SIX2 and SIX3 coordinately regulate functional maturity and fate of human pancreatic ß cells.

The physiological functions of many vital tissues and organs continue to mature after birth, but the genetic mechanisms governing this postnatal maturation remain an unsolved mystery. Human pancreatic ß cells produce and secrete insulin in response to physiological cues like glucose, and these hallmark functions improve in the years after birth. This coincides with expression of the transcription factors SIX2 and SIX3, whose functions in native human ß cells remain unknown. Here, we show that shRNA-mediated SIX2 or SIX3 suppression in human pancreatic adult islets impairs insulin secretion. However, transcriptome studies revealed that SIX2 and SIX3 regulate distinct targets. Loss of SIX2 markedly impaired expression of genes governing ß-cell insulin processing and output, glucose sensing, and electrophysiology, while SIX3 loss led to inappropriate expression of genes normally expressed in fetal ß cells, adult α cells, and other non-ß cells. Chromatin accessibility studies identified genes directly regulated by SIX2. Moreover, ß cells from diabetic humans with impaired insulin secretion also had reduced SIX2 transcript levels. Revealing how SIX2 and SIX3 govern functional maturation and maintain developmental fate in native human ß cells should advance ß-cell replacement and other therapeutic strategies for diabetes.

The septin cytoskeleton is required for plasma membrane repair.

Plasma membrane repair is a fundamental homeostatic process of eukaryotic cells. Here, we report a new function for the conserved cytoskeletal proteins known as septins in the repair of cells perforated by pore-forming toxins or mechanical disruption. Using a silencing RNA screen, we identified known repair factors (e.g. annexin A2, ANXA2) and novel factors such as septin 7 (SEPT7) that is essential for septin assembly. Upon plasma membrane injury, the septin cytoskeleton is extensively redistributed to form submembranous domains arranged as knob and loop structures containing F-actin, myosin IIA, S100A11, and ANXA2. Formation of these domains is Ca2+-dependent and correlates with plasma membrane repair efficiency. Super-resolution microscopy revealed that septins and F-actin form intertwined filaments associated with ANXA2. Depletion of SEPT7 prevented ANXA2 recruitment and formation of submembranous actomyosin domains. However, ANXA2 depletion had no effect on domain formation. Collectively, our data support a novel septin-based mechanism for resealing damaged cells, in which the septin cytoskeleton plays a key structural role in remodeling the plasma membrane by promoting the formation of SEPT/F-actin/myosin IIA/ANXA2/S100A11 repair domains.

Intravenous immunoglobulin resistance in Kawasaki disease patients: prediction using clinical data.

BACKGROUND: About 10-20% of Kawasaki disease (KD) patients are resistant to the initial infusion of intravenous immunoglobin (IVIG). The aim of this study was to assess whether IVIG resistance in KD patients could be predicted using standard clinical and laboratory features. METHODS: Data were from two cohorts: a Korean cohort of 7101 KD patients from 2015 to 2017 and a cohort of 649 KD patients from San Diego enrolled from 1998 to 2021. Features included laboratory values, the worst Z-score from the initial echocardiogram or during hospitalization, and the five clinical KD signs at presentation. RESULTS: Five machine learning models achieved a maximum median AUC of 0.711 [IQR: 0.706-0.72] in the Korean cohort and 0.696 [IQR: 0.609-0.722] in the San Diego cohort during stratified 10-fold cross-validation using significant laboratory features identified from univariate analysis. Adding the Z-score, KD clinical signs, or both did not considerably improve the median AUC in either cohort. CONCLUSIONS: Using commonly measured clinical laboratory data alone or in conjunction with echocardiographic findings and clinical features is not sufficient to predict IVIG resistance. Further attempts to predict IVIG resistance will need to incorporate additional data such as transcriptomics, proteomics, and genetics to achieve meaningful predictive utility. IMPACT: We demonstrated that laboratory, echocardiographic, and clinical findings cannot predict intravenous immunoglobin (IVIG) resistance to a clinically meaningful extent using machine learning in a homogenous Asian or ethnically diverse population of patients with Kawasaki disease (KD). Visualizing these features using uniform manifold approximation and projection (UMAP) is an important step to evaluate predictive utility in a qualitative manner. Further attempts to predict IVIG resistance in KD patients will need to incorporate novel biomarkers or other specialized features such as genetic differences or transcriptomics to be clinically useful.

Evaluating Dental Monitoring effectiveness compared with conventional monitoring of clear aligner therapy using the Peer Assessment Rating index.

INTRODUCTION: This study aimed to evaluate the effectiveness of Dental Monitoring (DM) (Dental Monitoring SAS, Paris, France) compared with conventional monitoring (CM) during active orthodontic treatment. METHODS: The Peer Assessment Rating (PAR) index was used to evaluate the pretreatment and posttreatment records of 51 patients, with 26 in the CM group and 25 in the DM group. The change in weighted PAR was analyzed to assess the effectiveness of treatment. RESULTS: The chi-square test revealed that the CM group had a higher percentage of patients in the great improvement category compared with the DM group. However, this difference was not statistically significant (P = 0.192). A repeated measures general linear model demonstrated significant improvement over time (P <0.001), with no statistically significant group differences noted between CM and DM (P = 0.181) and no statistically significant time-by-group interaction (P = 0.299). CONCLUSIONS: Both CM and DM showed significant improvements in weighted PAR scores, but no statistically significant difference is present between the 2 groups.

Assembly of Luminescent Chiral Gold(I)-Sulfido Clusters via Chiral Self-Sorting.

Due to the ubiquity of chirality in nature, chiral self-assembly involving self-sorting behaviors has remained as one of the most important research topics of interests. Herein, starting from a racemic mixture of SEG-based (SEG=SEGPHOS) chlorogold(I) precursors, a unique chiral butterfly-shape hexadecanuclear gold(I) cluster (Au16 ) with different ratios of RSEG and SSEG ligands is obtained via homoleptic and heterochiral self-sorting. More interestingly, by employing different chlorogold(I) precursors of opposite chirality (such as RSEG -Au2 and SBIN -Au2 (BIN=BINAP)), an unprecedented heteroleptic and heterochiral self-sorting strategy has been developed to give a series of heteroleptic chiral decanuclear gold(I) clusters (Au10 ) with propellor-shape structures. Heterochiral and heteroleptic self-sorting have also been observed between enantiomers of homoleptic chiral Au10 clusters to result in the heteroleptic chiral Au10 clusters via cluster-to-cluster transformation. Incorporation of heteroleptic ligands is found to decrease the symmetry from S4 of homoleptic meso Au10 to C2 of heteroleptic chiral Au10 clusters. The chirality has been transferred from the axial chiral ligands and stored in the heteroleptic gold(I) clusters.

Molecular and genetic regulation of pig pancreatic islet cell development.

Reliance on rodents for understanding pancreatic genetics, development and islet function could limit progress in developing interventions for human diseases such as diabetes mellitus. Similarities of pancreas morphology and function suggest that porcine and human pancreas developmental biology may have useful homologies. However, little is known about pig pancreas development. To fill this knowledge gap, we investigated fetal and neonatal pig pancreas at multiple, crucial developmental stages using modern experimental approaches. Purification of islet ß-, α- and δ-cells followed by transcriptome analysis (RNA-seq) and immunohistology identified cell- and stage-specific regulation, and revealed that pig and human islet cells share characteristic features that are not observed in mice. Morphometric analysis also revealed endocrine cell allocation and architectural similarities between pig and human islets. Our analysis unveiled scores of signaling pathways linked to native islet ß-cell functional maturation, including evidence of fetal α-cell GLP-1 production and signaling to ß-cells. Thus, the findings and resources detailed here show how pig pancreatic islet studies complement other systems for understanding the developmental programs that generate functional islet cells, and that are relevant to human pancreatic diseases.

Molybdenum chloride catalysts for Z-selective olefin metathesis reactions.

The development of catalyst-controlled stereoselective olefin metathesis processes has been a pivotal recent advance in chemistry. The incorporation of appropriate ligands within complexes based on molybdenum, tungsten and ruthenium has led to reactivity and selectivity levels that were previously inaccessible. Here we show that molybdenum monoaryloxide chloride complexes furnish higher-energy (Z) isomers of trifluoromethyl-substituted alkenes through cross-metathesis reactions with the commercially available, inexpensive and typically inert Z-1,1,1,4,4,4-hexafluoro-2-butene. Furthermore, otherwise inefficient and non-stereoselective transformations with Z-1,2-dichloroethene and 1,2-dibromoethene can be effected with substantially improved efficiency and Z selectivity. The use of such molybdenum monoaryloxide chloride complexes enables the synthesis of representative biologically active molecules and trifluoromethyl analogues of medicinally relevant compounds. The origins of the activity and selectivity levels observed, which contradict previously proposed principles, are elucidated with the aid of density functional theory calculations.

Comparative assessment of treatment efficiency and patient experience between Dental Monitoring and conventional monitoring of clear aligner therapy: A single-center randomized controlled trial.

INTRODUCTION: This 2-arm randomized controlled clinical trial (RCT) aimed to assess the effect of Dental Monitoring (DM) on the efficiency of clear aligner therapy (CAT) and patient experience compared with conventional monitoring (CM) used for regularly scheduled clinical appointments. METHODS: Fifty-six patients with full permanent dentition treated with CAT participated in this RCT. Patients were recruited from a single private practice and treated by 1 experienced orthodontist. Randomization was performed with permutated blocks of 8 patients assigned to either a CM or DM group with allocations concealed in opaque, sealed envelopes. It was not feasible to blind subjects or investigators. The primary treatment efficiency outcome assessed was the number of appointments. Secondary outcomes included the time to reach the first refinement, the number of refinements, the total number of aligners, and treatment duration. The patient experience was assessed using a visual analog scale questionnaire administered at the end of CAT. RESULTS: No patients were lost to follow-up. There was no significant difference in the number of refinements (mean = 0.1; 95% confidence interval [CI], -0.2 to 0.5; P = 0.43) and the number of total aligners (median = 5; 95% CI, -1 to 13; P = 0.09). There was a significant difference in the number of appointments, with the DM group requiring 1.5 fewer visits (95% CI, -3.3, -0.7; p = 0.02) as well as overall treatment duration, with the DM group taking 1.9 months longer (95% CI, 0.0-3.6; P = 0.04). There was a difference between study groups regarding the importance of face-to-face appointments, with the DM group not perceiving face-to-face appointments as important (P = 0.03). CONCLUSIONS: DM with CAT resulted in 1.5 fewer clinical appointments and a longer treatment duration of 1.9 months. There were no significant intergroup differences in the number of refinements or total aligners. CM and DM groups had similarly high levels of satisfaction with CAT. REGISTRATION: The trial was registered at Australian New Zealand Clinical Trials Registry (ACTRN12620000475943). PROTOCOL: The protocol was published before trial commencement. FUNDING: This research did not receive any grant from funding agencies.

Temperature-Modulated Selective Detection of Part-per-Trillion NO2 Using Platinum Nanocluster Sensitized 3D Metal Oxide Nanotube Arrays.

Semiconductor chemiresistive gas sensors play critical roles in a smart and sustainable city where a safe and healthy environment is the foundation. However, the poor limits of detection and selectivity are the two bottleneck issues limiting their broad applications. Herein, a unique sensor design with a 3D tin oxide (SnO2 ) nanotube array as the sensing layer and platinum (Pt) nanocluster decoration as the catalytic layer, is demonstrated. The Pt/SnO2 sensor significantly enhances the sensitivity and selectivity of NO2 detection by strengthening the adsorption energy and lowering the activation energy toward NO2 . It not only leads to ultrahigh sensitivity to NO2 with a record limit of detection of 107 parts per trillion, but also enables selective NO2 sensing while suppressing the responses to interfering gases. Furthermore, a wireless sensor system integrated with sensors, a microcontroller, and a Bluetooth unit is developed for the practical indoor and on-road NO2 detection applications. The rational design of the sensors and their successful demonstration pave the way for future real-time gas monitoring in smart home and smart city applications.

A regional approach to reduce postoperative opioid prescribing in Ontario, Canada.

BACKGROUND: Opioid-related morbidity and mortality continue to rise in the province of Ontario. We implemented a provincial campaign to reduce the number of opioid pills prescribed at discharge after surgery in the Ontario Surgical Quality Improvement Network (ON-SQIN). METHODS: Activities related to the provincial campaign were implemented between April 2019 and March 2020 and between October 2020 and March 2021. Self-reported data from participating hospitals were used to determine changes in postoperative opioid prescribing patterns across participating hospitals. RESULTS: A total of 33 and 26 hospitals participated in the provincial campaign in the first and second year, respectively. During the first year of the campaign, the median morphine equivalent (MEQ) from opioid prescriptions decreased significantly in a number of surgical specialties, including General Surgery (from 105 [75-130] to 75 [55-107], P < 0.001) (median, interquartile range) and Orthopedic Surgery (from 450 [239-600] to 334 [167-435], P < 0.001). The median number of opioid pills prescribed at discharge per surgery also decreased significantly, from 25 (15-53) to 15 (11-38) for 1 mg hydromorphone (P < 0.001) and 25 (20-51) to 20 (15-30) for oxycodone (P < 0.001). The decrease in opioid prescriptions continued in the second year of the campaign. CONCLUSIONS: Our approach resulted in a significant reduction in the number of postoperative opioids prescribed across a number of surgical specialties. Our findings indicate that evidence-based strategies derived from a regional collaborative network can be leveraged to promote and sustain quality improvement activities.

A GWAS approach identifies Dapp1 as a determinant of air pollution-induced airway hyperreactivity.

Asthma is a chronic inflammatory disease of the airways with contributions from genes, environmental exposures, and their interactions. While genome-wide association studies (GWAS) in humans have identified ~200 susceptibility loci, the genetic factors that modulate risk of asthma through gene-environment (GxE) interactions remain poorly understood. Using the Hybrid Mouse Diversity Panel (HMDP), we sought to identify the genetic determinants of airway hyperreactivity (AHR) in response to diesel exhaust particles (DEP), a model traffic-related air pollutant. As measured by invasive plethysmography, AHR under control and DEP-exposed conditions varied 3-4-fold in over 100 inbred strains from the HMDP. A GWAS with linear mixed models mapped two loci significantly associated with lung resistance under control exposure to chromosomes 2 (p = 3.0x10-6) and 19 (p = 5.6x10-7). The chromosome 19 locus harbors Il33 and is syntenic to asthma association signals observed at the IL33 locus in humans. A GxE GWAS for post-DEP exposure lung resistance identified a significantly associated locus on chromosome 3 (p = 2.5x10-6). Among the genes at this locus is Dapp1, an adaptor molecule expressed in immune-related and mucosal tissues, including the lung. Dapp1-deficient mice exhibited significantly lower AHR than control mice but only after DEP exposure, thus functionally validating Dapp1 as one of the genes underlying the GxE association at this locus. In summary, our results indicate that some of the genetic determinants for asthma-related phenotypes may be shared between mice and humans, as well as the existence of GxE interactions in mice that modulate lung function in response to air pollution exposures relevant to humans.

Population-Wide Peer Comparison Audit and Feedback to Reduce Antibiotic Initiation and Duration in Long-Term Care Facilities with Embedded Randomized Controlled Trial.

BACKGROUND: Antibiotic overprescribing in long-term care settings is driven by prescriber preferences and is associated with preventable harms for residents. We aimed to determine whether peer comparison audit and feedback reporting for physicians reduces antibiotic overprescribing among residents. METHODS: We employed a province wide, difference-in-differences study of antibiotic prescribing audit and feedback, with an embedded pragmatic randomized controlled trial (RCT) across all long-term care facilities in Ontario, Canada, in 2019. The study year included 1238 physicians caring for 96 185 residents. In total, 895 (72%) physicians received no feedback; 343 (28%) were enrolled to receive audit and feedback and randomized 1:1 to static or dynamic reports. The primary outcomes were proportion of residents initiated on an antibiotic and proportion of antibiotics prolonged beyond 7 days per quarter. RESULTS: Among all residents, between the first quarter of 2018 and last quarter of 2019, there were temporal declines in antibiotic initiation (28.4% to 21.3%) and prolonged duration (34.4% to 29.0%). Difference-in-differences analysis confirmed that feedback was associated with a greater decline in prolonged antibiotics (adjusted difference -2.65%, 95% confidence interval [CI]: -4.93 to -.28%, P = .026), but there was no significant difference in antibiotic initiation. The reduction in antibiotic durations was associated with 335 912 fewer days of treatment. The embedded RCT detected no differences in outcomes between the dynamic and static reports. CONCLUSIONS: Peer comparison audit and feedback is a pragmatic intervention that can generate small relative reductions in the use of antibiotics for prolonged durations that translate to large reductions in antibiotic days of treatment across populations. Clinical Trials Registration. NCT03807466.

The Multifaceted B Cell Response to Influenza Virus.

Protection from yearly recurring, highly acute infections with a pathogen that rapidly and continuously evades previously induced protective neutralizing Abs, as seen during seasonal influenza virus infections, can be expected to require a B cell response that is too highly variable, able to adapt rapidly, and able to reduce morbidity and death when sterile immunity cannot be garnered quickly enough. As we outline in this Brief Review, the influenza-specific B cell response is exactly that: it is multifaceted, involves both innate-like and conventional B cells, provides early and later immune protection, employs B cells with distinct BCR repertoires and distinct modes of activation, and continuously adapts to the ever-changing virus while enhancing overall protection. A formidable response to a formidable pathogen.

Subgaleal haematoma as a cause of periorbital necrotising fasciitis: a case report.

Subgaleal haematoma in adulthood and periorbital necrotising fasciitis are unusual occurrences that have not been reported together. We discuss the first observed case of a 35-year-old female with periorbital necrotising fasciitis postulated to be caused by subgaleal haematoma following head trauma that was successfully managed with antibiotics and surgery.

Health Insurance Portability and Accountability Act Noncompliance in Patient Photograph Management in Plastic Surgery.

BACKGROUND: Today, plastic surgeons have largely transitioned to digital photography. This shift has introduced new risks to daily workflows, notably data theft and Health Insurance Portability and Accountability Act (HIPAA) violations. METHODS: We performed a national survey of digital photograph management patterns among members of the American Society of Plastic Surgery and trainees in Accreditation Council for Graduate Medical Education-accredited plastic surgery programs. RESULTS: Our findings showed that attendings preferred the use of stand-alone digital cameras (91.4%), whereas trainees preferred the use of smartphones (96.1%) for capturing patient photographs. The rate of noncompliance was nearly identical; 82.8% of attendings were HIPAA noncompliant when using stand-alone digital cameras compared with 90.2% of trainees using smartphones. Both groups also breached HIPAA rules when using other photographic management modalities. CONCLUSIONS: This is the first study to quantify the prevalence of noncompliance with regard to an entire digital photograph management workflow. These findings were consistent with previous studies that reported that younger physicians tend to embrace newer technologies, whereas older attendings are more reluctant. The findings also suggest that HIPAA noncompliance in digital photograph security and management is a significant problem within the plastic surgery community.

Periumbilical Perforator-Sparing Abdominoplasty in Patients With Abdominal Scars.

Abdominoplasty is one of the most common cosmetic surgical procedures. Patients who undergo abdominoplasties with abdominal scars are at an increased risk for skin necrosis and wound breakdown. To prevent further disruption of vascularity, the dissection and mobilization is often limited resulting in a suboptimal esthetic result. The periumbilical perforator-sparing technique allows for vascular preservation and adequate mobilization to produce excellent esthetic results in patients with abdominal scars.

Assessing Risk for Victimization in a Forensic Psychiatric Setting Using the Short-Term Assessment of Risk and Treatability.

Although a growing literature on community-based victimization of people with mental illness exists, victimization within institutional settings is comparatively understudied. The current study seeks to fill this gap by exploring factors related to risk of victimization in a male forensic psychiatric sample using a relatively new risk assessment measure. The Short-Term Assessment of Risk and Treatability (START) is a short-term risk assessment measure that compiles information about several clinically relevant risk factors to evaluate risk of victimization, among other adverse outcomes. Nearly one-third (31.3%) of the sample experienced some type of victimization during their hospitalization. The summary risk judgment and subsets of select START items effectively predicted risk of victimization in this sample with a fair degree of accuracy over a 2-month period.

Lack of autophagy induces steroid-resistant airway inflammation.

BACKGROUND: Neutrophilic corticosteroid-resistant asthma accounts for a significant proportion of asthma; however, little is known about the mechanisms that underlie the pathogenesis of the disease. OBJECTIVE: We sought to address the role of autophagy in lung inflammation and the pathogenesis of corticosteroid-resistant neutrophilic asthma. METHODS: We developed CD11c-specific autophagy-related gene 5 (Atg5)(-/-) mice and used several murine models to investigate the role of autophagy in asthmatic patients. RESULTS: For the first time, we found that deletion of the Atg5 gene specifically in CD11c(+) cells, which leads to impairment of the autophagy pathway, causes unprovoked spontaneous airway hyperreactivity and severe neutrophilic lung inflammation in mice. We found that severe lung inflammation impairs the autophagy pathway, particularly in pulmonary CD11c(+) cells in wild-type mice. We further found that adoptive transfer of Atg5(-/-), but not wild-type, bone marrow-derived dendritic cells augments lung inflammation with increased IL-17A levels in the lungs. Our data indicate that neutrophilic asthma in Atg5(-/-) mice is glucocorticoid resistant and IL-17A dependent. CONCLUSION: Our results suggest that lack of autophagy in pulmonary CD11c(+) cells induces neutrophilic airway inflammation and hyperreactivity.

Synthesis and Evaluation of Molybdenum and Tungsten Monoaryloxide Halide Alkylidene Complexes for Z-Selective Cross-Metathesis of Cyclooctene and Z-1,2-Dichloroethylene.

Molybdenum complexes with the general formula Mo(NR)(CHR')(OR″)(Cl)(MeCN) (R = t-Bu or 1-adamantyl; OR″ = a 2,6-terphenoxide) recently have been found to be highly active catalysts for cross-metathesis reactions between Z-internal olefins and Z-1,2-dichloroethylene or Z-(CF3)CH═CH(CF3). In this paper we report methods of synthesizing new potential catalysts with the general formula M(NR)(CHR')(OR″)(Cl)(L) in which M = Mo or W, NR = N-2,6-diisopropylphenyl or NC6F5, and L is a phosphine, a pyridine, or a nitrile. We also test and compare all catalysts in the cross-metathesis of Z-1,2-dichloroethylene and cyclooctene. Our investigations indicate that tungsten complexes are inactive in the test reaction either because the donor is bound too strongly or because acetonitrile inserts into a W═C bond. The acetonitrile or pivalonitrile Mo(NR)(CHR')(OR″)(Cl)(L) complexes are found to be especially reactive because the 14e Mo(NR)(CHR')(OR″)Cl core is accessible through dissociation of the nitrile to a significant extent. Pivalonitrile can be removed (>95%) from Mo(NAr)(CHCMe2Ph)(OHMT)(Cl)(t-BuCN) (Ar = 2,6-diisopropylphenyl; OHMT = 2,6-dimesitylphenoxide) to give 14e Mo(NAr)(CHCMe2Ph)(OHMT)Cl in solution as a mixture of syn and anti (60:40 at 0.015 M) nitrile-free isomers, but these 14e complexes have not yet been isolated in pure form. The syn isomer of Mo(NAr)(CHCMe2Ph)(OHMT)Cl binds pivalonitrile most strongly. Other Mo(NR)(CHR')(OR″)(Cl)(L) complexes can be activated through addition of B(C6F5)3. High stereoselectivities (>98% Z,Z) of ClCH═CH(CH2)6CH═CHCl are not restricted to tert-butylimido or adamantylimido complexes; 96.2% Z selectivity is observed with boron-activated Mo(NC6F5)(CHR')(OHIPT)(Cl)(PPhMe2). So far no Mo═CHCl complexes, which are required intermediates in the test reaction, have been observed in NMR studies at room temperature.