The lattice symmetry of a crystal is one of the most important factors in determining its physical properties. Particularly, low-symmetry crystals offer powerful opportunities to control light propagation, polarization and phase^1-4. Materials featuring extreme optical anisotropy can support a hyperbolic response, enabling coupled light-matter interactions, also known as polaritons, with highly directional propagation and compression of light to deeply sub-wavelength scales⁵. Here we show that monoclinic crystals can support hyperbolic shear polaritons, a new polariton class arising in the mid-infrared to far-infrared due to shear phenomena in the dielectric response. This feature emerges in materials in which the dielectric tensor cannot be diagonalized, that is, in low-symmetry monoclinic and triclinic crystals in which several oscillators with non-orthogonal relative orientations contribute to the optical response^6,7. Hyperbolic shear polaritons complement previous observations of hyperbolic phonon polaritons in orthorhombic^1,3,4 and hexagonal^8,9 crystal systems, unveiling new features, such as the continuous evolution of their propagation direction with frequency, tilted wavefronts and asymmetric responses. The interplay between diagonal loss and off-diagonal shear phenomena in the dielectric response of these materials has implications for new forms of non-Hermitian and topological photonic states. We anticipate that our results will motivate new directions for polariton physics in low-symmetry materials, which include geological minerals¹⁰, many common oxides¹¹ and organic crystals¹², greatly expanding the material base and extending design opportunities for compact photonic devices.

Study design: Cross-sectional study.

Objectives: This study aimed to explore and report on health care and rehabilitation service utilization, rehabilitation service benefits, and levels of satisfaction of individuals with spinal cord injury (SCI) living in communities in Thailand.

Setting: Four rehabilitation facilities in Thailand, two university hospitals (Maharaj Nakorn Chiang Mai Hospital in Chiang Mai Province and Siriraj Hospital in Bangkok), one large provincial hospital (Ratchaburi Hospital in Ratchaburi Province), and one national rehabilitation institute (Sirindhorn National Medical Rehabilitation Institute in Nonthaburi Province).

Methods: This study was part of the International Spinal Cord Injury Community Survey (InSCI). Individuals with SCI completed a set of questionnaires, then data related to their health care and rehabilitation services were extracted and analyzed.

Results: Of the 320 participants, most were male (71%), and the majority were living with paraplegia (73%). In cases of mild illnesses where hospitalization was not required, 46% went to a nearby health service hospital. In cases of serious illnesses where hospitalization was required, 39% went to a higher-level hospital. The majority (80%) were satisfied with their experience with health care services. The three top preferred products and services in descending order were wheelchairs and cushions, increased disability pension, medication and medical equipment including bladder relaxants, urinary catheters and urine bags.

Conclusions: Individuals with SCI living in communities in Thailand preferred treatment at a nearby district hospital for mild illnesses with one-third transferring to a higher-level hospital for serious illnesses. The majority were satisfied with the health care services and rehabilitation services.

Study design: Retrospective anonymized cohort study.

Objectives: To study X-ray images of video urodynamics (VUD) in patients with spinal cord injury (SCI).

Setting: Single-center study.

Methods: X-ray images during VUD were categorized. Relation with the American Spinal Injury Association Impairment Scale (AIS), time since and level of SCI, cystometric data, method of bladder management, findings of flexible cystoscopy, and renal ultrasound were evaluated. Changes over time were studied.

Results: In 231 consecutive patients, VUD was done at a mean of 8.5 years after SCI. X3-ray bladder appearance was categorized as normal/standard, tonic, or flaccid. In 19 patients, specific findings were seen: diverticula, cystocele, vesicoureteral reflux. X-ray images differed by maximum cystometric capacity, presence of neurogenic detrusor overactivity, and maximum detrusor pressure during detrusor overactivity, but not by bladder compliance. There was no difference in the categories found in different levels and completeness of SCI. In the 23 patients able to void no pathology was seen on urethral images. Renal ultrasound was normal in >99%. In 86 patients, repeated testing after 72 ± 143 weeks showed changed findings in 30%. Cystoscopy showed significantly more local pathologies.

Conclusion: Complications in the lower urinary tract were seen on imaging only in a limited number of our cohort. As our findings represent a real-life example of the actual yield of VUD in patients with neurogenic bladder due to SCI treated following the international guidelines, further multicentre evaluation is needed to determine when imaging should be used or not.

Objective: To present the diagnostic, clinical, and radiological features of pigmented villonodular synovitis (PVNS), create awareness of this rare condition, and provide guidance for conservative healthcare practitioners for further referral and appropriate management.

Case presentation: We present the case of a 41-year-old recreational runner who presented to the clinic with anterior hip pain of one year duration. Following a clinical history and examination, the patient was diagnosed with clinical femoroacetabular impingement. Radiographs taken at that time displayed mild degenerative joint disease of the left hip joint with coxa profunda. After four weeks of conservative care, the patient reported no improvement in symptoms. The patient was then referred for an MRI, while conservative care continued. Ten weeks later, the patient's symptoms and functional abilities had worsened. The MRI was obtained and the diagnosis of PVNS was made.

Summary: PVNS is a rare disease that can mimic mechanical hip pain. A high index of suspicion should be utilized when symptoms worsen despite conservative care. Referral for advanced imaging is critical for appropriate diagnosis of PVNS.

Objectif: Présenter les caractéristiques diagnostiques, cliniques et radiologiques de la synovite villonodulaire pigmentée (PVNP), sensibiliser le public à cette maladie rare et fournir aux praticiens de santé conservateurs des conseils pour le renvoi des patients et la prise en charge.

Présentation du cas: Nous présentons le cas d’un coureur amateur de 41 ans qui s’est présenté à la clinique avec une douleur antérieure de la hanche depuis un an. Après une anamnèse et un examen clinique, on a diagnostiqué un conflit fémoroacétabulaire. Les radiographies prises à ce moment-là révélaient une légère maladie dégénérative de la hanche gauche avec coxa profunda. Après quatre semaines de soins conservateurs, les symptômes du patient n’étaient pas soulagés. On lui a demandé de subir un examen par IRM et on a poursuivi les traitements conservateurs. Dix semaines plus tard, les symptômes et les capacités fonctionnelles du patient s’étaient aggravés. On a obtenu les résultats de l’examen par IRM et on a diagnostiqué une PVNP.

Résumé: La PVNP est une maladie rare qui peut imiter une douleur mécanique de la hanche. L’indice de suspicion est élevé lorsque les symptômes s’aggravent malgré des soins conservateurs. Un examen par imagerie avancée est essentiel pour un établir un diagnostic de PVNP.

Keywords: FAI; chiropractic; chiropratique; conflit fémoro-acétabulaire; douleur; hanche; hip; mechanical; mécanique; pain; pigmented villonodular synovitis; synovite villonodulaire pigmentée.

Background: The use of in vitro maturation (IVM) has allowed patients with polycystic ovary syndrome (PCOS) to have a positive fertility outcome, as it allows utilisation of immature oocytes to mature in vitro.

Aim: The aim of the study is to establish an optimum intra-cytoplasmic sperm injection (ICSI) timing for IVM oocytes (germinal vesicles [GV] →, metaphase I [MI]→ and metaphase II [MII]) using time lapse system (TLS) for patients with PCOS.

Setting and design: Patients included in this study were diagnosed with PCOS, ≤35 years of age, anti-Müllerian hormone levels >6 ng/ml and antral follicle counts <40. Furthermore, we included only GV oocytes at the time of denudation in our study.

Materials and methods: Patients were minimally stimulated and their oocytes were retrieved. In vitro maturated oocytes were monitored using TLS to a maximum of 30 h. MII oocytes were further cultured and injected at five different time intervals (1-2 h, 3-4 h, 5-6 h, 7-8 h and >8 h) to observe for fertilisation, cleavage and utilisation rate.

Statistical analysis: Chi-square test was applied to compared the treatment groups.

Results: Amongst 328 oocytes retrieved from 27 female patients, 162 oocytes were in the time-monitored cohort and 162 oocytes were grouped as the control cohort. Maturation rate between GV→ MII was highest at 18 h in the time-monitored cohort MII (n = 57). Utilisation rate was highest when ICSI was performed between 5 and 6 h after the first polar body extrusion, n = 17 (63%).

Conclusion: This study provides valuable insight into the optimal maturation timing using a TLS to yield the good number of oocytes. In addition, optimising ICSI timing is important to provide the best utilisation rate in an IVM cycle to achieve synchrony between nuclear and cytoplasmic maturation.

Keywords: Cleavage; fertilisation; mitosis; polycystic ovary syndrome; utilisation.

Background: Evidence regarding impact of pre-ovulatory hormone levels on assisted reproductive technique (ART) outcomes in different ovarian response groups is sparse.

Aims: The objective of this study was to evaluate and compare the association between pre-ovulatory hormonal profile and ART outcomes in different ovarian responses.

Setting and design: This is a single-centre retrospective cohort study of 273 non-donor fresh ART cycles between January 2013 and June 2016.

Materials and methods: Data on clinical profile, basal and peak hormonal levels, characteristics of controlled ovarian stimulation and ART outcomes were collected. Progesterone elevation (PE) was defined as pre-ovulatory serum progesterone >1.5 ng/mL or progesterone to oestradiol ratio >1. The association between peak hormonal levels and ART outcomes in poor (≤4 oocytes retrieved), intermediate (5-13 oocytes retrieved) and high (≥14 oocytes retrieved) ovarian responders was analysed and compared.

Statistical analysis: Continuous and categorical variables were summarised as median (interquartile range) and percentages, respectively, and compared using Kruskal-Wallis H-test or Mann-Whitney U-test and Chi-square test or Fisher's exact test, respectively.

Results: The incidence of PE, by both criteria and clinical pregnancy rates (35.7%, 36.8% and 18.6% in high, normal and poor responders, respectively; P = 0.073), was similar among the three response groups. Except fertilisation rates in normo-responders, PE did not influence ART outcomes in any response group. Furthermore, there were no differences between peak hormone concentrations or incidence of PE between those who conceived and those who did not.

Conclusion: Pre-ovulatory sex steroid levels do not seem to be the primary determinant of ART outcomes in any ovarian response category; hence, decision to freeze all embryos in the event of PE should be tailored.

Keywords: Assisted reproductive techniques; ovarian response; progesterone elevation.

The objective of this present research is to use agricultural residues as a source of energy for heating greenhouses during winter seasons and sequestrating soil carbon dioxide through adding biochar to the soil media. To fulfill the objective of the research work, summer squash was transplanted in a constructed greenhouse and heated using an attached biomass-burning system. The performance of the attached biomass-burning system was experimentally studied under different agricultural residues (corn stalks, cotton stalks and okra stalks), heating fluids (water and oil) and air fan operating periods (10, 15 and 20 min/h). Results indicated that the biomass-burning system allowed increasing temperature and relative humidity inside the greenhouse up to 27.2 and 80 %, respectively. The maximum biomass-burning system efficiency of 81 % was achieved with the use of okra stalks as a source of energy and oil as a heating fluid side by side with adjusting the suction fan operating period at 15 min/h. Adding bio-charcoal to the soil media, enhanced the soil carbon, resulting in a total fresh yield of 3.7 and 2.9 kg/pot with a total number of leaves per plant of 55 and 47 leaves under conditions of with and without charcoal addition, respectively.

Keywords: Agricultural residues; Biomass-burning system; Carbon dioxide sequestration; Greenhouse; Summer squash productivity; Thermal performance analysis.

Objective: To assess the comprehensiveness of primary healthcare (PHC) in different countries.

Method: PubMed, Virtual Health Library (BVS), and Scopus were systematically searched. Observational studies published from 2017 to 2019, using the Adult Primary Care Assessment Tool (PCAT) to assess comprehensiveness were included without limits regarding language of publication or country. The quality of studies was assessed using the Newcastle-Ottawa scale (NOS).

Results: Of 124 articles initially selected, 13 were included: four from China, two from Japan, and two from Vietnam; considering the Americas, all four studies were performed in Brazil. Only one study from Africa, performed in Malawi, was included. The quality of studies according to the NOS was acceptable. Considering the availability of services, eight facilities had low comprehensiveness, vs. five with high comprehensiveness. Considering the services performed at the facility, nine had low comprehensiveness, and only four had high comprehensiveness.

Conclusion: The low degree of PHC orientation in terms of comprehensiveness in terms of both services performed and services provided may reflect a lack of understanding of the demands of users, and indicates the need for concrete action to strengthen PHC as the basis of healthcare systems.

Objetivo: Evaluar la integralidad en la atención primaria de salud en distintos países.

Métodos: Se realizó una revisión sistemática en las bases de datos de PubMed, la Biblioteca Virtual de Salud y Scopus. Se seleccionaron estudios observacionales publicados en el período del 2017 al 2019, sin restricciones de idioma ni país, en los cuales se evaluara la integralidad en la atención primaria de salud por medio de la herramienta de evaluación de la atención primaria de salud (Primary Care Assessment Tool o PCATool), en su versión para adultos. La calidad de los estudios se determinó con la escala de Newcastle-Ottawa.

Resultados: En el estudio se incluyeron 13 de los 124 artículos seleccionados inicialmente, a saber, cuatro de China, dos de Japón y cuatro de Vietnam; además de cuatro estudios del continente americano realizados en Brasil y un único estudio correspondiente a África hecho en Malawi. La calidad de los estudios determinada con la escala de Newcastle-Ottawa fue satisfactoria. En la evaluación de la integralidad en cuanto a la disponibilidad de los servicios se clasificaron ocho lugares con un grado bajo y cinco con un grado alto de orientación hacia la atención primaria de salud. En lo que respecta a los servicios prestados, nueve lugares se clasificaron con un grado bajo y cuatro con un grado alto de orientación hacia la atención primaria de salud.

Conclusión: El grado bajo de orientación hacia la atención primaria de salud en cuanto a la integralidad de los servicios disponibles y prestados puede interpretarse como una falta de comprensión de las demandas reales de los usuarios, lo cual exige una acción concreta para fortalecer la atención primaria de salud como base de los sistemas de salud.

Keywords: Primary health care; health care evaluation mechanisms; integrality in health.

In forensic science, accurate estimation of the age of a victim or suspect can facilitate the investigators to narrow a search and aid in solving a crime. Aging is a complex process associated with various molecular regulations on DNA or RNA levels. Recent studies have shown that circular RNAs (circRNAs) upregulate globally during aging in multiple organisms such as mice and C.elegans because of their ability to resist degradation by exoribonucleases. In the current study, we attempted to investigate circRNAs' potential capability of age prediction. Here, we identified more than 40,000 circRNAs in the blood of thirteen Chinese unrelated healthy individuals with ages of 20-62 years according to their circRNA-seq profiles. Three methods were applied to select age-related circRNA candidates including the false discovery rate, lasso regression, and support vector machine. The analysis uncovered a strong bias for circRNA upregulation during aging in human blood. A total of 28 circRNAs were chosen for further validation in 30 healthy unrelated subjects by RT-qPCR, and finally, 5 age-related circRNAs were chosen for final age prediction models using 100 samples of 19-73 years old. Several different algorithms including multivariate linear regression (MLR), regression tree, bagging regression, random forest regression (RFR), and support vector regression (SVR) were compared based on root mean square error (RMSE) and mean average error (MAE) values. Among five modeling methods, regression tree and RFR performed better than the others with MAE values of 8.767 years (S.rho = 0.6983) and 9.126 years (S.rho = 0.660), respectively. Sex effect analysis showed age prediction models significantly yielded smaller prediction MAE values for males than females (MAE = 6.133 years for males, while 10.923 years for females in the regression tree model). In the current study, we first used circRNAs as additional novel age-related biomarkers for developing forensic age estimation models. We propose that the use of circRNAs to obtain additional clues for forensic investigations and serve as aging indicators for age prediction would become a promising field of interest.

Keywords: age prediction; biomarkers; circular RNA; forensic genetics; machine learning.

Background: Endotracheal tube (ETT) occlusion is a potentially life-threatening event. This study describes a quality improvement project to prevent ETT occlusion in critically ill patients.

Methods: After a cluster of clinically significant ETT occlusion incidents at a tertiary-care intensive care unit (ICU), the root cause analysis suggested that the universal use of heat moisture exchangers (HMEs) was a major cause. Then, we prospectively audited new ETT occlusion incidents after changing our practices to evidence-based active and passive humidification during mechanical ventilation (MV). We also compared the outcomes of affected patients with matched controls.

Results: During 100 weeks, 18 incidents of clinically significant ETT occlusion occurred on a median of 7 days after intubation (interquartile range, 4.8-9.5): 8 in the 10 weeks before and 10 in the 90 weeks after changing humidification practices (8.1 vs. 1.0 incidents per 1000 ventilator days, respectively). The incidents were not suspected in 94.4%, the peak airway pressure was >30 cm H₂O in only 25%, and 55.6% were being treated for pneumonia when ETT occlusion occurred. Compared with 51 matched controls, ETT occlusion cases had significantly longer MV duration (median of 13.5 vs. 4.0 days; P = 0.002) and ICU stay (median of 26.5 vs. 11.0 days; P = 0.006) and more tracheostomy (55.6% vs. 9.8%; P < 0.001). The hospital mortality was similar in cases and controls.

Conclusions: The rate of ETT occlusion decreased after changing humidification practices from universal HME use to evidence-based active and passive humidification. ETT occlusion was associated with more tracheostomy and a longer duration of MV and ICU stay.

Keywords: Complications; cost; heat moisture exchanger; intensive care; intratracheal intubation; mechanical ventilation.

Gelatin-free capsules are possibly produced through an innovation which involves utilizing environmentally friendly materials derived from plants such as bagasse which are produced into nanocrystalline cellulose (NCC). This research was conducted to report the extraction and characterization of NCC from the abundant industrial plantation waste of sugarcane and its application as the base material for gelatin-free capsule shell material. The process involved using different concentrations of NCC at 1%, 2%, 4%, and 7% (in wt. %) with the addition of 1% hydroxypropyl methylcellulose (HPMC) (in wt. %) and 1% carbopol (in wt. %). Moreover, the NCC capsules obtained from sugarcane bagasse were tested for moisture content, tensile strength, elongation, solubility, and pH. The results showed that sugarcane bagasse contains 40-50% cellulose, 6.15%-9.5% moisture content which indicates they are potentially better in terms of storage, 7.25-7.85 pH, and 0.05-0.136 MPa gel strength, and the elongation value ranges from 7.19 to 87.51%. These values were discovered to have satisfied the standard requirements as indicated by the optimal concentration of 4% NCC +1% HPMC, which is in line with the Japanese Industrial Standard (JIS), thereby leading to the consideration of the material safe to be used as raw material in making capsule shells.

Hypochlorous acid (HOCl) was crucial for maintaining the homeostasis in cells and plays vital roles in many physiological and pathological processes. In this work, a highly selective fluorescent probe for hypochlorous acid in living cells was constructed and prepared based on a naphthalene derivative. A naphthalene derivative was utilized as the fluorescent group, and N,N-dimethylthiocarbamate was applied as the selective recognition site for HOCl. Before adding HOCl, the fluorescent probe exhibited weak fluorescence. Upon adding HOCl, the fluorescent probe displayed remarkable fluorescence enhancement. The fluorescence intensity at 502 nm showed a linear response to the concentration of HOCl from 3.0 × 10^-7 to 1.0 × 10^-5 mol·L^-1. The detection limit was estimated to be 1.5 × 10^-7 mol·L^-1 for HOCl. The fluorescent probe showed fast response and outstanding selectivity toward HOCl. It owned good biocompatibility and had also been successfully applied in the confocal imaging of exogenous and endogenous HOCl in living cells.

Gut microbiota play a significant role for animals to adapt to the changing environment. Host species and habitats are key drivers in shaping the diversity and composition of the microbiota, but the determinants of composition of the sympatric host gut microbiome remain poorly understood within an ecosystem. In this study, we examined the effects of habitats of different succession stages and host species on the diversity and composition of fecal gut microbiota in four sympatric rodent species (Apodemus draco, Leopoldamys edwardsi, Niviventer confucianus, and Niviventer fulvescens) in a subtropical forest. We found, as compared to the differences between species, habitat types showed a much larger effect on the gut microbiota of rodents. Alpha diversity of the microbial community of A. draco, N. fulvescens, and N. confucianus was highest in farmland, followed by primary forest and shrubland, and lowest in secondary forest. Beta diversity of the three rodent species showed significant different among habitats. The alpha diversity of gut microbiota of L. edwardsi was significantly higher than those of A. draco and N. confucianus, and its beta diversity showed significant difference from A. draco. Our results suggested that gut microbiota were important for animals in responding to diet changes in different habitats under human disturbances.

Keywords: 16S; diet shift; forest succession; gut microbiota; habitat; host species; rodents.

Rationale: The morbidity and mortality of heart failure (HF) have been increasing rapidly in recent years. However, the molecular events that link to the phenotype of HF remain unclear. This study aimed to investigate the molecular alterations in the pathogenesis of HF induced by pressure overload. Methods: Transverse aortic constriction was conducted to generate the HF mouse model. A multi-omics study was performed, including integrative analysis of scRNA-seq, scATAC-seq, bulk ATAC-seq and miRNA-seq data. The results of omics analysis were verified by immunofluorescence staining. Results: scRNA-seq analysis identified five major cell types, which exhibits consistency with previous studies. Integrative analysis of ATAC-seq and miRNA-seq showed the alterations of gene expression in HF. Activation of genes involved in immune response at transcriptional level and perturbed expression of their upstream miRNAs confirmed the function of immune cells in the pathogenesis of HF. Analysis of scATAC-seq revealed a NO biosynthetic related gene regulation pattern in endothelial cells of failing hearts. Conclusion: We performed a multi-omics analysis, comparing the transcriptomic, miRNA expression, and chromatin accessibility profile between the HF and control mice, thus providing mechanistic insights into the pathogenesis of pressure overload-induced HF.

Keywords: heart failure; multi-omics analysis; scATAC-seq; scRNA-seq.

With precision medicine as the goal, the human biobank of each country should be analyzed to determine the complete research results related to genetic diseases. In addition, with the increase in medical imaging data, automatic image processing with image recognition has been widely studied and applied in biomedicine. However, case-control data imbalance often occurs in human biobanks, which is usually solved by the statistical method SAIGE. Due to the huge amount of genetic data in human biobanks, the direct use of the SAIGE method often faces the problem of insufficient computer memory to support calculations and excessive calculation time. The other method is to use sampling to adjust the data to balance the case-control ratio, which is called Synthetic Minority Oversampling Technique (SMOTE). Our study employed the Manhattan plot and genetic disease information from the Taiwan Biobank to adjust the imbalance in the case-control ratio by SMOTE, called "TW-SMOTE." We further used a deep learning image recognition system to identify the TW-SMOTE. We found that TW-SMOTE can achieve the same results as that of SAIGE and the UK Biobank (UKB). The processing of the technical data can be equivalent to the use of data plots with a relatively large UKB sample size and achieve the same effect as that of SAIGE in addressing data imbalance.

Keywords: biobank; deep learning; genome-wide association analyses; image identification; imbalanced data; mManhattan plot.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood mental disorder with undetermined pathophysiological mechanisms. The gut microbiota and immunological dysfunction may influence brain functions and social behaviours. In the current study, we aimed to explore the correlation of gut microbiome imbalance and inflammation in the pathophysiology of ADHD. Forty-one children with ADHD and thirty-nine healthy-control (HC) individuals were recruited. Faecal samples from all participants were collected and submitted for 16 S rRNA V3-V4 amplicon microbiome sequencing analysis. The plasma levels of 10 cytokines, including TNF-α, IL-6, IL-1β, IL-2, IL-10, IL-13, IL-17A, IFN-α2, IFN-γ, and MCP-1, were determined using a custom-made sandwich enzyme-linked immunosorbent assay (ELISA) developed by Luminex Flowmetrix. There was no significant difference between the ADHD and HC groups in species diversity in the faeces, as determined with α-diversity and β-diversity analysis. In the ADHD group, three differentially abundant taxonomic clades at the genus level were observed, namely Agathobacter, Anaerostipes, and Lachnospiraceae. Top differentially abundant bacteria and representative biological pathways were identified in children with ADHD using linear discriminant analysis (LDA) effect size (LEfSe), and the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analysis, respectively. The plasma levels of TNF-α were significantly lower in children with ADHD than in HCs. Within the ADHD group, the levels of TNF-α were negatively correlated with ADHD symptoms and diversity of the gut microbiome. Our study provides new insights into the association between gut microbiome dysbiosis and immune dysregulation, which may contribute to the pathophysiology of ADHD.

Anxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. In the present study, we find that the global Slack KO male mice exhibit anxious behaviors whereas the Slack Y777H male mice manifest anxiolytic behaviors. The expression of Slack channels is rich in BLA glutamatergic neurons and down-regulated in chronic corticosterone-treated mice. In addition, electrophysiological data show enhanced excitability of BLA glutamatergic neurons in the Slack KO mice and decreased excitability of these neurons in the Slack Y777H mice. Furthermore, the Slack channel deletion in BLA glutamatergic neurons is sufficient to result in enhanced avoidance behaviors while Kcnt1 gene expression in the BLA or BLA-vHPC glutamatergic projections reverses anxious behaviors of the Slack KO mice. Our study identifies the role of the Slack channel in controlling anxious behaviors by decreasing the excitability of BLA-vHPC glutamatergic projections, providing a potential target for anxiolytic therapies.SIGNIFICANCE STATEMENTAnxiety disorders are a series of mental disorders characterized by anxiety and fear, but the molecular basis of these disorders remains unclear. Here, we examined the loss- and gain-of-function Slack channel mice's behaviors in elevated plus maze and open field tests and found the anxiolytic role of the Slack channel. By altering the Slack channel expression in the specific neuronal circuit, we demonstrated that the Slack channel played its anxiolytic role by decreasing the excitability of BLA-vHPC glutamatergic projections. Our data reveal the role of the Slack channel in the regulation of anxiety, which may provide a potential molecular target for anxiolytic therapies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages lung epithelial stem/progenitor cells. Ideal anti-SARS-CoV-2 drug candidates should be screened to prevent secondary injury to the lungs. Here, we propose that in vitro three-dimensional organoid and lung injury repair mouse models are powerful models for the screening antiviral drugs. Lung epithelial progenitor cells, including airway club cells and alveolar type 2 (AT2) cells, were co-cultured with supportive fibroblast cells in transwell inserts. The organoid model was used to evaluate the possible effects of hydroxychloroquine, which is administered as a symptomatic therapy to COVID-19 patients, on the function of mouse lung stem/progenitor cells. Hydroxychloroquine was observed to promote the self-renewal of club cells and differentiation of ciliated and goblet cells in vitro. Additionally, it inhibited the self-renewal ability of AT2 cells in vitro. Naphthalene- or bleomycin-induced lung injury repair mouse models were used to investigate the in vivo effects of hydroxychloroquine on the regeneration of club and AT2 cells, respectively. The naphthalene model indicated that the proliferative ability and differentiation potential of club cells were unaffected in the presence of hydroxychloroquine. The bleomycin model suggested that hydroxychloroquine had a limited effect on the proliferation and differentiation abilities of AT2 cells. These findings suggest that hydroxychloroquine has limited effects on the regenerative ability of epithelial stem/progenitor cells. Thus, stem/progenitor cell-derived organoid technology and lung epithelial injury repair mouse models provide a powerful platform for drug screening, which could possibly help end the pandemic.

Keywords: alveolar type 2 cells; club cells; epithelial regeneration; lung organoids; mouse model.

Objective: To identify the class of evidence for aducanumab use for the treatment of Alzheimer disease and present clinical considerations regarding use.

Methods: The author panel systematically reviewed available clinical trial data detailing aducanumab use in individuals with early symptomatic Alzheimer disease. Level of evidence statements were assigned in accordance with the American Academy of Neurology's 2017 therapeutic classification of evidence scheme. Safety information, regulatory decisions, and clinical context were also reviewed.

Results: Data were identified from 4 clinical trials, 1 rated Class I and 3 rated Class II. The Class I study showed that single doses of aducanumab up to 30 mg/kg were safe and well tolerated. All 3 Class II studies provided evidence that aducanumab (3-10 mg/kg) decreased amyloid deposition on brain PET at 1-year vs placebo. Efficacy data in the Class II studies varied by dose and outcome, but aducanumab either had no effect on mean change on the Clinical Dementia Rating^® Sum-of-Boxes scores or resulted in less worsening (vs placebo) that was of uncertain clinical importance. Adverse amyloid-related imaging abnormalities occurred in approximately 40% of individuals treated with aducanumab vs 10% receiving placebo.

Clinical context: Administration of aducanumab will require expanded clinical infrastructure. Evidence-based guidance is needed to address key questions (e.g., safety in populations not enrolled in Phase 3 studies, expected benefits on daily function, treatment duration) and critical issues relating to access to aducanumab (e.g., coverage, costs, burden of monthly infusions) that will inform shared decision-making between patients and providers.

Patient-derived (PDX) and cell-derived (CDX) xenograft models are widely used in preclinical studies of human neuroblastoma. In this study, we constructed orthotopic and subcutaneous neuroblastoma CDX models by injecting human neuroblastoma cells into the adrenal gland and the flanks of immunodeficient mice, respectively. The tumorigenesis, metastasis and response to chemotherapy for the two models were also compared. Our results indicated that orthotopic tumor mice showed significantly faster tumor growth than that of subcutaneous mice. Importantly, the expression of PHOX2B and GAB2 was dramatically increased in the tumors of orthotopic CDX mice. Furthermore, orthotopic CDX mice developed multiple organ metastasis resembling that of neuroblastoma patients, while metastasis occurred predominantly in lung in subcutaneous CDX mice. Moreover, the two CDX models showed comparable response to cyclophosphamide treatment. Our results suggest that orthotopic CDX mice are superior to subcutaneous CDX mice as a preclinical model to study human neuroblastoma.

Keywords: disease model; metastasis; neuroblastoma; orthotopic human NB CDX model; subcutaneous human NB CDX model.

Children exposed to intimate partner violence (IPV) are at risk for posttraumatic stress symptoms (PTSS) and alterations in hypothalamic-pituitary-adrenal (HPA) axis functioning. The current study investigated children's threat and self-blame appraisals about parental conflict as potential mechanisms leading to these adverse outcomes. Parent-child relationships were also examined. The sample consisted of 119 10-year-olds and their mothers who were recruited from the community as part of a larger study of IPV. Children's reports of IPV directed at their mother in the past year were not associated with PTSS; however, IPV exposure was associated with attenuated cortisol output in response to a social stressor. IPV exposure was also associated with greater threat appraisals and poorer quality parent-child relationships. These results provide further evidence that witnessing IPV is threatening for children, has negative consequences for parent-child relationships, and can impact children's HPA axis functioning.

Keywords: HPA axis; PTSD; cortisol; domestic violence.