFLAM pigs were smaller (P = 0.04) at birth and tended (P = 0.09) to be smaller at weaning. Muscle and organ weights did not differ (P ≥ 0.17) between treatments, with the exception of semitendinosus, which was smaller (P < 0.01) in INFLAM pigs. INFLAM pigs tended (P = 0.06) to have larger type I fibers. INFLAM pig TNF-α concentration did not differ across time, while CON pig TNF-α concentration peaked (P = 0.01) 4 h postinjection. TNF-α concentration did not differ between treatments at 0 and 8 h postinjection, but CON pigs had increased (P = 0.01) TNF-α compared to INFLAM pigs 4 h postinjection. Overall, maternal immune activation did not alter pig muscle development, but resulted in suppressed innate immune activation.

Maternal inflammation or immune activation impacts fetal development and subsequently the offspring's postnatal performance. In particular, maternal immune activation may be detrimental to fetal muscle development and alter postnatal immune responses, both of which are vital in determining livestock efficiency. However, understanding the relationship between maternal immune activation and offspring development is difficult as many models use a live pathogen. This introduces many confounding factors, including increased mortality, persistent postnatal infection, and potential copathogens. Therefore, the objective of this study was to determine the effect of maternal inflammation on offspring muscle development and postnatal inflammatory response using repeated injections of a nonpathogenic immune stimulant. Each injection successfully induced an inflammatory response as indicated by increased rectal temperature and circulating inflammatory markers. The gestational challenge did not result in increased litter mortality. Further, muscle development was not altered in piglets exposed to gestational inflammation. However, when challenged with the same immune stimulant given to the dams, pigs exposed to maternal inflammation had a remarkably suppressed immune response compared to controls. Overall, maternal inflammation independent of infection affected offspring immune function, but not muscle development.

Preoperative and pre-chemotherapy CA-125 levels in high-risk early-stage ovarian cancer - An NRG/GOG study.

OBJECTIVES: To determine clinical significance of preoperative and pre-chemotherapy CA-125 in high-risk early-stage epithelial ovarian cancer patients. METHODS: All patients with stage IA/IB and grade 3, stage IC, clear cell, or completed resected stage II cancer were enrolled in a phase III trial and treated with chemotherapy. Kaplan-Meier method and Cox proportional hazards model were used for statistical analyses. RESULTS: 427 patients with high-risk early-stage ovarian cancer were enrolled. Of 213 patients with preoperative CA-125 data, 79% had elevated CA-125. Median preoperative CA-125 level was 103 U/mL. Patients with ≤10, 11-15, and > 15 cm tumors had median preoperative CA-125 levels of 62, 131 and 158 U/mL, respectively (p = 0.002). For the 350 patients with data for pre-chemotherapy CA-125 level, 69% had elevated pre-chemotherapy CA-125 above 35 U/mL with median value of 65 U/mL. However, age, race, stage, cell type and grade of disease were not correlated with CA-125 levels before and after surgery. On multivariate analysis, elevated pre-chemotherapy CA-125 independently predicted worse recurrence-free survival (HR = 2.13, 95% CI: 1.23-3.69; p = 0.007) and overall survival (HR = 1.99, 95% CI: 1.10-3.59; p = 0.022) after adjusting for age, stage, cell type and grade of disease. Compared to those with normal CA-125, patients with elevated pre-chemotherapy CA-125 had lower recurrence-free survival (RFS, 87% vs. 75%; p = 0.007) and overall survival (OS, 88% vs. 82%; p = 0.02). However, preoperative CA-125 was not prognostic of RFS (p = 0.699) or OS (p = 0.701). CONCLUSIONS: Preoperative CA-125 was elevated in nearly 80% of high-risk early-stage ovarian cancer patients. Pre-chemotherapy CA-125 was associated with recurrence-free and overall survival; however, preoperative CA-125 was not prognostic.

Functional, Morphological and Molecular Changes Reveal the Mechanisms Associated with Age-Related Vestibular Loss.

Age-related loss of vestibular function and hearing are common disorders that arise from the loss of function of the inner ear and significantly decrease quality of life. The underlying pathophysiological mechanisms are poorly understood and difficult to investigate in humans. Therefore, our study examined young (1.5-month-old) and old (24-month-old) C57BL/6 mice, utilizing physiological, histological, and transcriptomic methods. Vestibular sensory-evoked potentials revealed that older mice had reduced wave I amplitudes and delayed wave I latencies, indicating reduced vestibular function. Immunofluorescence and image analysis revealed that older mice exhibited a significant decline in type I sensory hair cell density, particularly in hair cells connected to dimorphic vestibular afferents. An analysis of gene expression in the isolated vestibule revealed the upregulation of immune-related genes and the downregulation of genes associated with ossification and nervous system development. A comparison with the isolated cochlear sensorineural structures showed similar changes in genes related to immune response, chondrocyte differentiation, and myelin formation. These findings suggest that age-related vestibular hypofunction is linked to diminished peripheral vestibular responses, likely due to the loss of a specific subpopulation of hair cells and calyceal afferents. The upregulation of immune- and inflammation-related genes implies that inflammation contributes to these functional and structural changes. Furthermore, the comparison of gene expression between the vestibule and cochlea indicates both shared and distinct mechanisms contributing to age-related vestibular and hearing impairments. Further research is necessary to understand the mechanistic connection between inflammation and age-related balance and hearing disorders and to translate these findings into clinical treatment strategies.

Extreme glacial cooling likely led to hominin depopulation of Europe in the Early Pleistocene.

The oldest known hominin remains in Europe [~1.5 to ~1.1 million years ago (Ma)] have been recovered from Iberia, where paleoenvironmental reconstructions have indicated warm and wet interglacials and mild glacials, supporting the view that once established, hominin populations persisted continuously. We report analyses of marine and terrestrial proxies from a deep-sea core on the Portugese margin that show the presence of pronounced millennial-scale climate variability during a glacial period ~1.154 to ~1.123 Ma, culminating in a terminal stadial cooling comparable to the most extreme events of the last 400,000 years. Climate envelope-model simulations reveal a drastic decrease in early hominin habitat suitability around the Mediterranean during the terminal stadial. We suggest that these extreme conditions led to the depopulation of Europe, perhaps lasting for several successive glacial-interglacial cycles.

Bilateral arm movements are coordinated via task-dependent negotiations between independent and codependent control, but not by a "coupling" control policy.

Prior research has shown that coordination of bilateral arm movements might be attributed to either control policies that minimize performance and control costs regardless of bilateral symmetry or by control coupling, which activates bilaterally homologous muscles as a single unit to achieve symmetric performance. We hypothesize that independent bimanual control (movements of one arm are performed without influence on the other) and codependent bimanual control (two arms are constrained to move together with high spatiotemporal symmetry) are two extremes on a coordination spectrum that can be negotiated to meet infinite variations in task demands. To better understand and distinguish between these views, we designed a task where minimization of either control costs or asymmetry would yield different patterns of coordination. Participants made bilateral reaches with a shared visual cursor to a midline target. We then covertly varied the gain contribution of either hand to the shared cursor's horizontal position. Across two experiments, we show that bilateral coordination retains high task-dependent sensitivity to subtle visual feedback gain asymmetries applied to the shared cursor. Specifically, we found a change from strong spatial covariation between hands during equal gains to more independent control during asymmetric gains, which occurred rapidly and with high specificity to the dimension of gain manipulation. Furthermore, the extent of spatial covariation was graded to the magnitude of perpendicular gain asymmetry between hands. These findings suggest coordination of bilateral arm movements flexibly maneuvers along a continuous coordination spectrum in a task-dependent manner that cannot be explained by bilateral control coupling.NEW & NOTEWORTHY Minimization of performance and control costs and efferent coupling between bilaterally homologous muscle groups have been separately hypothesized to describe patterns of bimanual coordination. Here, we address whether the mechanisms mediating independent and codependent control between limbs can be weighted for successful task performance. Using bilaterally asymmetric visuomotor gain perturbations, we show bimanual coordination can be characterized as a negotiation along a spectrum between extremes of independent and codependent control, but not efferent control coupling.

Neuromuscular rate of force development discriminates fallers in ambulatory persons with multiple sclerosis - an exploratory study.

BACKGROUND: Falls as well as fall-related injuries (e.g., bone fractures) are common in persons with multiple sclerosis (pwMS). Whilst some studies have identified lower extremity maximal muscle strength (Fmax) as one among several risk factors, no previous studies have investigated the association between rate of force development (RFD; ability to generate a rapid rise in muscle force) and falls in pwMS. Not only is RFD substantially compromised (and more so than Fmax) in pwMS, studies involving other neurodegenerative populations have shown that RFD - to a greater extent than Fmax - is crucial for counteracting unexpected perturbations and avoiding falling. OBJECTIVE: To explore whether knee extensor RFD (and Fmax) can discriminate fallers from non-fallers in pwMS. METHODS: Knee extensor neuromuscular function (comprising RFD50ms and RFD200ms (force developed in the interval 0-50 ms and 0-200 ms, respectively) as well as Fmax) of the weaker leg was assessed by isokinetic dynamometry. Falls were determined by 1-year patient recall, with pwMS subsequently being classified as non-fallers (0 falls), fallers (1-2 falls), or recurrent fallers (≥3 falls). RESULTS: A total of n=53 pwMS were enrolled in the study, with n=24 classified as non-fallers (63% females, 48 years, EDSS 2.2), n=16 as fallers (88% females, 57 years, EDSS 3.3), and n=13 as recurrent fallers (46% females, 60 years, EDSS 4.2). Compared with non-fallers, neuromuscular function was reduced in both fallers (RFD50 -4.42 [-7.47;-1.37] Nm.s-1.kg-1, -48%; RFD200 -1.45 [-2.98;0.07] Nm.s-1.kg-1, -24%; Fmax -0.42 [-0.81;-0.03] Nm.kg-1, -21%) and recurrent fallers (RFD50 -5.69 [-8.94;-2.43] Nm.s-1.kg-1, -62%; RFD200 -2.26 [-3.89;-0.63] Nm.s-1.kg-1, -38%; Fmax -0.38 [-0.80;0.03] Nm.kg-1, -19%). Across all participants, associations were observed between RFD50ms and falls (rs = -0.46 [-0.67;-0.24], between RFD200ms and falls (rs = -0.34 [-0.59;-0.09]), and between Fmax and falls (rs = -0.24 [-0.48;0.01]). CONCLUSION: In this exploratory study, knee extensor neuromuscular function was able to discriminate fallers from non-fallers in pwMS, with RFD being superior to Fmax. Routine assessment of lower extremity neuromuscular function (RFD50ms in particular) may be a helpful tool in identifying pwMS at future risk of falling.