The increasingly dominant role of climate change on length of day variations.

The melting of ice sheets and global glaciers results in sea-level rise, a pole-to-equator mass transport increasing Earth's oblateness and resulting in an increase in the length of day (LOD). Here, we use observations and reconstructions of mass variations at the Earth's surface since 1900 to show that the climate-induced LOD trend hovered between 0.3 and 1.0 ms/cy in the 20th century, but has accelerated to 1.33 [Formula: see text] 0.03 ms/cy since 2000. We further show that surface mass transport fully explains the accelerating trend in the Earth oblateness observed in the past three decades. We derive an independent measure of the decreasing LOD trend induced by Glacial Isostatic Adjustment (GIA) of [Formula: see text]0.80 [Formula: see text] 0.10 ms/cy, which provides a constraint for the mantle viscosity. The sum of this GIA rate and lunar tidal friction fully explains the secular LOD trend that is inferred from the eclipse record in the past three millennia prior to the onset of contemporary climate change. Projections of future climate warming under high emission scenarios suggest that the climate-induced LOD rate may reach 2.62 [Formula: see text] 0.79 ms/cy by 2100, overtaking lunar tidal friction as the single most important contributor to the long-term LOD variations.

Adjustment of scRNA-seq data to improve cell-type decomposition of spatial transcriptomics.

Most sequencing-based spatial transcriptomics (ST) technologies do not achieve single-cell resolution where each captured location (spot) may contain a mixture of cells from heterogeneous cell types, and several cell-type decomposition methods have been proposed to estimate cell type proportions of each spot by integrating with single-cell RNA sequencing (scRNA-seq) data. However, these existing methods did not fully consider the effect of distribution difference between scRNA-seq and ST data for decomposition, leading to biased cell-type-specific genes derived from scRNA-seq for ST data. To address this issue, we develop an instance-based transfer learning framework to adjust scRNA-seq data by ST data to correctly match cell-type-specific gene expression. We evaluate the effect of raw and adjusted scRNA-seq data on cell-type decomposition by eight leading decomposition methods using both simulated and real datasets. Experimental results show that data adjustment can effectively reduce distribution difference and improve decomposition, thus enabling for a more precise depiction on spatial organization of cell types. We highlight the importance of data adjustment in integrative analysis of scRNA-seq with ST data and provide guidance for improved cell-type decomposition.

Pituitary volumes in patients with adjustment disorder.

The pituitary gland plays an important role in the stress response mechanism. Given the direct link between adjustment disorder and stress, we hypothesized that there might be changes in the pituitary gland in these patients. The study comprised a patient group of 19 individuals with adjustment disorder according to the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition, and 18 healthy controls. The mean pituitary gland volumes of the patient group were not statistically significantly different from those of the healthy control group (80.81 ± 1.82 mm3 in patients with adjustment disorder vs. 81.10 ± 7.04 mm3 in healthy controls, with a statistically nonsignificant difference of P > 0.05). This finding is contrary to our previous findings in anxiety-related disorders. In this regard, adjustment disorder is not similar to anxiety-related disorders in terms of pituitary gland volumes. We should also clearly state that our study is a pioneering study and that studies with large samples are needed to support our findings. The limitations of our study can be attributed to the small sample size, the utilization of a cross-sectional design, and the inclusion of patients using psychotropic drugs.

CsSHMT3 gene enhances the growth and development in cucumber seedlings under salt stress.

Salt stress is one of the major factors limiting plant growth and productivity. Many studies have shown that serine hydroxymethyltransferase (SHMT) gene play an important role in growth, development and stress response in plants. However, to date, there have been few studies on whether SHMT3 can enhance salt tolerance in plants. Therefore, the effects of overexpression or silencing of CsSHMT3 gene on cucumber seedling growth under salt stress were investigated in this study. The results showed that overexpression of CsSHMT3 gene in cucumber seedlings resulted in a significant increase in chlorophyll content, photosynthetic rate and proline (Pro) content, and antioxidant enzyme activity under salt stress condition; whereas the content of malondialdehyde (MDA), superoxide anion (H2O2), hydrogen peroxide (O2·-) and relative conductivity were significantly decreased when CsSHMT3 gene was overexpressed. However, the content of chlorophyll and Pro, photosynthetic rate, and antioxidant enzyme activity of the silenced CsSHMT3 gene lines under salt stress were significantly reduced, while MDA, H2O2, O2·- content and relative conductivity showed higher level in the silenced CsSHMT3 gene lines. It was further found that the expression of stress-related genes SOD, CAT, SOS1, SOS2, NHX, and HKT was significantly up-regulated by overexpressing CsSHMT3 gene in cucumber seedlings; while stress-related gene expression showed significant decrease in silenced CsSHMT3 gene seedlings under salt stress. This suggests that overexpression of CsSHMT3 gene increased the salt tolerance of cucumber seedlings, while silencing of CsSHMT3 gene decreased the salt tolerance. In conclusion, CsSHMT3 gene might positively regulate salt stress tolerance in cucumber and be involved in regulating antioxidant activity, osmotic adjustment, and photosynthesis under salt stress. KEY MESSAGE: CsSHMT3 gene may positively regulate the expression of osmotic system, photosynthesis, antioxidant system and stress-related genes in cucumber.

Repeated context-specific actions disrupt feedforward adjustments in motor commands in younger and older adults.

The flexibility of the motor system to adjust a planned action before or during the execution of the movement in response to sensory information is critical for preventing errors in motor control. As individuals age, this function declines, leading to an increased incidence of motor errors. Although sensory processing and cognitive decline are known contributors to this impairment, here, we test the hypothesis that repetition of context-specific planned actions interferes with the adjustment of feedforward motor commands. Younger and older participants were instructed to grasp and lift a T-shaped object with a concealed, off-sided center of mass and minimize its roll through anticipatory force control, relying predominantly on predictive model-driven planning (i.e., sensorimotor memories) developed through repeated lifts. We selectively manipulate the number of trial repeats with the center of mass on one side before switching it to the other side of the T-shaped object. The results showed that increasing the number of repetitions improved performance in manipulating an object with a given center of mass but led to increased errors when the object's center of mass was switched. This deleterious effect of repetition on feedforward motor adjustment was observed in younger and older adults. Critically, we show these effects on an internal model-driven motor planning task that relies predominantly on sensorimotor memory, with no differences in sensory inputs from the repetition manipulation. The findings indicate that feedforward motor adjustments are hampered by repetitive stereotyped planning and execution of motor behavior.NEW & NOTEWORTHY Adjusting planned actions in response to sensory stimuli degrades with age contributing to increased incidence of errors ranging from clumsy spills to catastrophic falls. Multiple factors likely contribute to age-related motor inflexibility, including sensory- and cognition-supporting system declines. Here, we present compelling evidence for repetition to disrupt feedforward adjusting of motor commands in younger and older adults, which suggests increases in stereotypy as a deleterious potentiator of motor control errors.

The experience of albinism in France: a qualitative study on dyads of parents and their adult child with albinism.

BACKGROUND: To date, almost no research on the psychosocial implications of albinism has been conducted in France and an exploration of albinism-related experiences could be beneficial, in order to better understand this condition. The aim of this study was to examine how French people with albinism and their parents live with and adapt to this condition in all the areas of their lives. METHODS: Semi-structured phone interviews were conducted with 9 parent-child dyads, each participating separately. Participants were recruited by convenience sampling, thanks to the combined efforts of a patient association (Genespoir) and professionals from the partner medical referral centers involved in the project. Dyads in which the individual with albinism had any comorbidity were excluded. The interviews were then transcribed and subjected to in-depth thematic analysis. Two codebooks were constructed in a mirrored process: one for people with albinism; the other for their parents. They were finally merged at the end of the coding step. RESULTS: Four main categories were identified: personal perceptions and social representations of albinism, difficulties and obstacles encountered by people with albinism, resources and facilitators, and the importance of parent-child functioning. The results indicated that experiences of stigmatization during childhood and adolescence are common and that people with albinism face challenges in adapting to certain obstacles related to their visual impairments (VI) (e.g., inability to drive a car; eye strain...). Parents emerged as one, if not as the main, source of support for people with albinism throughout their development. Although external support systems exist to assist them in various aspects of their lives, some of them primarily rely on their own personal resources to cope. CONCLUSIONS: This research highlights the importance of a systemic and transdisciplinary approach to make sure families receive the support that best meets their needs.

Hydraulic plasticity and water use regulation act to maintain the hydraulic safety margins of Mediterranean trees in rainfall exclusion experiments.

Hydraulic failure due to xylem embolism has been identified as one of the main mechanisms involved in drought-induced forest decline. Trees vulnerability to hydraulic failure depends on their hydraulic safety margin (HSM). While it has been shown that HSM globally converges between tree species and biomes, there is still limited knowledge regarding how HSM can adjust locally to varying drought conditions within species. In this study, we relied on three long-term partial rainfall exclusion experiments to investigate the plasticity of hydraulic traits and HSM for three Mediterranean tree species (Quercus ilex L., Quercus pubescens Willd., and Pinus halepensis Mill.). For all species, a homeostasis of HSM in response to rainfall reduction was found, achieved through different mechanisms. For Q. ilex, the convergence in HSM is attributed to the adjustment of both the turgor loss point (Ψtlp) and the water potential at which 50% of xylem conductivity is lost due to embolism (P50). In contrast, the maintenance of HSM for P. halepensis and Q. pubescens is related to its isohydric behavior for the first and leaf area adjustment for the latter. It remains to be seen whether this HSM homeostasis can be generalized and if it will be sufficient to withstand extreme droughts expected in the Mediterranean region.

Psychosocial outcomes of children born via embryo donation.

STUDY QUESTION: What are parents' perceptions of their relationships with and the psychosocial adjustments of their children who are born via embryo donation? SUMMARY ANSWER: Families created through embryo donation have well-adjusted parent-child relationships and reassuring child psychosocial outcomes. WHAT IS KNOWN ALREADY: Embryo donation is an effective and growing form of third-party reproduction, but there is limited research in this field. Prior studies suggest that families created through gamete donation function well regarding parent-child relationship quality and child behavioral and socioemotional adjustment. STUDY DESIGN, SIZE, DURATION: This is a cross-sectional survey study with 187 total participants. PARTICIPANTS/MATERIALS, SETTING, METHODS: Parents of children born via embryo donation were recruited nationally by contacting all embryo donation programs registered with the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) as well as medically directed embryo donation or 'embryo adoption' centers. Participants completed three online Qualtrics questionnaires. The first was a survey including 33 questions on demographics, the procurement process, and self-reported obstetric outcomes. Participants also completed two standardized measures assessing children's behavior and parents' adjustment to parenthood: the Strengths and Difficulties Questionnaire (SDQ) and the Parental Acceptance-Rejection Questionnaire (PARQ). Scoring of the SDQ and PARQ was totaled and compared to standardized values (SDQ) or previously published results on other forms of gamete donation (PARQ), such as oocyte donation and sperm donation. MAIN RESULTS AND THE ROLE OF CHANCE: On the SDQ (n = 46), the average total difficulties scores by age were: 8.2 ± 0.98 for ages 2-4, 7.6 ± 0.93 for ages 5-10, and 3.5 ± 0.77 for ages 11-17; this is compared to the normal reported range of 0-13, which indicates that clinically significant psychosocial problems are unlikely. Across all ages and individual categories (emotional symptoms, conduct problem, hyperactivity, peer problem, prosocial), scores on the SDQ were within the normal ranges. The average PARQ score (n = 70) for all respondents was 27.5 ± 1.18 (range: 24-96), suggesting perceived parental acceptance. LIMITATIONS, REASONS FOR CAUTION: Because this study was cross-sectional, it could not capture familial relationships over time. This survey-based study design allows for potential selection bias (parents of well-adjusted children may be more likely to participate). Additionally, the overall sample size is relatively small; however, it remains one of the largest published to date. Another significant limitation to this study is the lack of generalizability: most participants were recruited from private, faith-based, embryo donation programs who are demographically similar. WIDER IMPLICATIONS OF THE FINDINGS: Though embryo donation is an established form of third-party reproduction, it is significantly less robustly studied compared to other forms of gamete donation (oocyte or sperm donation). This study provides a larger data set with a more expanded age range of children compared to the limited number of previously published studies. Furthermore, these findings indicate a high parental disclosure rate with respect to the use of embryo donation which contrasts previous findings. STUDY FUNDING/COMPETING INTEREST(S): No external funding source was utilized for the completion of this study. No conflicts are disclosed. TRIAL REGISTRATION NUMBER: N/A.

Psychosocial experiences of involuntary definitive childless women: a comparative study based on reproductive status.

STUDY QUESTION: Do involuntary definitive childless women have lower psychosocial adjustment levels than women with infertility diagnoses actively trying to conceive and presumably fertile women? SUMMARY ANSWER: Involuntary definitive childless women have lower levels of sexual functioning than infertile women actively trying to conceive and presumably fertile women, and higher levels of depression than presumably fertile women. WHAT IS KNOWN ALREADY: Involuntary definitive childless defines those who wanted to become parents but were unable to do so. Studies have provided evidence about infertility and its psychosocial consequences, but there is a lack of knowledge about the impact of involuntary definitive childlessness, namely on sexual function, social support, marital satisfaction, and psychological adjustment. STUDY DESIGN, SIZE, DURATION: This associative study was conducted between July 2021 and January 2022 for involuntary definitive childless women and between July 2016 and February 2018 for women with an infertility diagnosis actively trying to conceive as well as presumably fertile women. An online questionnaire announced in social media and gynaecology and fertility clinics was used. The inclusion criteria for all participants were being childless, in a heterosexual relationship and cohabiting for at least 2 years. Specific inclusion criteria for involuntary definitive childless women were: trying to conceive for at least 2 years; not achieving pregnancy because of biological and medical constraints; and not undergoing fertility treatment or being a candidate for adopting a child at time of the study. For women with an infertility diagnosis the inclusion criteria were: actively trying to conceive (naturally or through fertility treatments); having a primary fertility diagnosis; and aged between 22 and 42 years old. For presumably fertile women, the inclusion criteria were: having a parenthood wish in the future; and not knowing of any condition that could prevent them from conceiving. PARTICIPANTS/MATERIALS, SETTING, METHODS: Out of 360 women completing the survey, only 203 were eligible for this study (60 involuntary definitive childless women, 78 women with an infertility diagnosis actively trying to conceive, and 65 presumably fertile women). All participants completed a questionnaire including sociodemographic and clinical data, the Female Sexual Function Index, the 2-Way Social Support Scale, the Relationship Assessment Scale, and Hospital Anxiety and Depression Scale. Binary logistic regression was performed to assess the relation between sexual function, social support, marital satisfaction, anxiety, depression, and reproductive status, adjusting for age, and cohabitation length. Presumably fertile women were used as a reference group. MAIN RESULTS AND THE ROLE OF CHANCE: Women were 34.31 years old (SD = 5.89) and cohabited with their partners for 6.55 years (SD = 4.57). The odds ratio (OR) showed that involuntary definitive childless women had significantly lower sexual function than infertile women actively trying to conceive (OR = 0.88, 95% CI = 0.79-0.99) and presumably fertile women (OR = 34.89, 95% CI = 1.98-614.03), and higher depression levels than presumably fertile women (OR = 99.89, 95% CI = 3.29-3037.87). Women with an infertility diagnosis actively trying to conceive did not differ from presumably fertile women in sexual function, social support, marital satisfaction, anxiety, and depression. LIMITATIONS, REASONS FOR CAUTION: The majority of childless women underwent fertility treatments, and childlessness for circumstantial reasons owing to lack of a partner was not included, therefore these results may not reflect the experiences of all women with an involuntary childless lifestyle. There was a time gap in the recruitment process, and only the definitive childlessness group filled out the questionnaire after the coronavirus disease 2019 pandemic. We did not ask participants if they self-identified themselves with the groups' terminology they were assigned to. WIDER IMPLICATIONS OF THE FINDINGS: Our results emphasize the importance of future research to provide a more comprehensive understanding of the adjustment experiences of childless women and an awareness of the poor adjustment they might experience, highlighting the need to keep following women after unsuccessful treatments. Clinical practitioners must attend to these dimensions when consulting involuntary definitive childless women who might not have gone through treatments but also experience these adverse outcomes. STUDY FUNDING/COMPETING INTEREST(S): This study was partially supported by the Portuguese Foundation for Science and Technology. The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Race-specific FRAX models are evidence-based and support equitable care: a response to the ASBMR Task Force report on Clinical Algorithms for Fracture Risk.

Task Force on 'Clinical Algorithms for Fracture Risk' commissioned by the American Society for Bone and Mineral Research (ASBMR) Professional Practice Committee has recommended that FRAX® models in the US do not include adjustment for race and ethnicity. This position paper finds that an agnostic model would unfairly discriminate against the Black, Asian and Hispanic communities and recommends the retention of ethnic and race-specific FRAX models for the US, preferably with updated data on fracture and death hazards. In contrast, the use of intervention thresholds based on a fixed bone mineral density unfairly discriminates against the Black, Asian and Hispanic communities in the US. This position of the Working Group on Epidemiology and Quality of Life of the International Osteoporosis Foundation (IOF) is endorsed both by the IOF and the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

Dose escalation of biologic treatment in patients with moderate-to-severe psoriasis in Japan.

Patients receiving interleukin (IL)-inhibiting biologics for moderate-to-severe psoriasis (PsO) may be treated with escalated doses to optimize outcomes. This study evaluated escalation prevalence in a Japanese claims analysis of patients with PsO diagnosis preceding IL-inhibiting biologic treatment and ≥1 post-induction maintenance claim (index date) with sufficient data availability from January 2014 to May 2022. Patients with non-persistence were excluded. Expected daily dose (EDD) was calculated as the recommended maintenance dose divided by the treatment interval. Dose escalation was defined as ≥2 claims showing a ≥20% increase in the observed average daily dose (ADD) over the EDD (with sensitivities requiring ≥1 claim and ≥30%). Significant differences were tested using multivariable regressions. The study included 982 unique patients treated with brodalumab (BRO; n = 104), guselkumab (GUS; n = 207), ixekizumab (IXE; n = 159), risankizumab (RIS; n = 135), secukinumab (SEC; n = 215) and ustekinumab (UST; n = 196). Within 12 months, dose escalation was observed for all IL-inhibiting biologics other than GUS and RIS: 44.4% for UST, 37.2% for IXE, 3.4% for SEC and 1.4% for BRO. In multivariable-adjusted analyses, odds of dose escalation were significantly lower for all products relative to UST. In sensitivities, escalation was observed for all products except RIS.

The effectiveness of couple-based interventions on the marital outcomes of women with genital and breast cancer and their partners: a systematic review and meta-analysis.

BACKGROUND: Breast cancer and genital cancer are known as cancers that affect people's relationships with their partners. Women with such cancers are emotionally vulnerable and need more support from their partners. The present systematic review and meta-analysis evaluated the effectiveness of couple-based interventions on the marital outcomes of patients with these cancers and their intimate partners. METHODS: To perform this systematic review, Google Scholar and databases such as PubMed, Web of Science, Cochrane, Scopus, SID (Scientific Information Database), and Magiran were searched systematically. The reviewed studies included randomized controlled trials and quasiexperimental studies in which the intervention group, couple-based interventions, and the control group received routine care, general education or no intervention for cancer treatment. In this study, the included participants were patients with breast cancer or genital cancer and their intimate partners. The primary outcomes considered in this study included patients' marital adjustment, patients' marital satisfaction, patients' marital intimacy, and patients' marital relationships. The secondary outcomes were partners' marital adjustment, partners' marital satisfaction, partners' marital intimacy, and partners' marital relationships. A meta-analysis was performed with Review Manager v. 5.3 software (The Nordic Cochrane Centre, Cochrane Collaboration, 2014; Copenhagen, Denmark). The intervention impacts on continuous outcomes were measured using standardized mean differences (SMDs) with 95% confidence interval because of the use of various scales to evaluate the outcomes. The quality of evidence presented in the included studies was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. In the subgroup analysis, the studied outcomes were divided into two parts (theory-based and non-theory-based) in terms of the theoretical context of couple-based interventions. RESULTS: From a total of 138 retrieved studies, 14 trials were eligible for inclusion in the study. The results of the meta-analysis showed that the patient's marital satisfaction increased significantly with couple-based interventions (SMD 0.46, 95% confidence interval 0.07 to 0.85; 7 trials, 341 patients, very low certainty) compared to the control group, but the evidence was uncertain. However, there were no significant differences between the groups in the partner's marital satisfaction, the patient's and partner's marital adjustment, and the patient's and partner's marital intimacy. Additionally, the results of the subgroup analysis showed that the couple-based interventions significantly increased the patient's marital adjustment (SMD 1.96, 95% CI 0.87 to 3.06; 4 trials, 355 patients, very low certainty), the partner's marital adjustment (SMD 0.53, 95% CI 0.20 to 0.86; 4 trials, 347 partners, very low certainty), the patient's marital satisfaction (SMD 0.89, 95% CI 0.35 to 1.43; 2 trials, 123 patients, very low certainty), and the partner's marital satisfaction (SMD 0.57, 95% CI 0.20 to 0.94; 2 trials, 123 partners, very low certainty) compared to the control group in theory-based studies. In. However, in non-theory-based studies, the results of the meta-analysis revealed no significant differences between the intervention and control groups. CONCLUSIONS: The results of this study demonstrated the impact of couple-based interventions on the marital outcomes of patients with breast and genital cancers. Because of the very low confidence in the evidence, high-quality randomized trials with a sufficient sample size should be conducted considering the proper theoretical context.

Positive thinking about negative studies.

The non-reporting of negative studies results in a scientific record that is incomplete, one-sided and misleading. The consequences of this range from inappropriate initiation of further studies that might put participants at unnecessary risk to treatment guidelines that may be in error, thus compromising day-to-day clinical practice.

A systematic review and meta-analysis of the morbidity of efficacy endpoints and bleeding events in elderly and young patients treated with the same dose rivaroxaban.

Rivaroxaban is a new direct oral anticoagulant, and the same dose is recommended for older and young patients. However, recent real-world studies show that older patients may need dose adjustment to prevent major bleeding. At present, the evidence for dose adjustment in older patients is extremely limited with only a few reports on older atrial fibrillation patients. The aim of this study was to review the morbidity data of adverse events and bleeding events across all indications for older and young patients treated with the same dose of rivaroxaban to provide some support for dosage adjustment in older patients. The PubMed, EMBASE, ClinicalTrials, Cochrane and Web of Science databases were searched for randomized controlled trials (RCTs) published between January 1, 2005, and October 10, 2023. The primary outcomes were the morbidity of bleeding events and efficacy-related adverse events. Summary estimates were calculated using a random effects model. Eighteen RCTs were included in the qualitative analysis. The overall morbidity of primary efficacy endpoints was higher in older patients compared to the young patients (3.37% vs. 2.60%, χ2 = 5.24, p = 0.022). Similarly, a higher morbidity of bleeding was observed in older patients compared to the young patients (4.42% vs. 6.03%, χ2 = 13.22, p < 0.001). Among all indications, deep vein thrombosis, pulmonary embolism and atrial fibrillation were associated with the highest incidence of bleeding in older patients, suggesting that these patients may be most need dose adjustment. Patients older than 75 years may require extra attention to prevent bleeding. The same dose of rivaroxaban resulted in higher bleeding morbidity and morbidity of efficacy-related adverse events in older patients compared to the young patients. An individualized dose adjustment may be preferred for older patients rather than a fixed dose that fits all.

Humanistic burden of haemophilia A without inhibitors: A cross-sectional analysis of the HemoLIFE study.

AIM: To evaluate the impact of haemophilia A without inhibitors on humanistic outcomes in patients and caregivers. Herein, we report a cross-sectional analysis of the baseline data of persons with haemophilia (PWH) participating in the prospective study HEMOLIFE. METHODS: These data are part of a prospective, observational, and multicentre study currently being conducted in 20 hospitals in Spain by haematologists. We included subjects 12 years or older diagnosed with haemophilia. The evaluations included the Maladjustment Scale, Haemophilia-Specific Quality of Life Questionnaire for Adults (HaemoQol)/HaemoQol Short Form (Children), haemophilia-specific version of the Work Productivity and Impairment Questionnaire plus the Classroom Impairment Questionnaire (WPAI+CIQ:HS), Haemophilia Activity List (HAL)/Paediatric Haemophilia Activities List (pedHAL), visual analogue scale (VAS) for evaluating pain, Coping Pain Questionnaire-Reduced (CAD-R), and Hospital Anxiety and Depression Scale (HADS). RESULTS: A total of 81 PWH were recruited at 18 centres; 66 PWH were ≥18 years (i.e., adults), and PWH 15 were <18 years (i.e., paediatric patients). Out of the 79 evaluable subjects, 16 (20%) showed an impact of haemophilia on daily life, and the areas most affected were "leisure time" (58% showed maladjustment) and "work/studies" (47% showed maladjustment). Patients reported a higher impact of haemophilia on quality of life (mean [SD] of the transformed score) in the dimensions of "sport" (49.4 [28.6]), "physical health" (40.5 [25.8]) and "future" (37.7 [28.9]). In adults, according to HAL scores, greater impairment of function was observed in "lying/sitting/kneeling/standing," "function of legs" and "leisure activities and sports," with mean normalized scores of 64.7, 65.1 and 69.0, respectively. Productivity was mostly impacted by presenteeism. The pain was infrequent and moderate. According to the HADS scores, nine (11.5%) patients had clinical anxiety and depression. CONCLUSION: PWH without inhibitors exhibited impairments in adjustment, quality of life and functionality, especially related to leisure and sports activities, and exhibit relevant levels of anxiety and depression.

Data derived extrapolation factors (DDEFs) for rat to human interspecies extrapolation for the HPPD inhibitor mesotrione.

In the risk assessment of agrochemicals, there has been a historical paucity of using data to refine the default adjustment factors, even though large datasets are available to support this. The current state of the science for addressing uncertainty regarding animal to human extrapolation (AFA) is to develop a "data-derived" adjustment factor (DDEF) to quantify such differences, if data are available. Toxicokinetic (TK) and toxicodynamic (TD) differences between species can be utilized for the DDEF, with human datasets being ideal yet rare. We identified a case for a currently registered herbicide, mesotrione, in which human TK and TD are available. This case study outlines an approach for the development of DDEFs using comparative human and animal data and based on an adverse outcome pathway (AOP) for inhibition of 4-hydroxyphenol pyruvate dioxygenase (HHPD). The calculated DDEF for rat to human extrapolation (AFA) for kinetics (AFAK = 2.5) was multiplied by the AFA for dynamics (AFAD = 0.3) resulting in a composite DDEF of ∼1 (AFA = 0.75). This reflects the AOP and available scientific evidence that humans are less sensitive than rats to the effects of HPPD inhibitors. Further analyses were conducted utilizing in vitro datasets from hepatocytes and liver cytosols and extrapolated to whole animal using in vitro to in vivo extrapolation (IVIVE) to support toxicodynamic extrapolation. The in vitro datasets resulted in the same AFAD as derived for in vivo data (AFAD = 0.3). These analyses demonstrate that a majority of the species differences are related to toxicodynamics. Future work with additional in vitro/in vivo datasets for other HPPD inhibitors and cell types will further support this result. This work demonstrates utilization of all available toxicokinetic and toxicodynamic data to replace default uncertainty factors for agrochemical human health risk assessment.

Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

Possible improvement of social adjustment after subthalamic deep brain stimulation in people with Parkinson's disease? A systematic review and meta-analysis.

Interactions with others need social adjustment (i.e., the constant accommodation to changing social situations). Mixed evidence indicates positive as well as negative changes in social adjustment after subthalamic nucleus deep brain stimulation (STN-DBS) in people with Parkinson's Disease (PwPD). To date, however, no meta-analysis of these changes exists. Thus, the study aim was to review evidence of the effects of STN-DBS on social adjustment in PwPD. For this purpose, a systematic literature search in MEDLINE was conducted. The meta-analysis was performed using a random effects model and standardized mean differences (SMDs) with 95% confidence intervals (CIs). The MINORS tool was used to assess the methodological quality of the studies. The initial literature search identified 13,124 articles, of which 1,550 full texts were assessed for eligibility. Eight studies were finally included; for seven articles sufficient data for a meta-analysis was available. Most studies found mild impairment in social adjustment impairment pre-surgery. The meta-analysis revealed no significant changes but a statistical trend towards improvement in social adjustment up to six months (SMD = 0.25; 95%CI=-0.03,0.53; P = 0.08) and over 12 months (SMD = 0.26; 95%CI=-0.03,0.55; P = 0.07) post-surgery. Methodological quality was moderate in 87.5% of the studies and good in 12.5%. While mild impairment in social adjustment pre-surgery was reported in most studies, the data indicate that STN-DBS might yield beneficial effects toward this outcome. However, not enough data yet exists to draw firm conclusions. As a crucial skill for everyday functioning, social adjustment should be more often defined as an outcome in STN-DBS trials in PwPD and should be considered in clinical routines.

Grape cultivars adapted to hotter, drier growing regions exhibit greater photosynthesis in hot conditions despite less drought-resistant leaves.

BACKGROUND AND AIMS: Many agricultural areas are expected to face hotter, drier conditions from climate change. Understanding the mechanisms that crops use to mitigate these stresses can guide breeding for more tolerant plant material. We tested relationships between traits, physiological function in hot conditions and historical climate associations to evaluate these mechanisms for winegrapes. We expected a more negative leaf osmotic potential at full hydration (πo), which reduces leaf turgor loss during drought, and either a metabolically cheaper or more osmoprotectant leaf chemical composition, to allow cultivars associated with hot, dry regions to maintain greater gas exchange in hot growing conditions. METHODS: We measured πo, gas exchange and leaf chemistry for seven commercially important winegrape cultivars that vary widely in historical climate associations. Vines were grown in common-garden field conditions in a hot wine-growing region (Davis, CA, USA) and measured over the hottest period of the growing season (July-September). KEY RESULTS: The value of πo varied significantly between cultivars, and all cultivars significantly reduced πo (osmotically adjusted) over the study period, although osmotic adjustment did not vary across cultivars. The value of πo was correlated with gas exchange and climate associations, but in the direction opposite to expected. Photosynthesis and πo were higher in the cultivars associated with hotter, less humid regions. Leaf chemical composition varied between cultivars but was not related to climate associations. CONCLUSIONS: These findings suggest that maintenance of leaf turgor is not a primary limitation on grapevine adaptation to hot or atmospherically dry growing conditions. Thus, selecting for a more negative πo or greater osmotic adjustment is not a promising strategy to develop more climate-resilient grape varieties, contrary to findings for other crops. Future work is needed to identify the mechanisms increasing photosynthesis in the cultivars associated with hot, dry regions.

Behavioral carry-over effect and power consideration in crossover trials.

A crossover trial is an efficient trial design when there is no carry-over effect. To reduce the impact of the biological carry-over effect, a washout period is often designed. However, the carry-over effect remains an outstanding concern when a washout period is unethical or cannot sufficiently diminish the impact of the carry-over effect. The latter can occur in comparative effectiveness research, where the carry-over effect is often non-biological but behavioral. In this paper, we investigate the crossover design under a potential outcomes framework with and without the carry-over effect. We find that when the carry-over effect exists and satisfies a sign condition, the basic estimator underestimates the treatment effect, which does not inflate the type I error of one-sided tests but negatively impacts the power. This leads to a power trade-off between the crossover design and the parallel-group design, and we derive the condition under which the crossover design does not lead to type I error inflation and is still more powerful than the parallel-group design. We also develop covariate adjustment methods for crossover trials. We evaluate the performance of cross-over design and covariate adjustment using data from the MTN-034/REACH study.