Modulation of receptor-like transmembrane kinase 1 nuclear localization by DA1 peptidases in Arabidopsis.

The cleavage of intracellular domains of receptor-like kinases (RLKs) has an important functional role in the transduction of signals from the cell surface to the nucleus in many organisms. However, the peptidases that catalyze protein cleavage during signal transduction remain poorly understood despite their crucial roles in diverse signaling processes. Here, we report in the flowering plant Arabidopsis thaliana that members of the DA1 family of ubiquitin-regulated Zn metallopeptidases cleave the cytoplasmic kinase domain of transmembrane kinase 1 (TMK1), releasing it for nuclear localization where it represses auxin-responsive cell growth during apical hook formation by phosphorylation and stabilization of the transcriptional repressors IAA32 and IAA34. Mutations in DA1 family members exhibited reduced apical hook formation, and DA1 family-mediated cleavage of TMK1 was promoted by auxin treatment. Expression of the DA1 family-generated intracellular kinase domain of TMK1 by an auxin-responsive promoter fully restored apical hook formation in a tmk1 mutant, establishing the function of DA1 family peptidase activities in TMK1-mediated differential cell growth and apical hook formation. DA1 family peptidase activity therefore modulates TMK1 kinase activity between a membrane location where it stimulates acid cell growth and initiates an auxin-dependent kinase cascade controlling cell proliferation in lateral roots and a nuclear localization where it represses auxin-mediated gene expression and growth.

Ubiquitylation activates a peptidase that promotes cleavage and destabilization of its activating E3 ligases and diverse growth regulatory proteins to limit cell proliferation in Arabidopsis.

The characteristic shapes and sizes of organs are established by cell proliferation patterns and final cell sizes, but the underlying molecular mechanisms coordinating these are poorly understood. Here we characterize a ubiquitin-activated peptidase called DA1 that limits the duration of cell proliferation during organ growth in Arabidopsis thaliana The peptidase is activated by two RING E3 ligases, Big Brother (BB) and DA2, which are subsequently cleaved by the activated peptidase and destabilized. In the case of BB, cleavage leads to destabilization by the RING E3 ligase PROTEOLYSIS 1 (PRT1) of the N-end rule pathway. DA1 peptidase activity also cleaves the deubiquitylase UBP15, which promotes cell proliferation, and the transcription factors TEOSINTE BRANCED 1/CYCLOIDEA/PCF 15 (TCP15) and TCP22, which promote cell proliferation and repress endoreduplication. We propose that DA1 peptidase activity regulates the duration of cell proliferation and the transition to endoreduplication and differentiation during organ formation in plants by coordinating the destabilization of regulatory proteins.

How do patient reported outcome measures affect treatment intensification and patient satisfaction in the management of psoriatic arthritis? A cross sectional study of 503 patients.

OBJECTIVES: The ASSIST study investigated prescribing in routine psoriatic arthritis (PsA) care and whether the patient reported outcome: PsA Impact of Disease questionnaire (PsAID-12), impacted treatment. This study also assessed a range of patient and clinician factors and their relationship to PsAID-12 scoring and treatment modification. METHODS: Patients with PsA were selected across the UK and Europe between July 2021-March 2022. Patients completed the PsAID questionnaire, with the results shared with their physician. Patient characteristics, disease activity, current treatment methods, treatment strategies, medication changes and patient satisfaction scores were recorded. RESULTS: 503 patients recruited. 36.2% had changes made to treatment, 88.8% of this had treatment escalation. Overall, the mean PsAID-12 score was higher for patients with treatment escalation; the PsAID-12 score was associated with odds of treatment escalation (OR: 1.58; p< 0.0001). However, most clinicians reported PsAID-12 did not impact their decision to escalate treatment, instead supporting treatment reduction decisions. Physician's assessment of disease activity had the most statistically significant effect on likelihood of treatment escalation, (OR = 2.68, per 1-point score increase). Escalation was more likely in patients not treated with biologic therapies. Additional factors associated with treatment escalation included: patient characteristics, physician characteristics, disease activity and disease impact. CONCLUSION: This study highlights multiple factors impacting treatment decision making for individuals with PsA. PsAID-12 scoring correlates with multiple measures of disease severity and odds of treatment escalation. However, most clinicians reported the PsAID-12 did not influence treatment escalation decisions. PsAID scoring could be used to increase confidence in treatment de-escalation.

Microbial modulation via cross-fostering prevents the effects of pervasive environmental stressors on microglia and social behavior, but not the dopamine system.

Environmental toxicant exposure, including air pollution, is increasing worldwide. However, toxicant exposures are not equitably distributed. Rather, low-income and minority communities bear the greatest burden, along with higher levels of psychosocial stress. Both air pollution and maternal stress during pregnancy have been linked to neurodevelopmental disorders such as autism, but biological mechanisms and targets for therapeutic intervention remain poorly understood. We demonstrate that combined prenatal exposure to air pollution (diesel exhaust particles, DEP) and maternal stress (MS) in mice induces social behavior deficits only in male offspring, in line with the male bias in autism. These behavioral deficits are accompanied by changes in microglial morphology and gene expression as well as decreased dopamine receptor expression and dopaminergic fiber input in the nucleus accumbens (NAc). Importantly, the gut-brain axis has been implicated in ASD, and both microglia and the dopamine system are sensitive to the composition of the gut microbiome. In line with this, we find that the composition of the gut microbiome and the structure of the intestinal epithelium are significantly shifted in DEP/MS-exposed males. Excitingly, both the DEP/MS-induced social deficits and microglial alterations in males are prevented by shifting the gut microbiome at birth via a cross-fostering procedure. However, while social deficits in DEP/MS males can be reversed by chemogenetic activation of dopamine neurons in the ventral tegmental area, modulation of the gut microbiome does not impact dopamine endpoints. These findings demonstrate male-specific changes in the gut-brain axis following DEP/MS and suggest that the gut microbiome is an important modulator of both social behavior and microglia.

Beyond the binary: Characterizing the relationships between sex and neuropeptide receptor binding density measures in the rat brain.

Sex differences exist in numerous parameters of the brain. Yet, sex-related factors are part of a large set of variables that interact to affect many aspects of brain structure and function. This raises questions regarding how to interpret findings of sex differences at the level of single brain measures and the brain as a whole. In the present study, we reanalyzed two datasets consisting of measures of oxytocin, vasopressin V1a, and mu opioid receptor binding densities in multiple brain regions in rats. At the level of single brain measures, we found that sex differences were rarely dimorphic and were largely persistent across estrous stage and parental status but not across age or context. At the level of aggregates of brain measures showing sex differences, we tested whether individual brains are 'mosaics' of female-typical and male-typical measures or are internally consistent, having either only female-typical or only male-typical measures. We found mosaicism for measures showing overlap between females and males. Mosaicism was higher a) with a larger number of measures, b) with smaller effect sizes of the sex difference in these measures, and c) in rats with more diverse life experiences. Together, these results highlight the limitations of the binary framework for interpreting sex effects on the brain and suggest two complementary pathways to studying the contribution of sex to brain function: (1) focusing on measures showing dimorphic and persistent sex differences and (2) exploring the relations between specific brain mosaics and specific endpoints.

Nintedanib preserves lung growth and prevents pulmonary hypertension in a hyperoxia-induced lung injury model.

BACKGROUND: Bronchopulmonary dysplasia (BPD), the chronic lung disease associated with prematurity, is characterized by poor alveolar and vascular growth, interstitial fibrosis, and pulmonary hypertension (PH). Although multifactorial in origin, the pathophysiology of BPD is partly attributed to hyperoxia-induced postnatal injury, resulting in lung fibrosis. Recent work has shown that anti-fibrotic agents, including Nintedanib (NTD), can preserve lung function in adults with idiopathic pulmonary fibrosis. However, NTD is a non-specific tyrosine kinase receptor inhibitor that can potentially have adverse effects on the developing lung, and whether NTD treatment can prevent or worsen risk for BPD and PH is unknown. HYPOTHESIS: We hypothesize that NTD treatment will preserve lung growth and function and prevent PH in an experimental model of hyperoxia-induced BPD in rats. METHODS: Newborn rats were exposed to either hyperoxia (90%) or room air (RA) conditions and received daily treatment of NTD or saline (control) by intraperitoneal (IP) injections (1 mg/kg) for 14 days, beginning on postnatal day 1. At day 14, lung mechanics were measured prior to harvesting lung and cardiac tissue. Lung mechanics, including total respiratory resistance and compliance, were measured using a flexiVent system. Lung tissue was evaluated for radial alveolar counts (RAC), mean linear intercept (MLI), pulmonary vessel density (PVD), and pulmonary vessel wall thickness (PVWT). Right ventricular hypertrophy (RVH) was quantified with cardiac weights using Fulton's index (ratio of right ventricle to the left ventricle plus septum). RESULTS: When compared with RA controls, hyperoxia exposure reduced RAC by 64% (p < 0.01) and PVD by 65% (p < 0.01) and increased MLI by 108% (p < 0.01) and RVH by 118% (p < 0.01). Hyperoxia increased total respiratory resistance by 94% and reduced lung compliance by 75% (p < 0.01 for each). NTD administration restored RAC, MLI, RVH, PVWT and total respiratory resistance to control values and improved PVD and total lung compliance in the hyperoxia-exposed rats. NTD treatment of control animals did not have adverse effects on lung structure or function at 1 mg/kg. When administered at higher doses of 50 mg/kg, NTD significantly reduced alveolar growth in RA controls, suggesting dose-related effects on normal lung structure. CONCLUSIONS: We found that NTD treatment preserved lung alveolar and vascular growth, improved lung function, and reduced RVH in experimental BPD in infant rats without apparent adverse effects in control animals. We speculate that although potentially harmful at high doses, NTD may provide a novel therapeutic strategy for prevention of BPD and PH. IMPACT: Anti-fibrotic therapies may be a novel therapeutic strategy for the treatment or prevention of BPD. High-dose anti-fibrotics may have adverse effects on developing lungs, while low-dose anti-fibrotics may treat or prevent BPD. There is very little preclinical and clinical data on the use of anti-fibrotics in the developing lung. Dose timing and duration of anti-fibrotic therapies may be critical for the treatment of neonatal lung disease. Currently, strategies for the prevention and treatment of BPD are lacking, especially in the context of lung fibrosis, so this research has major clinical applicability.

Anaplastic sarcoma of the kidney (DICER1-sarcoma of the kidney): A report from the International Pleuropulmonary Blastoma/DICER1 Registry.

BACKGROUND: Anaplastic sarcoma of the kidney (ASK) is a DICER1-related neoplasm first identified as a distinctive tumor type through the evaluation of unusual cases of putative anaplastic Wilms tumors. Subsequent case reports identified the presence of biallelic DICER1 variants as well as progression from cystic nephroma, a benign DICER1-related neoplasm. Despite increasing recognition of ASK as a distinct entity, the optimal treatment remains unclear. METHODS: Individuals with known or suspected DICER1-related tumors including ASK were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry. Additionally, a comprehensive review of reported cases of ASK was undertaken, and data were aggregated for analysis with the aim to identify prognostic factors and clinical characteristics to guide decisions regarding genetic testing, treatment, and surveillance. RESULTS: Ten cases of ASK were identified in the Registry along with 37 previously published cases. Staging data, per Children's Oncology Group guidelines, was available for 40 patients: 13 were stage I, 12 were stage II, 10 were stage III, and five were stage IV. Outcome data were available for 37 patients. Most (38 of 46) patients received upfront chemotherapy and 14 patients received upfront radiation. Two-year event-free survival (EFS) for stage I-II ASK was 81.8% (95% confidence interval [CI]: 67.2%-99.6%), compared with 46.6% EFS (95% CI: 24.7%-87.8%) for stage III-IV (p = .07). Two-year overall survival (OS) for stage I-II ASK was 88.9% (95% CI: 75.5%-100.0%), compared with 70.0% (95% CI: 46.7%-100.0%) for stage III-IV (p = .20). Chemotherapy was associated with improved EFS and OS with hazard ratios of 0.09 (95% CI: 0.02-0.31) and 0.08 (95% CI: 0.02-0.42), respectively. CONCLUSION: ASK is a rare DICER1-related renal neoplasm. In the current report, we identify clinical and treatment-related factors associated with outcome including the importance of chemotherapy in treating ASK. Ongoing data collection and genomic analysis are indicated to optimize outcomes for children and adults with these rare tumors.

In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial ß-glucuronidase targeting compound Inh 1.

In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial ß-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species.The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively.The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat.Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.

Community Collaboration to Develop a Curriculum on Settler Colonialism and the Social Determinants of Health.

American Indian/Alaska Native (AI/AN) communities continue to experience health disparities and poor health outcomes, which are influenced by social determinants of health. The theory of settler colonialism provides a framework for understanding the structures that affect social determinants of health and the resulting health disparities. Western biomedicine and medical education have been implicated in perpetuating settler colonialism, and as a result Indigenous medical educators and leaders have called for increased education and understanding of the structural and social determinants of health affecting Indigenous populations. One important method is through community-based approaches to curriculum design. In collaboration with community leaders and experts, we identified the need for a curriculum on health in the context of settler colonialism, with a focus on resilience and community-directed efforts to improve wellness and care. Alongside Indigenous leaders and educators, we developed a unique curriculum focused on settler colonialism, the social determinants of health, and the assets inherent to the Native Nation where we work. Developed for non-Native learners and clinicians, the curriculum is designed to help provide context for the historical and political etiologies of health inequities experienced by the local community. Local educators helped shape a video lecture series associated with readings and experiential learning activities in 10 domains, providing an overview of settler colonialism and how it affects the social determinants of health. Our model of education draws upon the strengths and assets of communities and can improve health outcomes as well as learners' understandings of AI/AN-specific needs. We expect that our collaborative approach results in improved relationships among the Non-Native learners and providers and community members.

Evaluating clinical reasoning in first year DPT students using a script concordance test.

BACKGROUND: A script concordance test (SCT) provides a series of clinical vignettes to assess clinical reasoning in uncertainty. Appraised throughout health education literature, SCTs are cognitive assessments of clinical reasoning, though their use in Doctor of Physical Therapy (DPT) entry-level education has not been investigated. The purpose of this study was to develop and explore the reliability and validity of a SCT for first year DPT students. METHODS: The SCT was developed and implemented over four phases. During phases one and two, DPT program faculty consulted on course content from the first-year curriculum. Thirty clinical vignettes with three follow-up questions each were constructed. The SCT was pilot tested with five clinicians in phase three to assess question clarity. During phase four, the SCT was administered to students and a reference panel via Qualtrics. First year DPT students (n = 44) and reference panel physical therapists with at least two years of experience and advanced certification (n = 15) completed the SCT. Internal consistency was analyzed using Cronbach's Alpha. Differences between student and reference panel percent-correct scores were analyzed with a t-test. Relationships between student SCT scores and academic records were explored with Spearman's Rho. RESULTS: The SCT had an internal consistency of 0.74. A significant difference in scores was found between the students [mean 58.5 (+/-5.31)] and reference panel [65.8 (+/-4.88), p < .01]. No significant correlations between student SCT scores and academic records were found. CONCLUSIONS: The developed SCT was reliable and demonstrated satisfactory internal consistency among test items. The SCT successfully differentiated between groups, with the reference panel demonstrating statistically significant higher percent-correct scores compared to students. SCTs may provide means to measure clinical reasoning in DPT students and lead to novel pedagogical approaches to enhance clinical reasoning.

Postoperative revision, complication and economic outcomes of patients with reverse or anatomic total shoulder arthroplasty at one year: a retrospective, United States hospital billing database analysis.

BACKGROUND: Data on the 1-year postoperative revision, complication, and economic outcomes in a hospital setting after total shoulder arthroplasty (TSA) are sparse. METHODS: A retrospective cohort study using the Premier Healthcare Database, a hospital-billing data source, evaluated 1-year postoperative revision, complication, and economic outcomes of reverse (RTSA) and anatomic (ATSA) TSA for patients who underwent the procedure from 2015 until 2021. All-cause revisits, including revision-related events (categorized as either irrigation and débridement or revision procedures and device removals) and shoulder/nonshoulder complications were collected. The incidences and costs of these revisits were evaluated. Generalized linear models were used to evaluate the associations between patient characteristics and revision and complication occurrences and costs. RESULTS: Among 51,478 RTSA and 34,623 ATSA patients (mean [standard deviation] ages RTSA 71.5 [8.1] years, ATSA 66.8 [9.0] years), 1-year adjusted incidences of all-cause revisits, irrigation/débridement, revision procedures/device removals, and shoulder/nonshoulder complications were RTSA: 45.0% (95% confidence interval (CI): 44.6%-45.5%), 0.1% (95% CI: 0.1%-0.2%), 2.1% (95% CI: 2.0%-2.2%), and 17.8% (95% CI: 17.5%-18.1%) and ATSA: 42.3% (95% CI: 41.8%-42.9%), 0.2% (95% CI: 0.1%-0.2%), 1.9% (95% CI: 1.8%-2.1%), and 14.4% (95% CI: 14.0%-14.8%), respectively; shoulder-related complications were RTSA: 12.4% (95% CI: 12.1%-12.7%) and ATSA: 9.9% (95% CI: 9.6%-10.3%). Significant factors associated with a high risk of revisions and complications included, but were not limited to, chronic comorbidities and noncommercial insurance. Per patient, the mean (standard deviations) total 1-year hospital cost was $25,225 ($15,911) and $21,520 ($13,531) for RTSA and ATSA, respectively. Revision procedures and device removals were most costly, averaging $22,920 ($18,652) and $26,911 ($18,619) per procedure for RTSA and ATSA, respectively. Patients with revision-related events with infections had higher total hospital costs than patients without this event (RTSA: $60,887 (95% CI: $56,951-$64,823) and ATSA: $59,478 (95% CI: $52,312-$66,644)), equating to a mean difference of $36,148 with RTSA and $38,426 with ATSA. Significant factors associated with higher costs of revision-related events and complications included age, race, chronic comorbidities, and noncommercial insurance. CONCLUSIONS: Nearly 45% RTSA and 42% ATSA patients returned to the hospital, most often for shoulder/nonshoulder complications (overall 17.8% RTSA and 14.4% ATSA, and shoulder-related 12.4% RTSA and 9.9% ATSA). Revisions and device removals were most expensive ($22,920 RTSA and $26,911 ATSA). Infection complications requiring revision had the highest 1-year hospital costs (∼$60,000). This study highlights the need for technologies and surgical techniques that may help reduce TSA health care utilization and economic burden.

Combining hypoxia with thermal stimuli in humans: physiological responses and potential sex differences.

Increasing prevalence of native lowlanders sojourning to high altitudes (>2,500 m) for recreational, occupational, military, and competitive reasons has generated increased interest in physiological responses to multistressor environments. Exposure to hypoxia poses recognized physiological challenges that are amplified during exercise and further complicated by environments that might include combinations of heat, cold, and high altitude. There is a sparsity of data examining integrated responses in varied combinations of environmental conditions, with even less known about potential sex differences. How this translates into performance, occupational, and health outcomes requires further investigation. Acute hypoxic exposure decreases arterial oxygen saturation, resulting in a reflex hypoxic ventilatory response and sympathoexcitation causing an increase in heart rate, myocardial contractility, and arterial blood pressure, to compensate for the decreased arterial oxygen saturation. Acute altitude exposure impairs exercise performance, for example, reduced time to exhaustion and slower time trials, largely owing to impairments in pulmonary gas exchange and peripheral delivery resulting in reduced V̇o2max. This exacerbates with increasing altitude, as does the risk of developing acute mountain sickness and more serious altitude-related illnesses, but modulation of those risks with additional stressors is unclear. This review aims to summarize and evaluate current literature regarding cardiovascular, autonomic, and thermoregulatory responses to acute hypoxia, and how these may be affected by simultaneous thermal environmental challenges. There is minimal available information regarding sex as a biological variable in integrative responses to hypoxia or multistressor environments; we highlight these areas as current knowledge gaps and the need for future research.

An international multi-centre analysis of current prescribing practices and shared decision-making in psoriatic arthritis.

OBJECTIVES: Shared decision-making (SDM) is advocated to improve patient outcomes in Psoriatic arthritis (PsA). We analysed current prescribing practices and the extent of SDM in PsA across Europe. METHODS: The ASSIST study was a cross-sectional observational study of PsA patients aged ≥18 years attending face-to-face appointments between July 2021-March 2022. Patient demographics, current treatment and treatment decisions were recorded. SDM was measured by the clinician's effort to collaborate (CollaboRATE questionnaire) and patient communication confidence (PEPPI-5 tool). RESULTS: 503 patients were included from 24 centres across the UK, France, Germany, Italy and Spain. Physician- and patient-reported measures of disease activity were highest in the UK. Conventional synthetic DMARDs constituted a higher percentage of current PsA treatment in UK than continental Europe (66.4% vs 44.9%), which differed from biologic DMARDs (36.4% vs 64.4%). Implementing treatment escalation was most common in the UK. CollaboRATE and PEPPI-5 scores were high across centres. Of 31 patients with low CollaboRATE scores (<4.5), no patients with low PsAID-12 scores (<5) had treatment escalation. However, of 465 patients with CollaboRATE scores ≥4.5, 59 patients with low PsAID-12 scores received treatment escalation. CONCLUSIONS: Higher rates of treatment escalation seen in the UK may be explained by higher disease activity and a younger cohort. High levels of collaboration in face-to-face PsA consultations suggests effective implementation of the SDM approach. Our data indicate that, in patients with mild disease activity, only those with higher perceived collaboration underwent treatment escalation. Prospective studies should examine the impact of SDM on PsA patient outcomes. TRIAL REGISTRATION: clinicaltrials.gov, NCT05171270.

Metric-based analysis of FTIR data to discriminate tissue types in oral cancer.

A machine learning algorithm (MLA) has predicted the prognosis of oral potentially malignant lesions and discriminated between lymph node tissue and metastatic oral squamous cell carcinoma (OSCC). The MLA analyses metrics, which are ratios of Fourier transform infrared absorbances, and identifies key wavenumbers that can be associated with molecular biomarkers. The wider efficacy of the MLA is now shown in the more complex primary OSCC tumour setting, where it is able to identify seven types of tissue. Three epithelial and four non-epithelial tissue types were discriminated from each other with sensitivities between 82% and 96% and specificities between 90% and 99%. The wavenumbers involved in the five best discriminating metrics for each tissue type were tightly grouped, indicating that small changes in the spectral profiles of the different tissue types are important. The number of samples used in this study was small, but the information will provide a basis for further, larger investigations.

Tissue discrimination in head and neck cancer using image fusion of IR and optical microscopy.

A regression-based fusion algorithm has been used to merge hyperspectral Fourier transform infrared (FTIR) data with an H&E image of oral squamous cell carcinoma metastases in cervical lymphoid nodal tissue. This provides insight into the success of the ratio of FTIR absorbances at 1252 cm-1 and 1285 cm-1 in discriminating between these tissue types. The success is due to absorbances at these two wavenumbers being dominated by contributions from DNA and collagen, respectively. A pixel-by-pixel fit of the fused spectra to the FTIR spectra of collagen, DNA and cytokeratin reveals the contributions of these molecules to the tissue at high spatial resolution.

Cephalic version by moxibustion for breech presentation.

BACKGROUND: Breech presentation at term can cause complications during birth and increase the chance of caesarean section. Moxibustion (a type of Chinese medicine which involves burning a herb close to the skin) at the acupuncture point Bladder 67 (BL67) (Chinese name Zhiyin), located at the tip of the fifth toe, has been proposed as a way of changing breech presentation to cephalic presentation. This is an update of a review first published in 2005 and last published in 2012. OBJECTIVES: To examine the effectiveness and safety of moxibustion on changing the presentation of an unborn baby in the breech position, the need for external cephalic version (ECV), mode of birth, and perinatal morbidity and mortality. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register (which includes trials from CENTRAL, MEDLINE, Embase, CINAHL, and conference proceedings), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) (4 November 2021). We also searched MEDLINE, CINAHL, AMED, Embase and MIDIRS (inception to 3 November 2021), and the reference lists of retrieved studies. SELECTION CRITERIA: The inclusion criteria were published and unpublished randomised or quasi-randomised controlled trials comparing moxibustion either alone or in combination with other techniques (e.g. acupuncture or postural techniques) with a control group (no moxibustion) or other methods (e.g. acupuncture, postural techniques) in women with a singleton breech presentation. DATA COLLECTION AND ANALYSIS: Two review authors independently determined trial eligibility, assessed trial quality, and extracted data. Outcome measures were baby's presentation at birth, need for ECV, mode of birth, perinatal morbidity and mortality, maternal complications and maternal satisfaction, and adverse events. We assessed the certainty of the evidence using the GRADE approach.   MAIN RESULTS: This updated review includes 13 studies (2181 women), of which six trials are new. Most studies used adequate methods for random sequence generation and allocation concealment. Blinding of participants and personnel is challenging with a manual therapy intervention; however, the use of objective outcomes meant that the lack of blinding was unlikely to affect the results. Most studies reported little or no loss to follow-up, and few trial protocols were available. One study that was terminated early was judged as high risk for other sources of bias. Meta-analysis showed that compared to usual care alone, the combination of moxibustion plus usual care probably reduces the chance of non-cephalic presentation at birth (7 trials, 1152 women; risk ratio (RR) 0.87, 95% confidence interval (CI) 0.78 to 0.99, I2 = 38%; moderate-certainty evidence), but the evidence is very uncertain about the effect of moxibustion plus usual care on the need for ECV (4 trials, 692 women; RR 0.62, 95% CI 0.32 to 1.21, I2 = 78%; low-certainty evidence) because the CIs included both appreciable benefit and moderate harm. Adding moxibustion to usual care probably has little to no effect on the chance of caesarean section (6 trials, 1030 women; RR 0.94, 95% CI 0.83 to 1.05, I2 = 0%; moderate-certainty evidence). The evidence is very uncertain about the effect of moxibustion plus usual care on the the chance of premature rupture of membranes (3 trials, 402 women; RR 1.31, 95% CI 0.17 to 10.21, I2 = 59%; low-certainty evidence) because there were very few data. Moxibustion plus usual care probably reduces the use of oxytocin (1 trial, 260 women; RR 0.28, 95% CI 0.13 to 0.60; moderate-certainty evidence). The evidence is very uncertain about the chance of cord blood pH less than 7.1 (1 trial, 212 women; RR 3.00, 95% CI 0.32 to 28.38; low-certainty evidence) because there were very few data. We are very uncertain whether the combination of moxibustion plus usual care increases the chance of adverse events (including nausea, unpleasant odour, abdominal pain and uterine contractions; intervention: 27/65, control: 0/57), as only one study presented data in a way that could be reanalysed (122 women; RR 48.33, 95% CI 3.01 to 774.86; very low-certainty evidence). When moxibustion plus usual care was compared with sham moxibustion plus usual care, we found that moxibustion probably reduces the chance of non-cephalic presentation at birth (1 trial, 272 women; RR 0.74, 95% CI 0.58 to 0.95; moderate-certainty evidence) and probably results in little to no effect on the rate of caesarean section (1 trial, 272 women; RR 0.84, 95% CI 0.68 to 1.04; moderate-certainty evidence). No study that compared moxibustion plus usual care with sham moxibustion plus usual care reported on the clinically important outcomes of need for ECV, premature rupture of membranes, use of oxytocin, and cord blood pH less than 7.1, and one trial that reported adverse events reported data for the whole sample. When moxibustion was combined with acupuncture and usual care, there was very little evidence about the effect of the combination on non-cephalic presentation at birth (1 trial, 226 women; RR 0.73, 95% CI 0.57 to 0.94) and at the end of treatment (2 trials, 254 women; RR 0.73, 95% CI 0.57 to 0.93), and on the need for ECV (1 trial, 14 women; RR 0.45, 95% CI 0.07 to 3.01). There was very little evidence about whether moxibustion plus acupuncture plus usual care reduced the chance of caesarean section (2 trials, 240 women; RR 0.80, 95% CI 0.65 to 0.99) or pre-eclampsia (1 trial, 14 women; RR 5.00, 95% CI 0.24 to 104.15). The certainty of the evidence for this comparison was not assessed. AUTHORS' CONCLUSIONS: We found moderate-certainty evidence that moxibustion plus usual care probably reduces the chance of non-cephalic presentation at birth, but uncertain evidence about the need for ECV. Moderate-certainty evidence from one study shows that moxibustion plus usual care probably reduces the use of oxytocin before or during labour. However, moxibustion plus usual care probably results in little to no difference in the rate of caesarean section, and we are uncertain about its effects on the chance of premature rupture of membranes and cord blood pH less than 7.1.  Adverse events were inadequately reported in most trials.

Specific psychological therapies versus other therapies or no treatment for severe and enduring anorexia nervosa.

BACKGROUND: Anorexia nervosa is a psychological condition characterised by self-starvation and fear or wait gain or other body image disturbance. The first line of treatment is specific psychological therapy; however, there is no consensus on best practice for treating people who develop severe and enduring anorexia nervosa (SEAN). Notably, there is no universal definition of SEAN. OBJECTIVES: To evaluate the benefits and harms of specific psychological therapies for severe and enduring anorexia nervosa compared with other specific therapies, non-specific therapies, no treatment/waiting list, antidepressant medication, dietary counselling alone, or treatment as usual. SEARCH METHODS: We used standard, extensive Cochrane search methods. The last search date was 22 July 2022. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs) of people (any age) with anorexia nervosa of at least three years' duration. Eligible experimental interventions were any specific psychological therapy for improved physical and psychological health in anorexia nervosa, conducted in any treatment setting with no restrictions in terms of number of sessions, modality, or duration of therapy. Eligible comparator interventions included any other specific psychological therapy for anorexia nervosa, non-specific psychological therapy for mental health disorders, no treatment or waiting list, antipsychotic treatment (with or without psychological therapy), antidepressant treatment (with or without psychological therapy), dietary counselling, and treatment as usual as defined by the individual trials. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were clinical improvement (weight restoration to within the normal weight range for participant sample) and treatment non-completion. Results were presented using the GRADE appraisal tool. MAIN RESULTS: We found two eligible studies, but only one study provided usable data. This was a parallel-group RCT of 63 adults with SEAN who had an illness duration of at least seven years. The trial compared outpatient cognitive behaviour therapy for SEAN (CBT-SEAN) with specialist supportive clinical management for SEAN (SSCM-SE) over eight months. It is unclear if there is any difference between the effect of CBT-SEAN versus SSCM-SE on clinical improvement at 12 months (risk ratio (RR) 1.42, 95% confidence interval (CI) 0.66 to 3.05) or treatment non-completion (RR 1.72, 95% CI 0.45 to 6.59). There were no reported data on adverse effects. The trial was at high risk of performance and detection bias. We rated the GRADE level of evidence as very low-certainty for both primary outcomes, downgrading for imprecision and risk of bias concerns. AUTHORS' CONCLUSIONS: This review reports evidence from one trial that evaluated CBT-SEAN versus SSCM-SE. There was very low-certainty evidence of little or no difference in clinical improvement and treatment non-completion between the two therapies. There is a need for larger high-quality trials to determine the benefits of specific psychological therapies for people with SEAN. These should take into account the duration of illness as well as participants' previous experience with evidence-based psychological therapy for anorexia nervosa.

Effect of acupuncture on IVF-related anxiety: a systematic review and meta-analysis.

Patients undergoing IVF experience high levels of IVF-related state anxiety. Non-pharmacological interventions such as acupuncture may provide support, but its effect on IVF-related anxiety is unclear. This was a systematic review and meta-analysis to examine the effect of acupuncture on IVF-related state anxiety. The primary outcome was state anxiety after embryo transfer or oocyte retrieval as assessed by the State-Trait Anxiety Inventory, Hamilton Anxiety Scale, visual analogue scale or Standard Form 36. Eight trials with 2253 participants were reviewed, and 1785 participants completed an anxiety assessment. Using the random effects model, the meta-analysis found small but significant effects on state anxiety with acupuncture versus any control (standardized mean difference -0.21, 95% confidence interval -0.39 to -0.04, representing very low certainty evidence). Evidence was limited by the moderate number of included studies of an intermediate median sample size (n = 191). There was also a high risk of performance bias and substantial heterogeneity across trials. Acupuncture is a drug-free and safe treatment that may benefit those who are burdened with IVF-related anxiety, but more investigation is needed for confirmation.

Locus coeruleus and dopaminergic consolidation of everyday memory.

The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH+) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH+ neurons project more profusely than ventral tegmental area TH+ neurons to the hippocampus, optogenetic activation of locus coeruleus TH+ neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH+ photoactivation are sensitive to hippocampal D1/D5 receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH+ neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.

Sickness and the Social Brain: How the Immune System Regulates Behavior across Species.

Many instances of sickness critically involve the immune system. The immune system talks to the brain in a bidirectional loop. This discourse affords the immune system immense control, such that it can influence behavior and optimize recovery from illness. These behavioral responses to infection are called sickness behaviors and can manifest in many ways, including changes in mood, motivation, or energy. Fascinatingly, most of these changes are conserved across species, and most organisms demonstrate some form of sickness behaviors. One of the most interesting sickness behaviors, and not immediately obvious, is altered sociability. Here, we discuss how the immune system impacts social behavior, by examining the brain regions and immune mediators involved in this process. We first outline how social behavior changes in response to infection in various species. Next, we explore which brain regions control social behavior and their evolutionary origins. Finally, we describe which immune mediators establish the link between illness and social behavior, in the context of both normal development and infection. Overall, we hope to make clear the striking similarities between the mechanisms that facilitate changes in sociability in derived and ancestral vertebrate, as well as invertebrate, species.