Search for a Sub-eV Sterile Neutrino Using Daya Bay's Full Dataset.

This Letter presents results of a search for the mixing of a sub-eV sterile neutrino with three active neutrinos based on the full data sample of the Daya Bay Reactor Neutrino Experiment, collected during 3158 days of detector operation, which contains 5.55×10^{6} reactor ν[over ¯]_{e} candidates identified as inverse beta-decay interactions followed by neutron capture on gadolinium. The analysis benefits from a doubling of the statistics of our previous result and from improvements of several important systematic uncertainties. No significant oscillation due to mixing of a sub-eV sterile neutrino with active neutrinos was found. Exclusion limits are set by both Feldman-Cousins and CLs methods. Light sterile neutrino mixing with sin^{2}2θ_{14}≳0.01 can be excluded at 95% confidence level in the region of 0.01 eV^{2}≲|Δm_{41}^{2}|≲0.1 eV^{2}. This result represents the world-leading constraints in the region of 2×10^{-4} eV^{2}≲|Δm_{41}^{2}|≲0.2 eV^{2}.

Metabolomic profiling of pheochromocytomas in dogs: Catecholamine phenotype and tricarboxylic acid cycle metabolites.

BACKGROUND: In humans with pheochromocytomas (PCCs), targeted metabolomics is used to determine the catecholamine phenotype or to uncover underlying pathogenic variants in tricarboxylic acid (TCA) cycle genes such as succinate dehydrogenase subunits (SDHx). HYPOTHESIS/OBJECTIVES: To analyze catecholamine contents and TCA cycle metabolites of PCCs and normal adrenals (NAs). ANIMALS: Ten healthy dogs, 21 dogs with PCC. METHODS: Prospective observational study. Dogs diagnosed with PCC based on histopathological and immunohistochemical confirmation were included. Tissue catecholamine contents and TCA metabolites in PCCs and NAs were measured by liquid chromatography with mass spectrometry or electrochemical detection. RESULTS: Compared to NAs, PCCs had significantly higher tissue proportion of norepinephrine (88% [median: range, 38%-98%] vs 14% [11%-26%]; P < .001), and significantly lower tissue proportion of epinephrine (12% [1%-62%] vs 86% [74%-89%]; P < .001). Pheochromocytomas exhibited significantly lower fumarate (0.4-fold; P < .001), and malate (0.5-fold; P = .008) contents than NAs. Citrate was significantly higher in PCCs than in NAs (1.6-fold; P = .015). One dog in the PCC group had an aberrant succinate : fumarate ratio that was 25-fold higher than in the other PCCs, suggesting an SDHx mutation. CONCLUSIONS AND CLINICAL IMPORTANCE: This study reveals a distinct catecholamine content and TCA cycle metabolite profile in PCCs. Metabolite profiling might be used to uncover underlying pathogenic variants in TCA cycle genes in dogs.

The Continuing Challenges of Studying Parallel Behaviours in Humans and Animal Models.

The use of animal models continues to be essential for carrying out research into clinical phenomena, including addiction. However, the complexity of the clinical condition inevitably means that even the best animal models are inadequate, and this may go some way to account for the apparent failures of discoveries from animal models, including the identification of potential novel therapies, to translate to the clinic. We argue here that it is overambitious and misguided in the first place to attempt to model complex, multifacetted human disorders such as addiction in animals, and especially in rodents, and that all too frequently "validity" of such models is limited to superficial similarities, referred to as "face validity", that reflect quite different underlying phenomena and biological processes from the clinical situation. Instead, a more profitable approach is to identify (a) well-defined intermediate human behavioural phenotypes that reflect defined, limited aspects of, or contributors to, the human clinical disorder, and (b) to develop animal models that are homologous with those discrete human behavioural phenotypes in terms of psychological processes, and underlying neurobiological mechanisms. Examples of past and continuing weaknesses and suggestions for more limited approaches that may allow better homology between the test animal and human condition are made.

Meaningful contributions of rehabilitation for people with persistent pain; a reflexive thematic analysis.

PURPOSE: This study aims to explore the meaningful contributions of rehabilitation for participants living with persistent pain. MATERIALS AND METHODS: A phenomenological methodology was used. Thirteen purposefully selected participants, who self-identified as substantially improved from persistent pain due to rehabilitation, were interviewed in-depth. Data were analyzed using reflexive thematic analyses. RESULTS: Participants included three men and ten women, age ranging from 22-69 years, pain duration was 2-30 years. Seven interconnected themes were developed: 1) indication of negative pain and health care experiences, 2) supporting working alliance with healthcare professionals, 3) Pain Dialogue, 4) improved self-awareness and self-regulation, 5) different view on pain, 6) autonomy and personal growth and 7) hope and new perspective. Integration of these themes provided a framework for understanding meaningful contributions of rehabilitation from the participants' perspective. CONCLUSIONS: The study identified seven interconnected themes enhancing meaningful contributions of rehabilitation for participants who have substantially improved from persistent pain. These findings provide a novel conceptual understanding of how rehabilitation can foster recovery. The themes strongly support person-centred care, an understanding of Pain Dialogue and personal growth through the lens of the lived experience. The quality of the therapeutic relationship is considered a central vehicle for improved health outcomes.

A rehabilitation participant perspective can contribute to better outcomes in pain rehabilitation.A shift from a pain-centred to a person-centred approach should be considered to enhance meaningful contributions of rehabilitation.Pain Education should be reconceptualized into Pain Dialogue.The quality of the therapeutic relationship can be regarded as a key driver for the effectiveness of person-centred care and Pain Dialogue.

Conditional Inhibition of Eip75B Eliminates the Effects of Mating and Mifepristone on Lifespan in Female Drosophila.

Mating in female Drosophila melanogaster causes midgut hypertrophy and reduced lifespan, and these effects are blocked by the drug mifepristone. Eip75B is a transcription factor previously reported to have pleiotropic effects on Drosophila lifespan. Because Eip75B null mutations are lethal, conditional systems and/or partial knock-down are needed to study Eip75B effects in adults. Previous studies showed that Eip75B is required for adult midgut cell proliferation in response to mating. To test the possible role of Eip75B in mediating the lifespan effects of mating and mifepristone, a tripartite FLP-recombinase-based conditional system was employed that provides controls for genetic background. Expression of a Hsp70-FLP transgene was induced in third instar larvae by a brief heat pulse. The FLP recombinase catalyzed the recombination and activation of an Actin5C-GAL4 transgene. The GAL4 transcription factor in turn activated expression of a UAS-Eip75B-RNAi transgene. Inhibition of Eip75B activity was confirmed by loss of midgut hypertrophy upon mating, and the lifespan effects of both mating and mifepristone were eliminated. In addition, the negative effects of mifepristone on egg production were eliminated. The data indicate that Eip75B mediates the effects of mating and mifepristone on female midgut hypertrophy, egg production, and lifespan.

Efficacy and safety of once daily oral administration of sodium-glucose cotransporter-2 inhibitor velagliflozin compared with twice daily insulin injection in diabetic cats.

BACKGROUND: Options for treatment of diabetes mellitus in cats are limited to insulin injections and monitoring for hypoglycemia. HYPOTHESIS: Once daily sodium-glucose cotransporter-2 inhibitor velagliflozin PO is noninferior to insulin injections. ANIMALS: Client-owned diabetic cats (127 safety; 116 efficacy assessment). METHODS: Prospective, randomized (1 mg/kg velagliflozin), positive controlled (titrated Caninsulin), open label, noninferiority field trial, comparing number of cats with treatment success in ≥1 clinical variable and ≥1 glycemic variable (margin Δ: 15%) on Day 45; secondary endpoints included glycemic and clinical assessments during 91 days. RESULTS: On Day 45, 29/54 (54%) velagliflozin-treated cats and 26/62 (42%) Caninsulin-treated cats showed treatment success, demonstrating noninferiority (difference -11.8%; upper 1-sided 97.5% confidence interval, -∞ to 6.3%). By Day 91, quality of life (QoL), polyuria, and polydipsia had improved in 81%, 54% and 61% (velagliflozin); on blood glucose (BG) curves, mean BG was <252 mg/dL in 42/54 (78%; velagliflozin) and 37/62 (60%; Caninsulin); minimum BG was <162 mg/dL in 41/54 (76%; velagliflozin) and 41/62 (66%; Caninsulin); serum fructosamine was <450 µmol/L in 41/54 (76%; velagliflozin) and 38/62 (61%; Caninsulin). Velagliflozin's most frequent adverse events were loose feces/diarrhea (n = 23/61, 38%), positive urine culture (n = 19/61, 31%), and nonclinical hypoglycemia (BG <63 mg/dL; n = 8/61, 13%); Caninsulin's: clinical and nonclinical hypoglycemia (n = 35/66, 53%), positive urine culture (n = 18/66, 27%), and loose feces/diarrhea (n = 10/66, 15%). Diabetic ketoacidosis occurred in 4/61 (7%; velagliflozin) and 0/66 (Caninsulin). CONCLUSIONS AND CLINICAL IMPORTANCE: Once daily oral administration of velagliflozin was noninferior to insulin injections, showed good QoL and glycemia without clinical hypoglycemia.

Predictors of psychiatric treatment-seeking attitudes in older adults.

OBJECTIVES: Understanding the factors that contribute to treatment-seeking attitudes among older adults-a growing population with frequent mental health concerns-is vital. Although past research has identified some demographic and belief-based predictors of mental health treatment attitudes among this population, previous studies are limited by only evaluating these variables in isolation and not distinguishing between different types of treatment (e.g. medication and psychotherapy). METHODS: In a pre-registered online survey of 606 older adults (age 60 years and older), we evaluated stigmatizing attitudes, etiological beliefs about depression, psychological symptoms, and health literacy as well as attitudes about psychotherapy and medication separately. RESULTS: Pre-registered linear regression analyses showed that greater stigmatizing attitudes uniquely predicted more negative attitudes for both therapy and medication treatment seeking over and above gender, education, income, extrinsic barriers, health literacy, depression, and anxiety. Additionally, loneliness was a significant predictor of less favorable medication attitudes. Exploratory analysis revealed that attributing depression to a chemical imbalance predicted positive attitudes about medication, but not psychotherapy. CONCLUSION: These findings indicate that older adults' treatment-seeking behaviors are separately influenced by stigma, etiological beliefs, and loneliness.

Immunotherapy drives mesenchymal tumor cell state shift and TME immune response in glioblastoma patients.

BACKGROUND: Glioblastoma is a highly aggressive type of brain tumor for which there is no curative treatment available. Immunotherapies have shown limited responses in unselected patients, and there is an urgent need to identify mechanisms of treatment resistance to design novel therapy strategies. METHODS: Here we investigated the phenotypic and transcriptional dynamics at single-cell resolution during nivolumab immune checkpoint treatment of glioblastoma patients. RESULTS: We present the integrative paired single-cell RNA-seq analysis of 76 tumor samples from patients in a clinical trial of the PD-1 inhibitor nivolumab and untreated patients. We identify a distinct aggressive phenotypic signature in both tumor cells and the tumor microenvironment in response to nivolumab. Moreover, nivolumab-treatment was associated with an increased transition to mesenchymal stem-like tumor cells, and an increase in TAMs and exhausted and proliferative T cells. We verify and extend our findings in large external glioblastoma dataset (n = 298), develop a latent immune signature and find 18% of primary glioblastoma samples to be latent immune, associated with mesenchymal tumor cell state and TME immune response. Finally, we show that latent immune glioblastoma patients are associated with shorter overall survival following immune checkpoint treatment (P = .0041). CONCLUSIONS: We find a resistance mechanism signature in one fifth of glioblastoma patients associated with a tumor-cell transition to a more aggressive mesenchymal-like state, increase in TAMs and proliferative and exhausted T cells in response to immunotherapy. These patients may instead benefit from neuro-oncology therapies targeting mesenchymal tumor cells.

Metronome-guided cochlear implantation for slower and smoother insertions of lateral wall electrodes.

INTRODUCTION: Achieving a slow and smooth electrode array insertion is paramount for preserving structural and functional integrity during cochlear implantation. This controlled study evaluates the efficacy of a metronome-guided insertion technique in enhancing the smoothness and speed of electrode array insertions. METHODS: In a prospective cohort study, patients undergoing cochlear implant surgery between 2022 and 2023 with lateral wall electrode arrays were included. Metronome guidance was delivered through an acoustic signal via headphones during electrode array insertion in cochlear implantation and compared to a control group without metronome-guidance. RESULTS: In total, 37 cases were evaluated, including 25 conventional insertions and 12 metronome-guided insertions. The results indicate that metronome-guided insertions were significantly slower (- 0.46 mm/s; p < 0.001) without extending the overall procedure time. This can be attributed to fewer paused sections observed in the metronome-guided technique. Moreover, metronome-guided insertions exhibited superior performance in terms of insertion smoothness and a reduced number of re-gripping events. CONCLUSIONS: The findings support the recommendation for the systematic application of metronome guidance in the manual insertion of cochlear implant electrode arrays, emphasizing its potential to optimize surgical outcomes.

Identity recognition from faces and bodies in schizophrenia spectrum disorders.

Deficits in facial identity recognition and its association with poor social functioning are well documented in schizophrenia, but none of these studies have assessed the role of the body in these processes. Recent research in healthy populations shows that the body is also an important source of information in identity recognition, and the current study aimed to thoroughly examine identity recognition from both faces and bodies in schizophrenia. Sixty-five individuals with schizophrenia and forty-nine healthy controls completed three conditions of an identity matching task in which they attempted to match unidentified persons in unedited photos of faces and bodies, edited photos showing faces only, or edited photos showing bodies only. Results revealed global deficits in identity recognition in individuals with schizophrenia (ηp2 = 0.068), but both groups showed better recognition from bodies alone as compared to faces alone (ηp2 = 0.573), suggesting that the ability to extract useful information from bodies when identifying persons may remain partially preserved in schizophrenia. Further research is necessary to understand the relationship between face/body processing, identity recognition, and functional outcomes in individuals with schizophrenia-spectrum disorders.

Stem cell secretome treatment improves whole-body metabolism, reduces adiposity, and promotes skeletal muscle function in aged mice.

Aging coincides with the progressive loss of muscle mass and strength, increased adiposity, and diminished physical function. Accordingly, interventions aimed at improving muscle, metabolic, and/or physical health are of interest to mitigate the adverse effects of aging. In this study, we tested a stem cell secretome product, which contains extracellular vesicles and growth, cytoskeletal remodeling, and immunomodulatory factors. We examined the effects of 4 weeks of 2×/week unilateral intramuscular secretome injections (quadriceps) in ambulatory aged male C57BL/6 mice (22-24 months) compared to saline-injected aged-matched controls. Secretome delivery substantially increased whole-body lean mass and decreased fat mass, corresponding to higher myofiber cross-sectional area and smaller adipocyte size, respectively. Secretome-treated mice also had greater whole-body physical function (grip strength and rotarod performance) and had higher energy expenditure and physical activity levels compared to control mice. Furthermore, secretome-treated mice had greater skeletal muscle Pax7+ cell abundance, capillary density, collagen IV turnover, reduced intramuscular lipids, and greater Akt and hormone sensitive lipase phosphorylation in adipose tissue. Finally, secretome treatment in vitro directly enhanced muscle cell growth and IL-6 production, and in adipocytes, it reduced lipid content and improved insulin sensitivity. Moreover, indirect treatment with secretome-treated myotube culture media also enhanced muscle cell growth and adipocyte size reduction. Together, these data suggest that intramuscular treatment with a stem cell secretome improves whole-body metabolism, physical function, and remodels skeletal muscle and adipose tissue in aged mice.

Depression self-labeling in U.S. college students: Associations with perceived control and coping strategies.

BACKGROUND: Research on mental illness labeling has demonstrated that self-labeling (identifying with a mental illness label, e.g., "I have depression") is associated with internalized stigma, maladaptive responses to that stigma, and lower quality of life. However, research has not yet examined the link between self-labeling and how individuals cope with emotional distress. It is important to understand this relationship because adaptive and maladaptive methods of coping can lead to positive and negative mental illness outcomes. METHODS: This cross-sectional study examined the link between depression self-labeling, depression symptoms, and three constructs related to depression self-management (perceived control over depression, cognitive emotion regulation strategies, and help-seeking beliefs) in a large (N = 1423) sample of U.S. college students. RESULTS: Approximately one-fifth of students (22.2 %) self-labeled as having depression, while 39.0 % were estimated to meet diagnostic criteria for MDD. After controlling for depression symptom severity, self-labeling was associated with lower levels of perceived control over depression (p = .002), more catastrophizing (p = .013), less perspective taking, refocusing, reappraisal, and planning (ps < 0.05), and more positive help-seeking attitudes towards medication (p < .001) but not therapy. LIMITATIONS: Results are non-causal and may not generalize to non-college populations. CONCLUSIONS: Self-labeling may inform how individuals cope with emotional distress, with the potential for positive and negative effects on clinical outcomes. This is consistent with well-established research on self-labeling with regards to stigma, but extends this research in important new directions.

The effectiveness of cognitive bias modification in reducing substance use in detained juveniles: An RCT.

BACKGROUND AND OBJECTIVE: Young offenders show high levels of substance use. Treatment programs within detention settings are less effective. Cognitive bias modification (CBM) is a promising supplement to substance use treatment. This study tests the effectiveness of CBM in young offenders to reduce cannabis and alcohol use, and delinquent recidivism. METHOD: A randomized controlled trial added CBM to treatment as usual (TAU), among 181 youth in juvenile detention centers. In a factorial design, participants were randomly assigned to either active- or sham-training for two varieties of CBM, targeting attentional-bias (AtB) and approach-bias (ApB) for their most used substance. Substance use was measured with the Alcohol and Cannabis Use Disorder Identification Tests. Delinquent recidivism was measured with the International Self-Report Delinquency (ISRD) survey. RESULTS: At pretest, participants showed AtB but no ApB for both substances. For alcohol, a decrease was found in AtB in the active-training group. For cannabis, a decrease was found in AtB for both active- and sham-training groups. Regardless of condition, no effects were found on substance use or ISRD scores at follow-up. LIMITATIONS: The sample is judicial, not clinical, as is the setting. TAU and participant goals are not necessarily substance related. CONCLUSIONS: Young offenders show a significant attentional-bias towards substance cues. CBM changed attentional-biases but not substance use. Combining CBM with a motivational intervention is advised. Follow-up research should better integrate CBM with running treatment programs. New developments regarding CBM task design could be used that link training better to treatment.

Dhr96[1] mutation and maternal tudor[1] mutation increase life span and reduce the beneficial effects of mifepristone in mated female Drosophila.

Mating and receipt of male Sex Peptide hormone cause increased egg laying, increased midgut size and decreased life span in female Drosophila. Feeding mated females with the synthetic steroid mifepristone decreases egg production, reduces midgut size, and increases life span. Here, several gene mutations were assayed to investigate possible mechanisms for mifepristone action. Drosophila Dhr96 is a hormone receptor, and a key positive regulator of midgut lipid uptake and metabolism. Dhr96[1] null mutation increased female life span, and reduced the effects of mifepristone on life span, suggesting that Dhr96[1] mutation and mifepristone may act in part through the same mechanism. Consistent with this idea, lipidomics analysis revealed that mating increases whole-body levels of triglycerides and fatty-acids in triglycerides, and these changes are reversed by mifepristone. Maternal tudor[1] mutation results in females that lack the germ-line and produce no eggs. Maternal tudor[1] mutation increased mated female life span, and reduced but did not eliminate the effects of mating and mifepristone on life span. This indicates that decreased egg production may be related to the life span benefits of mifepristone, but is not essential. Mifepristone increases life span in w[1118] mutant mated females, but did not increase life span in w[1118] mutant virgin females. Mifepristone decreased egg production in w[1118] mutant virgin females, indicating that decreased egg production is not sufficient for mifepristone to increase life span. Mifepristone increases life span in virgin females of some, but not all, white[+] and mini-white[+] strains. Backcrossing of mini-white[+] transgenes into the w[1118] background was not sufficient to confer a life span response to mifepristone in virgin females. Taken together, the data support the hypothesis that mechanisms for mifepristone life span increase involve reduced lipid uptake and/or metabolism, and suggest that mifepristone may increase life span in mated females and virgin females through partly different mechanisms.

Efeitos paramonoclorofenol canforado e concentraçöes aquosas implantados com esponja polivinílica sobre o tecido conjuntivo de ratos (estudo bioquímico e histológico) / The effects of camphorated parachlorophenol and varying concentration de aqueous parachlorophenol on rat connective tissues of polyvinil sponge implants

Os autores realizaram uma investigaçäo para determinar os efeitos do paramonoclorofenol canforado e de várias concentraçöes aquosas de paramonoclorofenol (2 por cento, 1 por cento, 0,1 por cento e 0,01 por cento) no tecido conjuntivo subcutâneo de ratos utilizando-se de implantes de esponja polivinílica. Foram realizadas observaçöes bioquímicas e histológicas. De acordo com as observaçöes realizadas pelos autores na presente investigaçäo e com os resultados encontrados na literatura pertinente, pode-se concluir que soluçöes aquosas de paramonoclorofenol a 1 por cento e 2 por cento forneceräo reaçöes texturais mínimas quando desejável o seu uso como medicaçäo intracanal