A few essential genetic loci distinguish Penstemon species with flowers adapted to pollination by bees or hummingbirds.

In the formation of species, adaptation by natural selection generates distinct combinations of traits that function well together. The maintenance of adaptive trait combinations in the face of gene flow depends on the strength and nature of selection acting on the underlying genetic loci. Floral pollination syndromes exemplify the evolution of trait combinations adaptive for particular pollinators. The North American wildflower genus Penstemon displays remarkable floral syndrome convergence, with at least 20 separate lineages that have evolved from ancestral bee pollination syndrome (wide blue-purple flowers that present a landing platform for bees and small amounts of nectar) to hummingbird pollination syndrome (bright red narrowly tubular flowers offering copious nectar). Related taxa that differ in floral syndrome offer an attractive opportunity to examine the genomic basis of complex trait divergence. In this study, we characterized genomic divergence among 229 individuals from a Penstemon species complex that includes both bee and hummingbird floral syndromes. Field plants are easily classified into species based on phenotypic differences and hybrids displaying intermediate floral syndromes are rare. Despite unambiguous phenotypic differences, genome-wide differentiation between species is minimal. Hummingbird-adapted populations are more genetically similar to nearby bee-adapted populations than to geographically distant hummingbird-adapted populations, in terms of genome-wide dXY. However, a small number of genetic loci are strongly differentiated between species. These approximately 20 "species-diagnostic loci," which appear to have nearly fixed differences between pollination syndromes, are sprinkled throughout the genome in high recombination regions. Several map closely to previously established floral trait quantitative trait loci (QTLs). The striking difference between the diagnostic loci and the genome as whole suggests strong selection to maintain distinct combinations of traits, but with sufficient gene flow to homogenize the genomic background. A surprisingly small number of alleles confer phenotypic differences that form the basis of species identity in this species complex.

DystoniaBoTXNet: Novel Neural Network Biomarker of Botulinum Toxin Efficacy in Isolated Dystonia.

OBJECTIVE: Isolated dystonia is characterized by abnormal, often painful, postures and repetitive movements due to sustained or intermittent involuntary muscle contractions. Botulinum toxin (BoTX) injections into the affected muscles are the first line of therapy. However, there are no objective predictive markers or standardized tests of BoTX efficacy that can be utilized for appropriate candidate selection prior to treatment initiation. METHODS: We developed a deep learning algorithm, DystoniaBoTXNet, which uses a 3D convolutional neural network architecture and raw structural brain magnetic resonance images (MRIs) to automatically discover and test a neural network biomarker of BoTX efficacy in 284 patients with 4 different forms of focal dystonia, including laryngeal dystonia, blepharospasm, cervical dystonia, and writer's cramp. RESULTS: DystoniaBoTXNet identified clusters in superior parietal lobule, inferior and middle frontal gyri, middle orbital gyrus, inferior temporal gyrus, corpus callosum, inferior fronto-occipital fasciculus, and anterior thalamic radiation as components of the treatment biomarker. These regions are known to contribute to both dystonia pathophysiology across a broad clinical spectrum of disorder and the central effects of botulinum toxin treatment. Based on its biomarker, DystoniaBoTXNet achieved an overall accuracy of 96.3%, with 100% sensitivity and 86.1% specificity, in predicting BoTX efficacy in patients with isolated dystonia. The algorithmic decision was computed in 19.2 seconds per case. INTERPRETATION: DystoniaBoTXNet and its treatment biomarker have a high translational potential as an objective, accurate, generalizable, fast, and cost-effective algorithmic platform for enhancing clinical decision making for BoTX treatment in patients with isolated dystonia. ANN NEUROL 2023;93:460-471.

Comparison of Human Long-Term Liver Models for Clearance Prediction of Slowly Metabolized Compounds.

The accurate prediction of human clearance is an important task during drug development. The proportion of low clearance compounds has increased in drug development pipelines across the industry since such compounds may be dosed in lower amounts and at lower frequency. These type of compounds present new challenges to in vitro systems used for clearance extrapolation. In this study, we compared the accuracy of clearance predictions of suspension culture to four different long-term stable in vitro liver models, including HepaRG sandwich culture, the Hµrel stochastic co-culture, the Hepatopac micropatterned co-culture (MPCC), and a micro-array spheroid culture. Hepatocytes in long-term stable systems remained viable and active over several days of incubation. Although intrinsic clearance values were generally high in suspension culture, clearance of low turnover compounds could frequently not be determined using this method. Metabolic activity and intrinsic clearance values from HepaRG cultures were low and, consequently, many compounds with low turnover did not show significant decline despite long incubation times. Similarly, stochastic co-cultures occasionally failed to show significant turnover for multiple low and medium turnover compounds. Among the different methods, MPCCs and spheroids provided the most consistent measurements. Notably, all culture methods resulted in underprediction of clearance; this could, however, be compensated for by regression correction. Combined, the results indicate that spheroid culture as well as the MPCC system provide adequate in vitro tools for human extrapolation for compounds with low metabolic turnover. SIGNIFICANCE STATEMENT: In this study, we compared suspension cultures, HepaRG sandwich cultures, the Hµrel liver stochastic co-cultures, the Hepatopac micropatterned co-cultures (MPCC), and micro-array spheroid cultures for low clearance determination and prediction. Overall, HepaRG and suspension cultures showed modest value for the low determination and prediction of clearance compounds. The micro-array spheroid culture resulted in the most robust clearance measurements, whereas using the MPCC resulted in the most accurate prediction for low clearance compounds.

Postpartum readmission risk: a comparison between stillbirths and live births.

BACKGROUND: Stillbirth occurs more commonly among pregnant people with comorbid conditions and obstetrical complications. Stillbirth also independently increases maternal morbidity and imparts a psychosocial hazard when compared with live birth. These distinct needs and burden may increase the risk for postpartum readmission after stillbirth. OBJECTIVE: This study aimed to examine the risk for maternal postpartum readmission after stillbirth in comparison with live birth and to identify indications for readmission and the associated risk factors. STUDY DESIGN: This was a retrospective cohort of patients with singleton stillbirths or live births, delivered at ≥20 weeks' gestation, who were identified from the 2019 Nationwide Readmissions Database. The primary outcome was all-cause readmission within 6 weeks of discharge from the childbirth hospitalization. The association between stillbirth (vs live birth) and risk for readmission was assessed using multivariable regression models with adjustment for maternal age, sociodemographic characteristics, maternal and obstetrical conditions, and delivery characteristics. Within the stillbirth group, risk factors for readmission were further examined using multivariable regression. The secondary outcomes included principal indication for readmission (categorized based on principal diagnosis code of the readmission hospitalization) and timing of readmission (number of weeks after childbirth hospitalization). Differences in these secondary outcomes were compared between the stillbirth and live birth groups using chi-square tests. All analyses accounted for the complex sample design to generate nationally representative estimates. RESULTS: Postpartum readmission occurred in 2.7% of 16,636 patients with stillbirths, whereas it occurred in 1.6% of 2,870,677 patients with live births (unadjusted risk ratio, 1.65; 95% confidence interval, 1.47-1.86). The higher risk for readmission after stillbirth (vs live birth) persisted after adjusting for maternal, obstetrical, and delivery characteristics (adjusted risk ratio, 1.27; 95% confidence interval, 1.11-1.46). The distribution of principal indication for readmission differed after stillbirth and after live birth and included hypertension (30.2% vs 39.5%; unadjusted risk ratio, 0.76; 95% confidence interval, 0.63-0.93), mental health or substance use disorders (6.8% vs 3.6%; unadjusted risk ratio, 1.90; 95% confidence interval, 1.15-3.16), and venous thromboembolism (5.8% vs 2.0%; unadjusted risk ratio, 2.87; 95% confidence interval, 1.60-5.17). Among patients with stillbirths, 56.0% of readmissions occurred within 1 week, 71.8% within 2 weeks, and 88.1% within 4 weeks; the timing of readmission did not differ significantly between the stillbirth and live birth cohorts. Pregestational diabetes (adjusted risk ratio, 1.87; 95% confidence interval, 1.20-2.93), gestational diabetes (adjusted risk ratio, 1.67; 95% confidence interval, 1.03-2.71), hypertensive disorders of pregnancy (adjusted risk ratio, 1.80; 95% confidence interval, 1.31-2.47), obesity (adjusted risk ratio, 1.46; 95% confidence interval, 1.01-2.12), and primary cesarean delivery (adjusted risk ratio, 1.74; 95% confidence interval, 1.17-2.58) were associated with a higher risk for readmission after stillbirth, whereas higher household income was associated with a lower risk for readmission (eg, adjusted risk ratio for income ≥$82,000 vs $1-$47,999, 0.48; 95% confidence interval, 0.30-0.77). CONCLUSION: When compared with live births, the risk for postpartum readmission was higher after stillbirths, even after adjustment for differences in the patient demographic and clinical characteristics. Readmission for mental health or substance use disorders and venous thromboembolism is more common after stillbirths than after live births.

CYCLOIDEA paralogs function partially redundantly to specify dorsal flower development in Mimulus lewisii.

PREMISE: Duplicated genes (paralogs) are abundant in plant genomes, and their retention may influence the function of genetic programs and contribute to evolutionary novelty. How gene duplication affects genetic modules and what forces contribute to paralog retention are outstanding questions. The CYCLOIDEA(CYC)-dependent flower symmetry program is a model for understanding the evolution of gene duplication, providing multiple examples of paralog partitioning and novelty. However, a novel CYC gene lineage duplication event near the origin of higher core Lamiales (HCL) has received little attention. METHODS: To understand the evolutionary fate of duplicated HCL CYC2 genes, we determined the effects on flower symmetry by suppressing MlCYC2A and MlCYC2B expression using RNA interference (RNAi). We determined the phenotypic effects on flower symmetry in single- and double-silenced backgrounds and coupled our functional analyses with expression surveys of MlCYC2A, MlCYC2B, and a putative downstream RADIALIS (MlRAD5) ortholog. RESULTS: MlCYC2A and MlCYC2B jointly contribute to bilateral flower symmetry. MlCYC2B exhibits a clear dorsal flower identity function and may additionally function in carpel development. MlCYC2A functions in establishing dorsal petal shape. Further, our results suggest an MlCYC2A-MlCYC2B regulatory interaction, which may affect pathway homeostasis. CONCLUSIONS: Our results suggest that CYC paralogs specific to higher core Lamiales may be selectively retained for their joint contribution to bilateral flower symmetry, similar to the independently derived CYC paralogs in the Lamiales model for bilateral flower symmetry research, Antirrhinum majus (snapdragon).

Effects of cancer severity on the relationship between emotional intelligence, perceived social support, and psychological distress in Italian women.

PURPOSE: This study aims to understand the association between emotional intelligence, perceived social support, and psychological distress (i.e., anxiety, depression, stress) in women with cancer at different stages. Specifically, the aims of this study were to investigate: i) the links between emotional intelligence and psychological distress (i.e., symptoms of anxiety, stress and depression); ii) the mediating role of perceived social support provided by family members, friends, and significant others in the relationship between emotional intelligence and psychological distress; iii) the impact of cancer type and cancer stage (I-II vs III-IV) in moderating these relationships, among Italian women. METHODS: The research sample consisted of 206 Italian women (mean age = 49.30 ± 10.98 years; 55% breast cancer patients) who were administered a questionnaire to assess emotional intelligence, perceived social support, and psychological distress. Structural equation model (SEM) analysis was carried out to confirm the hypothetical-theoretical model. RESULTS: Emotional intelligence had a positive association with perceived social support, which in turn prevented psychological distress only in women with early-stages cancers. The type of cancer has no effect on these relationships. CONCLUSIONS: The findings of this study indicate a pressing need to screen and recognize women with lower emotional intelligence and perceived social support, as they may be more prone to experiencing psychological distress. For such individuals, our results recommend the implementation of psychological interventions aimed at enhancing emotional intelligence and fortifying their social support networks, with consideration for the stage of cancer they are facing.

Investigating Alexithymia as a Moderator of Outcomes in a Randomized Controlled Trial of an Online Intervention for Co-Occurring Depression and Hazardous Alcohol Use: Enquête sur l'alexithymie en tant que modérateur des résultats dans un essai randomisé contrôlé d'une intervention en ligne pour la dépression concomitante et la consommation dangereuse d'alcool.

OBJECTIVE: Alexithymia is characterized by difficulty identifying and/or describing emotions, reduced imaginal processes, and externally oriented thinking. High levels of alexithymia may increase the challenge of supporting individuals with co-occurring depression and hazardous alcohol use. This secondary analysis sought to investigate whether or not alexithymia moderated the outcomes of an online intervention for depression and alcohol use. METHOD: As part of a randomized controlled trial, 988 participants were randomly assigned to receive an intervention dually focused on depression and alcohol use, or an intervention only focused on depression. The pre-specified mediation hypothesis was that changes in drinking at 3 months follow-up would effect the association between the intervention and change in depression at 6 months. This secondary analysis extends the investigation by adding alexithymia as a moderator. RESULTS: The current analysis demonstrated that including alexithymia as a moderator resulted in a conditional direct effect. Specifically, there was an intervention effect where participants who received the combined depression and alcohol intervention had larger improvements in their depression scores at 6 months, but this was only when their alexithymia score at baseline was also high (60.5 or higher). CONCLUSION: These results suggest that treatment planning and intervention effectiveness could be informed and optimized by taking alexithymia severity into consideration. This is especially merited as alexithymia can contribute to the weaker therapeutic alliance, more distress and dysphoria, shorter periods of abstinence, and more severe depression, compounding the complexity of supporting individuals with comorbid conditions. More research is needed to systematically investigate these possible modifying effects. PLAIN LANGUAGE TITLE: Does difficulty identifying/describing emotions or externally-oriented thinking influence the effectiveness of an intervention among people with both depression and hazardous alcohol use?

In a recent study we recruited participants who were concerned with both their alcohol use and low mood. We provided two different online interventions. Half of the participants received an intervention designed for both concerns and half received an intervention that addressed only depression. We hypothesized that receiving the combined intervention for both concerns would result in greater benefits, however, our results indicated no apparent difference. This analysis uses the same data, but investigated the influences of alexithymia on the effectiveness of the interventions. Alexithymia is defined as having difficulty identifying/describing emotions and/or thinking more about external events than internal feelings. It commonly co-occurs with depression and with hazardous alcohol use and can increase the challenge of supporting individuals with these co-occurring concerns. The results of this analysis showed support for our original hypothesis that participants who received the intervention that addressed both their mood and alcohol concerns had lower depression scores 6-months later, but only among individuals who also had alexithymia scores above 60.5. Taking alexithymia severity into consideration during treatment planning may help optimize the effectiveness of interventions. These results show merit for future research to consider alexithymia as a variable that could potentially impact outcomes among individuals with co-occurring depression and hazardous alcohol use.

Computer-Based Training for Cognitive Behavioural Therapy for Substance Use Disorder: A Randomized Controlled Trial Including Quantitative and Qualitative Health and Economic Outcomes: Formation informatisée pour la thérapie cognitivo-comportementale pour les troubles liés à l'usage de substances : un essai randomisé contrôlé y compris les résultats quantitatifs et qualitatifs en matière de santé et d'économie.

OBJECTIVES: Heavy alcohol and drug use is reported by a substantial number of Canadians; yet, only a minority of those experiencing substance use difficulties access specialized services. Computer-Based Training for Cognitive Behavioural Therapy (CBT4CBT) offers a low-cost method to deliver accessible and high-quality CBT for substance use difficulties. To date, CBT4CBT has primarily been evaluated in terms of quantitative outcomes within substance use disorder (SUD) samples in the United States. A comparison between CBT4CBT versus standard care for SUDs in a Canadian sample is critical to evaluate its potential for health services in Canada. We conducted a randomized controlled trial of CBT4CBT versus standard care for SUD. METHODS: Adults seeking outpatient treatment for SUD (N = 50) were randomly assigned to receive either CBT4CBT or treatment-as-usual (TAU) for 8 weeks. Measures of substance use and associated harms and quality of life were completed before and after treatment and at 6-month follow-up. Qualitative interviews were administered after treatment and at follow-up, and healthcare utilization and costs were extracted for the entire study period. RESULTS: Participants exhibited improvements on the primary outcome as well as several secondary outcomes; however, there were no differences between groups. A cost-effectiveness analysis found lower healthcare costs in CBT4CBT versus TAU in a subsample analysis, but more days of substance use in CBT4CBT. Qualitative analyses highlighted the benefits and challenges of CBT4CBT. DISCUSSION: Findings supported an overall improvement in clinical outcomes. Further investigation is warranted to identify opportunities for implementation of CBT4CBT in tertiary care settings.Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03767907.

Evaluating a digital intervention targeting substance use difficultiesPlain Language SummaryWhy was the study done?Heavy alcohol and drug use is frequent in the Canadian population, although very few people have access to treatment. The digital intervention, Computer-Based Training for Cognitive Behavioural Therapy (CBT4CBT), may provide a low-cost, high-quality, and easily accessible method of treatment for substance use difficulties. Limited research on this digital intervention has been conducted in Canadian populations, and few studies thus far have evaluated participants' subjective experience using the intervention, along with the cost on the Canadian healthcare system.What did the researchers do?The research team recruited participants and provided access to either CBT4CBT or to standard care at a mental health hospital for 8 weeks. Participants were asked questions about their substance use and related consequences, quality of life, and thoughts on the treatment they received. Information regarding healthcare use and the cost to the healthcare system was also gathered.What did the researchers find?Participants in both groups improved with regards to their substance use, some related consequences, and psychological quality of life. Participants provided insight on the benefits and challenges of both types of treatment. It was also found that the CBT4CBT intervention was less costly.What do these findings mean?These findings support that adults receiving CBT4CBT and standard care both improved to a similar degree in this sample. Participant feedback may inform future studies of how best to implement this intervention in clinical studies. Future studies with larger samples are needed to further examine whether CBT4CBT can increase access to supports and be beneficial in the Canadian healthcare system.

A Transferable Lidar-Based Method to Conduct Contactless Assessments of Gait Parameters in Diverse Home-like Environments.

Gait abnormalities in older adults are linked to increased risks of falls, institutionalization, and mortality, necessitating accurate and frequent gait assessments beyond traditional clinical settings. Current methods, such as pressure-sensitive walkways, often lack the continuous natural environment monitoring needed to understand an individual's gait fully during their daily activities. To address this gap, we present a Lidar-based method capable of unobtrusively and continuously tracking human leg movements in diverse home-like environments, aiming to match the accuracy of a clinical reference measurement system. We developed a calibration-free step extraction algorithm based on mathematical morphology to realize Lidar-based gait analysis. Clinical gait parameters of 45 healthy individuals were measured using Lidar and reference systems (a pressure-sensitive walkway and a video recording system). Each participant participated in three predefined ambulation experiments by walking over the walkway. We observed linear relationships with strong positive correlations (R2>0.9) between the values of the gait parameters (step and stride length, step and stride time, cadence, and velocity) measured with the Lidar sensors and the pressure-sensitive walkway reference system. Moreover, the lower and upper 95% confidence intervals of all gait parameters were tight. The proposed algorithm can accurately derive gait parameters from Lidar data captured in home-like environments, with a performance not significantly less accurate than clinical reference systems.

Nonlinear Effects in Asymmetric Catalysis by Design: Concept, Synthesis, and Applications.

Asymmetric synthesis constitutes a key technology for the preparation of enantiomerically pure compounds as well as for the selective control of individual stereocenters in the synthesis of complex compounds. It is thus of extraordinary importance for the synthesis of chiral drugs, dietary supplements, flavors, and fragrances, as well as novel materials with tunable and reconfigurable chiroptical properties or the assembly of complex natural products. Typically, enantiomerically pure catalysts are used for this purpose. To prepare enantiomerically pure ligands or organocatalysts, one can make use of the natural chiral pool. Ligands and organocatalysts with an atropisomeric biphenyl and binaphthyl system have become popular, as they are configurationally stable and contain a C2-symmetric skeleton, which has been found to be particularly privileged. For catalysts with opposite configurations, both product enantiomers can be obtained. Configurationally flexible biphenyl systems initially appeared to be unsuitable for this purpose, as they racemize after successful enantiomer separation and thus are neither storable nor afford a reproducible enantioselectivity. However, there are strategies that exploit the dynamics of such ligands to stereoconvergently enrich one of the catalyst enantiomers. This can be achieved, for example, by coordinating an enantiomerically pure additive to a ligand-metal complex, which results in deracemization of the configurationally flexible biphenyl system, thereby enriching the thermodynamically preferred diastereomer. In this Account, we present our strategy to design stereochemically flexible catalysts that combine the properties of supramolecular recognition, stereoconvergent alignment, and catalysis. Such systems are capable to recognize the chirality of the target product, leading to an increase in enantioselectivity during asymmetric catalysis. We have systematically developed and investigated these smart catalyst systems and have found ways to specifically design and synthesize them for various applications. In addition to (i) reaction product-induced chiral amplification, we have developed systems with (ii) intermolecular and (iii) intramolecular recognition, and successfully applied them in asymmetric catalysis. Our results pave the way for new applications such as temperature-controlled enantioselectivity, controlled inversion of enantioselectivity with the same chirality of the recognition unit, generation of positive nonlinear effects, and targeted design of autocatalytic systems through dynamic formation of transient catalysts. Understanding such systems is of enormous importance for catalytic processes leading to symmetry breaking and amplification of small imbalances of enantiomers and offer a possible explanation of homochirality of biological systems. In addition, we are learning how to target supramolecular interactions to enhance enantioselectivities in asymmetric catalysis through secondary double stereocontrol. Configurationally flexible catalysts will enable future resource-efficient development of asymmetric syntheses, as enantioselectivities can be fully switched by stereoselective alignment of the stereochemically flexible ligand core on demand.

Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study.

BACKGROUND: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities. OBJECTIVE: We conducted a proof-of-concept, open-label phase II study to examine the efficacy and central effects of sodium oxybate in patients with alcohol-responsive ETv. METHODS: All subjects received 1.0 to 1.5 g of oral sodium oxybate and underwent brain functional magnetic resonance imaging. The primary endpoint was the number of patients (% from total) with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. The secondary endpoint included changes in brain activity after sodium oxybate intake compared to baseline. RESULTS: Sodium oxybate reduced ETv symptoms on average by 40.8% in 92.9% of patients. Drug effects were observed about 40 to 45 minutes after intake, lasting about 3.5 hours, and gradually wearing off by the end of the fifth hour. The central effects of sodium oxybate were associated with normalized activity in the cerebellum, inferior/superior parietal lobules, inferior frontal gyrus, and insula and re-established functional relationships between these regions. CONCLUSIONS: Sodium oxybate showed high efficacy in ETv patients, with a likely central action on disorder pathophysiology. Sodium oxybate may be an effective novel oral drug for treatment of alcohol-responsive ETv patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Using blastocyst re-expansion rate for deciding when to warm a new blastocyst for single vitrified-warmed blastocyst transfer.

RESEARCH QUESTION: Can predictive post-warm parameters that support the decision to transfer a warmed blastocyst or to warm another blastocyst be identified in women with multiple frozen-vitrified blastocysts? DESIGN: Retrospective single-centre observational cohort analysis. A total of 1092 single vitrified-warmed blastocyst transfers (SVBT) with known Gardner score, maternal age and live birth were used to develop live birth prediction models based on logistic regression, including post-warm re-expansion parameters. Time-lapse incubation was used for pre-vitrification and post-warm embryo culture. A dataset of 558 SVBT with the same inclusion criteria was used to validate the model, but with known clinical pregnancy outcome instead of live birth outcome. RESULTS: Three different logistic regression models were developed for predicting live birth based on post-warm blastocyst re-expansion. Different post-warm assessment times indicated that a 2-h post-warm culture period was optimal for live birth prediction (model 1). Adjusting for pre-vitrification Gardner score (model 2) and in combination with maternal age (model 3) further increased predictability (area under the curve [AUC] = 0.623, 0.633, 0.666, respectively). Model validation gave an AUC of 0.617, 0.609 and 0.624, respectively. The false negative rate and true negative rate for model 3 were 2.0 and 10.1 in the development dataset and 3.5 and 8.0 in the validation dataset. CONCLUSIONS: Clinical application of a simple model based on 2 h of post-warm re-expansion data, pre-vitrification Gardner score and maternal age can support a standardized approach for deciding if warming another blastocyst may increase the likelihood of live birth in SVBT.

Therapeutic Drug Monitoring of Ganciclovir in Cytomegalovirus-Infected Patients With Solid Organ Transplants and Its Correlation to Efficacy and Toxicity.

BACKGROUND: Cytomegalovirus causes morbidity and mortality, especially in immunocompromised patients, and is treated with (val)ganciclovir. Therapeutic drug monitoring of ganciclovir is often performed; however, clinically established target trough levels corresponding to efficacy are lacking. In 2021, our clinic increased the target trough level for ganciclovir from 1 to 2 mg/L to 2-4 mg/L. This study aims to compare both target trough levels in efficacy, toxicity, and occurrence of resistance. METHODS: A retrospective cohort study was performed in adult solid organ recipients treated for cytomegalovirus infection with (val)ganciclovir. Clinical efficacy was defined as the absence of treatment failure, defined as > 1 log 10 increase in viral load within 2 weeks of treatment initiation, therapy switch to foscarnet, and/or request for resistance analysis. RESULTS: A total of 46 patients were involved in the study, with 200 ganciclovir trough levels obtained. The composite endpoint was recorded in 23 (69.7%) and 10 (76.9%) patients in the 1-2 mg/L and the 2-4 mg/L group, respectively ( P = 0.18). No association was found between ganciclovir trough levels and the composite endpoint ( P = 1.0). However, a correlation was found between ganciclovir trough levels and the occurrence of lymphopenia ( P = 0.02). CONCLUSIONS: Our study could not establish a difference in clinical efficacy or toxicity between target trough levels of 1-2 mg/L or 2-4 mg/L because of the lack of clinical differences between the compared groups. However, a correlation was found between ganciclovir trough levels and lymphopenia, which warrants further investigation.

Successful rehabilitation after multiple severe complications following orthognathic surgery: a case report.

BACKGROUND: Complications of orthognathic surgery are quite rare, but they cause suffering in affected individuals. The range of complications is broad and includes both hard and soft tissue. CASE PRESENTATION: We here present a case of a fully healthy woman without signs of impaired healing capacity. The patient underwent bimaxillary orthognathic surgery and experienced multiple complications both peri- and post-operatively. During the post operative period, the patient also suffered from soft tissue complications after an orthopaedic injury. Therefore, we referred the patient to her general practitioner for further medical investigation. We also present the result after restorative surgery and endodontic and prosthodontic treatment resulting in a successful rehabilitation. CONCLUSION: This case report clearly shows the need for a good collaboration between different odontological and medical fields to achieve a good and predictable result. In situations where normal healing processes do not occur, in-depth analysis must be carried out. HIGHLIGHTS: Orthognathic surgery affects soft and hard tissue which can result in adverse healing and complications. It is of great importance to follow up performed surgery to see late complications. Be restrictive with early re-operations when there are signs of necrosis. Always use a multidisciplinary approach when handling complications after surgery.

Fluctuating heat stress during development exposes reproductive costs and putative benefits.

Temperature and thermal variability are increasing worldwide, with well-known survival consequences. However, effects on other potentially more thermally sensitive reproductive traits are less understood, especially when considering thermal variation. Studying the consequences of male reproduction in the context of climate warming and ability to adapt is becoming increasingly relevant. Our goals were to test how exposure to different average temperatures that either fluctuated or remained constant impacts different male reproductive performance traits and to assess adaptive potential to future heat stress. We took advantage of a set of Drosophila melanogaster isogenic lines of different genotypes, exposing them to four different thermal conditions. These conditions represented a benign and a stressful mean temperature, applied either constantly or fluctuating around the mean and experienced during development when heat stress avoidance is hindered because of restricted mobility. We measured subsequent male reproductive performance for mating success, fertility, number of offspring produced and offspring sex ratio, and calculated the influence of thermal stress on estimated heritability and evolvability of these reproductive traits. Both costs and benefits to different thermal conditions on reproductive performance were found, with some responses varying between genotypes. Mating success improved under fluctuating benign temperature conditions and declined as temperature stress increased regardless of genotype. Fertility and productivity were severely reduced at fluctuating mean high temperature for all genotypes, but some genotypes were unaffected at constant high mean temperature. These more thermally robust genotypes showed a slight increase in productivity under the fluctuating benign condition compared to constant high temperature, despite both thermal conditions sharing the same temperature for 6 hr daily. Increasing thermal stress resulted in higher heritability and evolvability. Overall, the effects of temperature on reproductive performance depended on the trait and genotype; performance of some traits slightly increased when high temperatures were experienced for short periods but decreased substantially even when experiencing a benign temperature for a portion of each day. While thermal stress increased genetic variation that could provide adaptive potential against climate warming, this is unlikely to compensate for the overall severe negative effect on reproductive performance as mean temperature and variance increase.

A Measure of Illness Awareness in Individuals With Nicotine Dependence-Nicotine Use Awareness and Insight Scale.

INTRODUCTION: Impaired illness awareness or the inability to recognize that one has a dependence on nicotine may be a major barrier to seeking cessation treatment. To better understand the role of impaired illness awareness on treatment-seeking behavior and clinical outcomes, we developed and examined the psychometric properties of a novel scale measuring illness awareness in individuals with dependence on nicotine. AIMS AND METHODS: We developed the Nicotine Use Awareness and Insight Scale (NAS), a 7-item self-report measure to assess the theoretical construct of illness awareness in individuals with dependence on nicotine (www.illnessawarenessscales.com). Data from participants 18 years of age or older were collected via a web-based survey company, Dynata. Participants with moderate dependence on nicotine were included, defined by a score of four or more on the Fagerström Test for Cigarette Dependence (FTCD) or the FTCD adapted for electronic cigarettes (eFTCD). RESULTS: A total of 100 participants (mean [SD] age = 49.1 [16.1] years, 52% women) that met the inclusion criteria for either FTCD (n = 50) or eFTCD (n = 50) were included. The NAS demonstrated good convergent (r = .74, p < .001) and discriminant validity (r = .03, p = .786). It also demonstrated good internal consistency (Cronbach's alpha = 0.78) and one-month test-retest reliability (intra-class correlation = 0.86). An exploratory factor analysis yielded the retention of two components. CONCLUSIONS: The NAS is a novel scale to asses illness awareness in individuals with dependence on nicotine. This study provides initial support for the psychometric validity and reliability of NAS. IMPLICATIONS: The NAS may be used in research and clinical practice to evaluate the impact of impaired illness awareness on treatment-seeking behavior and clinical outcomes.

Impact of histopathological classification of non-functioning adenomas on long term outcomes: comparison of the 2004 and 2017 WHO classifications.

PURPOSE: Outcomes of patients with non-functioning pituitary adenomas categorized using the 2004 and 2017 WHO classification systems are understudied. We report outcomes from the University of Virginia of patients with non-functioning pituitary adenomas categorized using both systems. METHODS: We constructed a database from all 239 patients who underwent resection of a non-functioning pituitary adenoma between 2003 and 2015 and had at least 5 years of follow-up. Pathologic diagnosis was determined under both the 2004 and 2017 WHO classification systems. We compared the rates of recurrence and progression between subtypes using univariate and multivariate Cox regression analyses. RESULTS: Nearly 30% of the tumors in our database were classified as null cell adenomas under the 2004 classification system, whereas only 10% of the tumors were classified as null cell adenomas using the 2017 classification system. Most of these tumors were reclassified as either corticotroph or gonadotroph adenomas. Despite our relatively large cohort and average follow-up of nearly 9 years, we did not detect a significant difference in recurrence and progression between subtypes. CONCLUSIONS: The majority of null cell adenomas diagnosed under the 2004 WHO classification system are reclassified as gonadotroph or corticotroph adenomas under the 2017 WHO classification system. Rates of progression and recurrence between subtypes are not as different as previously believed at our institution and require a larger cohort to further investigate.

Treatment of Opioid Use Disorder in Canadian Psychosocial Addiction Programs: A National Survey of Policy, Attitudes, and Practice.

OBJECTIVE: To describe current approaches in treatment of opioid use disorder (OUD) within Canadian psychosocial outpatient, day, and residential addiction treatment programs, with an emphasis on the use of opioid agonist therapy (OAT). METHOD: An online census survey was conducted in English and French of Canadian psychosocial addiction treatment programs (N = 214). RESULTS: Programs estimated that 25% of their clients have OUD. A slight majority of programs provide some type of specialized services to clients with OUD (58%), most frequently providing or facilitating access to OAT but also specialized counselling, case management, education, and harm reduction services.Most programs reported that they admitted clients on OAT (88%) and only a minority expected or encouraged clients to taper (14%) or discontinue (6%). Programs focusing on client abstinence as the treatment goal were more likely to expect or encourage tapering or discontinuation than programs that focus on helping clients achieve personal consumption goals. Of programs that did not currently facilitate OAT, 44% indicated that they would provide OAT, but lacked the necessary accreditation, physician support, or other resources. No philosophical objections to OAT were noted.OAT initiation was provided by 30% of programs, 23% referred to another service within their organization, and 29% referred to a service outside their organization. The remaining 18% did not facilitate OAT initiation at all, ranging from 0% in Quebec to 23% in the Prairies. Overdose response kits were provided by 86% of programs. The majority not providing kits indicated willingness if policy support and resources were provided (67%). CONCLUSIONS: Overall, the results demonstrate that psychosocial programs provide some specialized services for OUD but desire further support specifically to provide OAT, including training, knowledge, and the expertise of individuals qualified to prescribe and dispense OAT. Many psychosocial treatment programs expressed a need for staff and resources for this purpose.

A Multi-Method Investigation of Normative and Pathological Personality Across the Spectrum of Gambling Involvement.

Pathological Gambling (PG) has been linked to both specific personality traits and personality disorders (PDs). However, previous studies have used a wide variety of research designs that preclude clear conclusions about the personality features that distinguish adults with PG from other groups. The current investigation seeks to advance this research by using a sample including adults who do not gamble, who gamble socially, and who exhibit PG, using self-report, informant-report, and interview-rated measures of personality traits and disorders. A total of 245 adults completed measures of gambling behaviour and problems, as well as normative and pathological personality over two assessment visits. A multivariate ANCOVA was conducted to investigate differences between groups. Analyses supported numerous group differences including differences between all groups on the Neuroticism facet of Impulsivity, and between non-gambling/socially gambling and PG groups on the Conscientiousness facet of Self-Discipline. Adults with PG exhibited more symptoms of Borderline, Paranoid, Schizotypal, Avoidant, and Dependent PDs than adults who gamble socially or not at all. The current investigation provides a comprehensive survey of personality across a wide range of gambling involvement, using a multi-method approach. Our findings help to clarify the most pertinent personality risk factors for PG.

A Measure to Assess Illness Awareness in Problem Gambling: Gambling Awareness and Insight Scale (GAS).

Impaired subjective awareness of problem gambling may act as a barrier to help-seeking and treatment adherence. However, the impact of impaired problem gambling awareness on clinical and social outcomes has received little empirical study. The aim of this study was to develop and investigate the psychometric properties of a novel scale that measures impaired illness awareness in individuals with problem gambling. We developed the Gambling Awareness and Insight Scale (GAS), a self-report measure that assesses the core theoretical constructs of illness awareness in problem gambling, namely General Disorder or Problem Awareness, Accurate Symptom Attribution, Awareness of Need for Treatment and the Negative Consequences attributable to problem gambling ( www.illnessawarenessscales.com ). Data were acquired from an online survey platform, Dynata, to evaluate the psychometric properties of the GAS. A total of 100 participants aged 18 years or older with problem gambling defined by a score of 4 or more on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) Pathological Gambling Diagnostic Form were included. The GAS demonstrated good convergent (r = 0.57, p < 0.001) and discriminant validity (r = - 0.18, p = 0.080). It also demonstrated good internal consistency (Cronbach's α = 0.80) and one-month test-retest reliability (intra-class correlation = 0.86). An exploratory factor analysis suggested retention of two components. The GAS is a novel psychometric tool designed to evaluate impaired subjective illness awareness in problem gambling. Initial evidence suggests that the GAS can be used in research and clinical settings to evaluate the impact of impaired problem gambling awareness on adherence to treatment programs, clinical and psychosocial outcomes. Replication in applied settings is needed.