Increased neoantigens in hypermutated cancers with DNA mismatch repair deficiency (dMMR) are proposed as the major contributor to the high objective response rate in anti-PD-1 therapy. However, the mechanism of drug resistance is not fully understood. Using tumor models defective in the MMR gene Mlh1 (dMLH1), we show that dMLH1 tumor cells accumulate cytosolic DNA and produce IFN-β in a cGAS-STING-dependent manner, which renders dMLH1 tumors slowly progressive and highly sensitive to checkpoint blockade. In neoantigen-fixed models, dMLH1 tumors potently induce T cell priming and lose resistance to checkpoint therapy independent of tumor mutational burden. Accordingly, loss of STING or cGAS in tumor cells decreases tumor infiltration of T cells and endows resistance to checkpoint blockade. Clinically, downregulation of cGAS/STING in human dMMR cancers correlates with poor prognosis. We conclude that DNA sensing within tumor cells is essential for dMMR-triggered anti-tumor immunity. This study provides new mechanisms and biomarkers for anti-dMMR-cancer immunotherapy.Single-cell transcriptomics has been widely applied to classify neurons in the mammalian brain, while systems neuroscience has historically analyzed the encoding properties of cortical neurons without considering cell types. Here we examine how specific transcriptomic types of mouse prefrontal cortex (PFC) projection neurons relate to axonal projections and encoding properties across multiple cognitive tasks. We found that most types projected to multiple targets, and most targets received projections from multiple types, except PFC→PAG (periaqueductal gray). By comparing Ca2+ activity of the molecularly homogeneous PFC→PAG type against two heterogeneous classes in several two-alternative choice tasks in freely moving mice, we found that all task-related signals assayed were qualitatively present in all examined classes. However, PAG-projecting neurons most potently encoded choice in cued tasks, whereas contralateral PFC-projecting neurons most potently encoded reward context in an uncued task. Thus, task signals are organized redundantly, but with clear quantitative biases across cells of specific molecular-anatomical characteristics.Complementary genome-wide CRISPR-Cas9 screens performed by multiple groups reveal new insights into SARS-CoV-2 biology including aspects of viral entry, translation, replication, egress, and the genes regulating these processes. Comparisons with other coronaviruses enhances our understanding of the cellular life cycle of this medically important family of emerging viruses.Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection, we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results, we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms present at nearly 20% in East Asian populations reduce flavivirus infection. Based on our mechanistic studies, we propose that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication.

The purpose of this study was to assess the validity of the medical insurance guidelines for orthognathic surgery used by the major American medical insurance companies.

This study assessed the validity of the medical insurance guidelines for orthognathic surgery used by Aetna, Anthem Blue Cross Blue Shield (BCBS), Cigna, Humana, and UnitedHealthcare (UHC). To evaluate the validity, we calculated the approval and denial rates of the 5 guidelines when we used them to assess the medical necessity for a control group of carefully selected patients. Patients were included in the control group if they met the criteria of a „prudent provider,” crafted for this study. All rejected cases were analyzed to determine the root cause of the denials. The validity of the guidelines was also ascertained by determining their completeness and correctness.

The current study proves that no insurance guideline is in agreement with the criteria of a „prudent provider.” When applied to carefully chosen patients, the requiremeal insurance plans need revision. The most consequential flaw was considering etiology in judging medical necessity. Fortunately, only one company adopted this policy. Moreover, all guidelines have omissions and errors in the way jaw deformity is determined and how health impairment is determined.In severe atrophic mandibular fractures, the absence of stable occlusion, as well as poor bone volume at the fracture site, constitutes a lack of references during surgery to achieve accurate fracture reduction. Unsuccessful reduction and stabilization can lead to several complications, such as fracture misalignments, malunion, and facial asymmetry. An alternative to avoid the aforementioned issues is fracture reduction based on virtual surgical planning (VSP) technology. However, there is little information regarding VSP protocols for the management of mandible fractures. Herein, a new technique with low cost is reported in which VSP and computer-aided manufacturing of a positioning guide were applied in a 72-year-old female patient with bilateral fractures in her atrophic mandible in the body region. The positioning guide was used during fracture reduction on the inferior surface of the mandible as per the virtual reduction. A 3-dimensional mandible model was also printed, facilitating the prebent 2.4-mm reconstructive plate. The surgical procedure was performed with no complications, resulting in the accurate fit of both the bent plate and the guide. A postoperative computed tomography scan showed good condylar position, fracture reduction, and hardware adaptation. A follow-up approximately 2 years later showed that she was successfully rehabilitated with the dental prosthesis. Therefore, VSP is a valuable tool for attaining a predictable result in the treatment of severe atrophic mandibular fracture, with a reduced operative duration, acceptable precision of fracture reduction, and low cost.

The removal of third molars (M3) is one of the most common oral-maxillofacial surgical procedures affecting periodontal tissues of neighboring secondmolars (M2). The aim of this study was to evaluate the periodontal status of lower M2 following the removal of unerupted lower M3 up to 5 years after removal.

Primary predictor variable in this prospective cohort-study was time [baseline (BL; preoperatively), 6 and 60months postoperatively]. The primary outcome variable was probing pocket depth (PPD). Clinical attachment level (CAL) was defined as a secondary outcome variable. Plaque index (PlI) and gingival index (GI) were assessed descriptively. All variables were compared using nonparametric tests. M3 were classified as either completely bony or partially bony unerupted. Risk factors (removed M3, type of impaction, mean BL PPD≥4mm, gender, age) were analyzed (repeated measures ANCOVA). The significance level was set at 0.05.

From originally 91 subjects enrolled in this study, 39 subjects (22 females; mean age 21.6±2.5years) contributing 39 M3 completed the study after 5 years. Average BL PPD significantly decreased at 6 (-0.50±0.61mm, P=.001), 60months (-0.81±0.56, P<.0001), as well as between 6 and 60months (-0.31±0.51mm, P=.030). Corresponding CAL values decreased accordingly (BL-6months -0.37±0.59mm, P=.004; BL-60months -0.67±0.55mm, P<.0001; 6 to 60months -0.34±0.48mm, P=.004). The was confirmed as risk factor for PPD (P=.026) and CAL (P=.042) changes.

Average PPD and CAL of mandibular M2 in young subjects improved 5 years after early removal of unerupted M3 in favor of an initial partially bony unerupted type of impaction.

Average PPD and CAL of mandibular M2 in young subjects improved 5 years after early removal of unerupted M3 in favor of an initial partially bony unerupted type of impaction.

Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme.

T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (11) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was donetreatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated.

Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers).

Dapagliflozin reduces the risk of kidney failure and heart failure in patients with chronic kidney disease. We aimed to investigate the effects of dapagliflozin on kidney, cardiovascular, and mortality outcomes according to presence or absence of type 2 diabetes and according to underlying cause of chronic kidney disease, reported as diabetic nephropathy, chronic glomerulonephritides, ischaemic or hypertensive chronic kidney disease, or chronic kidney disease of other or unknown cause.

DAPA-CKD was a multicentre, double-blind, placebo-controlled, randomised trial done at 386 study sites in 21 countries, in which participants with a urinary albumin-to-creatinine ratio of 200-5000 mg/g and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min per 1·73m

were randomly assigned (11) to dapagliflozin 10 mg once daily or matching placebo, as an adjunct to standard care. The primary outcome was a composite of sustained decline in eGFR of at least 50%, end-stage kidney disease, or kidney-related or cardhose without type 2 diabetes.

Dapagliflozin reduces the risks of major adverse kidney and cardiovascular events and all-cause mortality in patients with diabetic and non-diabetic chronic kidney disease.

AstraZeneca.

AstraZeneca.Memory T cell responses have been demonstrated in COVID-19 convalescents, but ex vivo phenotypes of SARS-CoV-2-specific T cells have been unclear. We detected SARS-CoV-2-specific CD8+ T cells by MHC class I multimer staining and examined their phenotypes and functions in acute and convalescent COVID-19. Multimer+ cells exhibited early differentiated effector-memory phenotypes in the early convalescent phase. The frequency of stem-like memory cells was increased among multimer+ cells in the late convalescent phase. Cytokine secretion assays combined with MHC class I multimer staining revealed that the proportion of interferon-γ (IFN-γ)-producing cells was significantly lower among SARS-CoV-2-specific CD8+ T cells than those specific to influenza A virus. Importantly, the proportion of IFN-γ-producing cells was higher in PD-1+ cells than PD-1- cells among multimer+ cells, indicating that PD-1-expressing, SARS-CoV-2-specific CD8+ T cells are not exhausted, but functional. Our current findings provide information for understanding of SARS-CoV-2-specific CD8+ T cells elicited by infection or vaccination.