Unleashing Type-2 Dendritic Cells to Drive Protective Antitumor CD4+ T Cell Immunity.

Differentiation of proinflammatory CD4+ conventional T cells (Tconv) is critical for productive antitumor responses yet their elicitation remains poorly understood. We comprehensively characterized myeloid cells in tumor draining lymph nodes (tdLN) of mice and identified two subsets of conventional type-2 dendritic cells (cDC2) that traffic from tumor to tdLN and present tumor-derived antigens to CD4+ Tconv, but then fail to support antitumor CD4+ Tconv differentiation. Regulatory T cell (Treg) depletion enhanced their capacity to elicit strong CD4+ Tconv responses and ensuing antitumor protection. Analogous cDC2 populations were identified in patients, and as in mice, their abundance relative to Treg predicts protective ICOS+ PD-1lo CD4+ Tconv phenotypes and survival. Further, in melanoma patients with low Treg abundance, intratumoral cDC2 density alone correlates with abundant CD4+ Tconv and with responsiveness to anti-PD-1 therapy. Together, this highlights a pathway that restrains cDC2 and whose reversal enhances CD4+ Tconv abundance and controls tumor growth.

The roles of geometry and viscosity in the mobilization of coarse sediment by finer sediment.

In rivers, the addition of finer sediment to a coarser riverbed is known to increase the mobility of the coarser fraction. Two mechanisms have been suggested for this: a geometric mechanism whereby smaller sizes smooth the bed, increasing near-bed velocity and thus mobility of the larger sizes, and a viscous mechanism whereby a transitionally smooth turbulent boundary layer forms, rendering the coarser grains more mobile. Here, we report on experiments using two sediment mixtures to better understand these proposed mechanisms. In Mixture 1, we used 0.5 and 5 mm grains, and in Mixture 2, we used 2 and 20 mm grains. If the entrainment of coarse gravel by finer sediment is a purely geometric effect, then the addition of finer material should produce the same effect on the mobility of the coarser material for both mixtures because they have the same size ratio. We show that addition of finer material has a different effect on the two mixtures. We observed an increase in the mobility of the coarse fraction for both mixtures, but the increase in coarse fraction mobility for Mixture 1 was almost twice that for Mixture 2. Our experiments show that in addition to the geometric effect, enhancement of coarse gravel transport by finer sediment is also driven by a viscous effect.

Poyang and Dongting Lakes, Yangtze River: tributary lakes blocked by main-stem aggradation.

During its 6,300-km course from the Tibetan Plateau to the ocean, the Yangtze River is joined by two large lakes: Dongting Lake and Poyang Lake. We explain why these lakes exist. Deglaciation forced the ocean adjacent to the Yangtze mouth to rise ∼120 m. This forced a wave of rising water surface elevation and concomitant bed aggradation upstream. While aggradation attenuated upstream, the low bed slope of the Middle-Lower Yangtze River (∼2 × 10-5 near Wuhan) made it susceptible to sea level rise. The main stem, sourced at 5,054 m above sea level, had a substantial sediment load to "fight" against water surface level rise by means of bed aggradation. The tributaries of the Middle-Lower Yangtze have reliefs of approximately hundreds of meters, and did not have enough sediment supply to fill the tributary accommodation space created by main-stem aggradation. We show that the resulting tributary blockage likely gave rise to the lakes. We justify this using field data and numerical modeling, and derive a dimensionless number capturing the critical rate of water surface rise for blockage versus nonblockage.

Dalbavancin for the treatment of bone and joint infections: A meta-analysis.

BACKGROUND: Bone and joint infections are challenging infectious diseases to treat and require prolonged antimicrobial treatment. Dalbavancin demonstrated promising pharmacokinetic/pharmacodynamic properties for the treatment of these infections. The objective of this meta-analysis is to compare the effectiveness of dalbavancin to standard of care (SOC) for the treatment of bone and joint infections. METHODS: Two independent authors performed a comprehensive search through the major databases up to September 2023. Interventional and observational studies that compared the clinical success of dalbavancin to SOC for the treatment of osteoarticular infections (OAI) were included. RESULTS: A total of 6 studies and 581 patients were included, 282 in dalbavancin group and 299 in SOC group. Only one study was randomized clinical trial. When the data from the 6 studies were pooled in a meta-analysis, clinical success did not differ in those who received dalbavancin versus SOC (OR = 1.55, 95 % CI = 0.95-2.55, I-squared = 15.89 %) for the treatment of OAI infections. Four studies compared the two groups in terms of hospital length of stay and demonstrated a significant shorter length of stay in dalbavancin group compared to SOC group. Treatment-emergent adverse effects were reported in up to 21.4 % of patients in the dalbavancin group and up to 36.7 % of patients in the SOC group. CONCLUSION: This meta-analysis showed that dalbavancin is as effective as SOC for the treatment of patients with OAI infections. More data are needed to validate these findings.

Prospective Real-Time Validation of a Lung Ultrasound Deep Learning Model in the ICU.

OBJECTIVES: To evaluate the accuracy of a bedside, real-time deployment of a deep learning (DL) model capable of distinguishing between normal (A line pattern) and abnormal (B line pattern) lung parenchyma on lung ultrasound (LUS) in critically ill patients. DESIGN: Prospective, observational study evaluating the performance of a previously trained LUS DL model. Enrolled patients received a LUS examination with simultaneous DL model predictions using a portable device. Clip-level model predictions were analyzed and compared with blinded expert review for A versus B line pattern. Four prediction thresholding approaches were applied to maximize model sensitivity and specificity at bedside. SETTING: Academic ICU. PATIENTS: One-hundred critically ill patients admitted to ICU, receiving oxygen therapy, and eligible for respiratory imaging were included. Patients who were unstable or could not undergo an LUS examination were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 100 unique ICU patients (400 clips) were enrolled from two tertiary-care sites. Fifty-six patients were mechanically ventilated. When compared with gold standard expert annotation, the real-time inference yielded an accuracy of 95%, sensitivity of 93%, and specificity of 96% for identification of the B line pattern. Varying prediction thresholds showed that real-time modification of sensitivity and specificity according to clinical priorities is possible. CONCLUSIONS: A previously validated DL classification model performs equally well in real-time at the bedside when platformed on a portable device. As the first study to test the feasibility and performance of a DL classification model for LUS in a dedicated ICU environment, our results justify further inquiry into the impact of employing real-time automation of medical imaging into the care of the critically ill.

SomatoSim: precision simulation of somatic single nucleotide variants.

BACKGROUND: Somatic single nucleotide variants have gained increased attention because of their role in cancer development and the widespread use of high-throughput sequencing techniques. The necessity to accurately identify these variants in sequencing data has led to a proliferation of somatic variant calling tools. Additionally, the use of simulated data to assess the performance of these tools has become common practice, as there is no gold standard dataset for benchmarking performance. However, many existing somatic variant simulation tools are limited because they rely on generating entirely synthetic reads derived from a reference genome or because they do not allow for the precise customizability that would enable a more focused understanding of single nucleotide variant calling performance. RESULTS: SomatoSim is a tool that lets users simulate somatic single nucleotide variants in sequence alignment map (SAM/BAM) files with full control of the specific variant positions, number of variants, variant allele fractions, depth of coverage, read quality, and base quality, among other parameters. SomatoSim accomplishes this through a three-stage process: variant selection, where candidate positions are selected for simulation, variant simulation, where reads are selected and mutated, and variant evaluation, where SomatoSim summarizes the simulation results. CONCLUSIONS: SomatoSim is a user-friendly tool that offers a high level of customizability for simulating somatic single nucleotide variants. SomatoSim is available at https://github.com/BieseckerLab/SomatoSim .

Low-level variant calling for non-matched samples using a position-based and nucleotide-specific approach.

BACKGROUND: The widespread use of next-generation sequencing has identified an important role for somatic mosaicism in many diseases. However, detecting low-level mosaic variants from next-generation sequencing data remains challenging. RESULTS: Here, we present a method for Position-Based Variant Identification (PBVI) that uses empirically-derived distributions of alternate nucleotides from a control dataset. We modeled this approach on 11 segmental overgrowth genes. We show that this method improves detection of single nucleotide mosaic variants of 0.01-0.05 variant allele fraction compared to other low-level variant callers. At depths of 600 × and 1200 ×, we observed > 85% and > 95% sensitivity, respectively. In a cohort of 26 individuals with somatic overgrowth disorders PBVI showed improved signal to noise, identifying pathogenic variants in 17 individuals. CONCLUSION: PBVI can facilitate identification of low-level mosaic variants thus increasing the utility of next-generation sequencing data for research and diagnostic purposes.

Effect of Environmental Contaminants on Antioxidant Defense System in Fringe-Lip Mullet (Crenimugil crenilabis) from Suez Canal, Egypt.

Fish are widely used as model organisms for the assessment of the quality of aquatic environment and can therefore serve as bio-indicators of environmental contamination. The current research investigates the eco-physiological damage to fishes in Suez Canal for enhancing the biomonitoring of this area through the biochemical investigation, were estimated in the gills, kidney and liver of Mullet, (Crenimugil crenilabis) from Suez Canal, Egypt. This area gets a lot of wastes discharged from several industries, and it is considered as the main routes of many tankers. Crenimugil crenilabis weigh up approximately 350-600 g were fished from Nabq Managed Resource Protected Area as a control area and Suez Canal as a polluted area. Compared with control, a significant changing in the biochemical analysis results, shows that there was an initiation of oxidative stress in the tissue of Mullet from the Suez Canal which indicating the contamination status of this area.

Correlation of Serum Vaspin, Omentin-1, and adiponectin with metabolic phenotypes in Type-2 diabetes mellitus patients.

OBJECTIVES: To investigate adipocytokines' (vaspin, omentin-1, and adiponectin) correlation with metabolic phenotypes in type 2 diabetes mellitus (T2DM) patients. METHODS: This case-control research was done at the Diabetic Clinic in Jeddah, Kingdom of Saudi Arabia (KSA), from November 2018 to March 2019. Seventy-five T2DM patients and 75 gender, age, and BMI-matched healthy subjects were recruited for this research. RESULTS: In DM patients, the concentrations of serum vaspin and omentin-1 were substantially lower (p<0.001) than in the control group. A significant positive relationship between vaspin concentration and DBP (p<0.001), BMI (p<0.001), and waist circumference (p<0.001) was found in patients and control subjects, while FPG (p<0.016), serum insulin (p<0.001), HOMA-IR (p<0.001), TC (p<0.001), TG (p<0.001), and LDLc (p<0.001) were significantly interrelated among patients. Serum concentrations of omentin-1 and ADN were significantly negatively correlated with serum insulin, HOMA-IR, and TG among the DM group. Serum vaspin and ADN levels were significantly higher in the cases and control groups with BMI>25, and no gender-wise variance was observed in adipocytokines levels. Binary logistic regression analysis showed a significantly negative predictive relationship of vaspin and omentin-1 with DM. CONCLUSION: The DM group displayed substantially lower serum vaspin and omentin-1 levels. However, there was no consistent relationship observed between these adipocytokines and metabolic phenotypes.

Parental Knowledge of Appropriate Placement of Child Restraint Systems Before and After Educational Intervention in a Pediatric Emergency Department.

OBJECTIVE: This study aimed to determine caregiver's knowledge of appropriate car restraint systems (CRSs) use and compare this with the actual use among children presenting to the pediatric emergency department (PED), and to determine the efficacy of PED-based intervention on improving knowledge. METHODS: We conducted a prospective, intervention study of children (<8 years old) during a 12-month period in the PED. Based on their height and weight, children were assigned to group 1 (rear facing), group 2 (forward facing), or group 3 (booster). Caregivers were surveyed in their baseline CRS knowledge. Certified child passenger safety technicians evaluated each CRS and gave caregivers one-on-one education. Participants were called back to answer a posttest to determine if the information given was retained. RESULTS: Of the 170 children enrolled, 64 (37.6%) were assigned to group 1, 68 (40%) to group 2, and 38 (22.3%) to group 3. Of these, 63% were not aware of the state law regarding CRS use. Among those without a CRS, 18% belonged to group 1, 36% to group 2, and 46% to group 3. Even among those who reportedly had CRS, 13% of children did not have one-on-on inspection. After inspection, 84% of group 1, 71% of group 2, and 70% of group 3 were in the appropriate one. Nearly 45% were not compliant with American Academy of Pediatrics guidelines of children riding in rear-facing CRS until 2 years of age. CONCLUSIONS: A significant proportion of children visiting the PED are not in appropriate CRS, and caretaker knowledge about correct CRS types and installation is poor. Future educational efforts should focus on rear-facing and booster seat age-group children.

Adherence to optical safety guidelines for laser-assisted hair removal.

BACKGROUND: In recent years, there was a rise in ocular injuries secondary to cosmetic laser-assisted hair removal. PURPOSE: To assess the level of adherence to optical safety guidelines during laser-assisted hair removal performed by nurses or physicians in private practice. METHODS: A cross-sectional study was conducted at thirty-one private laser-assisted hair removal clinics. An electronic random number generator using a cluster random sampling technique was used to select the clinics. The Alexlazr™ (Candela Corp.) device operator's manual checklist was modified to collect data from laser device operators and patients by surveying the laser rooms, interviewing the patients, and observing the treatments. RESULTS: Ninety-four patients treated by different service providers were included from 31 private centers. All treatment sessions were delivered by trained nurses. Only 9.5% had acceptable adherence to optical safety guidelines during hair removal treatment, while the majority (90.5%) of service providers were poorly adherent. None of the providers achieved excellent adherence to optical safety guidelines. The item with the least adherence was the lack of non-reflective floors inside laser rooms in 72.3% of centers. All service providers were familiar with the laser system controls and emergency shutdown (100% adherence). CONCLUSION: There is a significant deficiency in the safety precautions at laser-assisted hair removal centers that can result in devastating ophthalmic injuries. Companies providing laser-assisted hair removal machines should be involved in aiding these centers to implement safety procedures.

Choice of Intravenous Crystalloid Fluid and Mortality in Critically Ill Adult Patients.

OBJECTIVES: Intravenous balanced crystalloid fluid therapy may improve mortality and other outcomes in critically ill adult patients, but data are conflicting. We conducted a meta-analysis and literature review to evaluate the impact of intravenous balanced crystalloid, as compared with normal saline, fluid therapy on outcomes in critically ill adult patients. METHODS: We searched PubMed, Scopus, MEDLINE, and the Cochrane Register of Clinical Trials for relevant studies. Randomized controlled trials comparing the effects of balanced intravenous crystalloids with normal saline on intensive care unit (ICU) or hospital mortality were included. Pooled risk ratios (RRs) were calculated using a fixed effects model. Heterogeneity was calculated using the I2 statistic. The risk of bias was assessed using the Cochrane tool. RESULTS: Seven randomized controlled trials with 20,171 patients (10,179 participants received balanced crystalloids and 9992 participants received normal saline) were included. For hospital mortality, the pooled RR (95% confidence interval [CI]) was 0.92 (0.85-1.00). For ICU mortality, the pooled RR (95% CI) was 0.91 (0.82-1.00). For major adverse kidney events at 30 days, pooled RR (95% CI) was 0.95 (0.88-1.01). For stage ≥2 acute kidney injury, the pooled RR (95% CI) was 0.94 (0.86-1.02). For receipt of new renal replacement therapy, the pooled RR (95% CI) was 0.91 (0.77-1.07). None of these findings reached statistical significance. CONCLUSIONS: Intravenous balanced crystalloid use, compared with normal saline, does not result in a statistically significant reduction in hospital or ICU mortality, major adverse kidney events at 30 days, stage ≥2 acute kidney injury, or receipt of new renal replacement therapy in critically ill adult patients.

Presumed tuberculous uveitis in a university-based tertiary referral center in Saudi Arabia.

PURPOSE: To describe clinical characteristics and outcomes of treatment in patients with presumed tuberculous uveitis (PTU). METHODS: All patients diagnosed with PTU between January 1996 and March 2013 were reviewed. The diagnosis was made when clinical findings were consistent with possible intraocular tuberculosis, strongly positive purified protein derivative (PPD) skin test result, and response to anti-tuberculous therapy with no other cause of uveitis as suggested by history, symptoms, or ancillary testing. RESULTS: Ninety patients (141 eyes) were identified. There were 43 males (47.3%) and 47 females (52.7%). Mean age was 48.2 ± 14.4 years. Mean duration of symptoms prior to presentation was 6.7 ± 8.3 months. Ten eyes (7.1%) had anterior uveitis, 18 eyes (12.8%) had intermediate uveitis, 34 eyes (24.1%) had posterior uveitis, and 79 eyes (56%) had panuveitis. Macular edema was present in 33.3% of the eyes at presentation. All patients received anti-tuberculous therapy and systemic corticosteroids. Mean follow-up after completion of therapy was 36 ± 2.5 months. Only 2 eyes developed recurrent inflammation after treatment completion. At last follow-up, all eyes showed resolution of inflammation, associated with significant improvement in visual acuity. There was a significant positive correlation between initial and final VA. Eyes that had macular edema at presentation showed a significant reduction in central macular thickness at final follow-up. CONCLUSIONS: There is delay in presentation of patients with PTU. The most common anatomic diagnosis was panuveitis. Treatment with anti-tuberculous therapy combined with systemic corticosteroids resulted in resolution of inflammation and macular edema with significant improvement in visual acuity.

Recent pharmacological advances in the management of gout.

Gout is the most common cause of inflammatory arthritis worldwide, and reports show that despite availability of therapies, management is still suboptimal. The new EULAR 2016 recommendations for the treatment of gout highlight the huge development in gout therapies, and the number of drugs being trialled only continues to increase. A clinical review of the evidence that underlies the recommendations from EULAR can reveal possible gaps in the literature and avenues for future research into gout therapies.

SURGICAL OUTCOMES AND COMPLICATIONS OF RHEGMATOGENOUS RETINAL DETACHMENT IN EYES WITH CHORIORETINAL COLOBOMA: The Results of the KKESH International Collaborative Retina Study Group.

PURPOSE: To study the outcomes of management of rhegmatogenous retinal detachment in eyes with chorioretinal colobomas. METHODS: A retrospective review of 119 patients (119 eyes) with chorioretinal colobomas who underwent surgical repair for rhegmatogenous retinal detachment was performed. Data were collected on the site of the retinal break, type of surgery, anatomical success, and complications. RESULTS: The most common location of the primary retinal break was the intercalary membrane in 58.8% of eyes. The most common surgical intervention was vitrectomy with endolaser and silicone oil tamponade (77.3% of eyes). Final anatomical success was achieved in 87.4% of eyes. Anatomical success was significantly higher in eyes that received long-acting tamponade (P = 0.006). Cryotherapy was significantly associated with failure of primary vitrectomy (P = 0.028). Placement of an encircling band did not affect anatomical outcomes (P = 0.75). Most of the eyes (60%) with recurrent retinal detachment after primary vitrectomy had a primary break within the normal retina. CONCLUSION: The optimal option for managing retinal detachment in eyes with chorioretinal colobomas is pars plana vitrectomy with long-acting tamponade (silicone oil or octafluoropropane) and retinopexy to the edge of the coloboma and the primary breaks. Cryotherapy is associated with poor anatomical outcomes. An encircling band does not seem to affect the final anatomical outcome.

Exome-based case-control association study using extreme phenotype design reveals novel candidates with protective effect in diabetic retinopathy.

UNLABELLED: Diabetic retinopathy (DR) is a common clinical expression of diabetes mellitus-induced vasculopathy and is a major cause of vision loss. Significant gaps remain in our understanding of the molecular pathoetiology of DR, and it is hoped that human genetic approaches can reveal novel targets especially since DR is a heritable trait. Previous studies have focused on genetic risk factors of DR but their results have been mixed. In this study, we hypothesized that the use of the extreme phenotype design will increase the power of a genomewide search for "protective" genetic variants. We enrolled a small yet atypical cohort of 43 diabetics who did not develop DR a decade or more after diagnosis (cases), and 64 diabetics with DR (controls), all of similar ethnic background (Saudi). Whole-exome sequencing of the entire cohort was followed by statistical analysis employing combined multivariate and collapsing methods at the gene level, to identify genes that are enriched for rare variants in cases vs. CONTROLS: Three genes (NME3, LOC728699, and FASTK) reached gene-based genome-wide significance at the 10(-08) threshold (p value = 1.55 × 10(-10), 6.23 × 10(-10), 3.21 × 10(-08), respectively). Our results reveal novel candidate genes whose increased rare variant burden appears to protect against DR, thus highlighting them as attractive candidate targets, if replicated by future studies, for the treatment and prevention of DR. Extreme phenotype design when implemented in sequencing-based genome-wide case-control studies has the potential to reveal novel candidates with a smaller cohort size compared to standard study designs.

Use of biologics in SLE: a review of the evidence from a clinical perspective.

With the explosion in biologics use in rheumatology, newer and smarter ways of using these drugs in different diseases have been advocated. SLE has to date been at the back of the biologics algorithms. Recently, the US Food and Drug Administration and European Medicines Evaluation Agency licensed belimumab for use in SLE, the first drug in >30 years. A clinical review of the evidence that underlies the use of belimumab and other biologics in SLE reveals possible reasons why the results are not as spectacular as they are in other diseases.

A NOVEL TECHNIQUE FOR SECURING SCLEROTOMIES IN 20-GAUGE TRANSCONJUNCTIVAL PARS PLANA VITRECTOMY: Surgical Outcomes and Complications in 529 Consecutive Cases.

PURPOSE: To describe a novel technique for securing sclerotomies after 20-gauge transconjunctival pars plana vitrectomy and determine the efficacy, and short-term safety in various vitreoretinal diseases. METHODS: Retrospective chart review of consecutive cases that underwent 20-gauge transconjunctival pars plana vitrectomy with sclerotomy hydration was conducted. The main outcome measures included intraocular pressure, intraocular gas bubble size in postoperative Day 1, and early postoperative complications. Secondary outcomes included postoperative visual acuity at 1-month postoperative visit. RESULTS: Five hundred and twenty-nine eyes were evaluated. Mean gas/air fill and mean intraocular pressure were 75.1% and 14.8 mmHg on postoperative Day 1. Seven eyes (1.32%) had hypotony (intraocular pressure <6 mmHg) on Day 1, which normalized in all eyes by Day 7 (P = 0.0083). On postoperative Day 7, mean intraocular pressure was 17.1 mmHg. Hypotony was associated with a preoperative diagnosis of retinal detachment (P = 0.022), and silicone oil tamponade (P = 0.017). Mean best corrected visual acuity was 20/320 preoperatively and 20/125 postoperatively at 1-month follow-up visit (P < 0.0001). Twenty-seven cases had intraoperative or postoperative complications (5.1%). Rate of complications was not associated with the type of tamponade (P = 0.076). CONCLUSION: Twenty-gauge transconjunctival sutureless vitrectomy with sclerotomy hydration appears to be safe with a low rate of hypotony and complications, and good final visual outcome.

What you need to know about statistics Part I: validity of diagnostic and screening tests.

The intent of this manuscript is to provide guidance and support to clinicians and investigators for reporting the results of screening and diagnostic tests. This article is the first of two parts addressing statistics in imaging research. In this part validity measures are discussed. In part II reliability measures will be discussed. In discussing validity, the following concepts will be introduced: (1) functions of diagnostic tests, (2) statistical characteristics of diagnostic tests and application of validity measures, (3) power and sample size for testing the sensitivity and specificity of the diagnostic test, (4) statistical versus clinical significance and (5) characteristics of a useful diagnostic test.