Lysosomal Disorders Drive Susceptibility to Tuberculosis by Compromising Macrophage Migration.

A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.

Leptin mediates the increase in blood pressure associated with obesity.

Obesity is associated with increased blood pressure (BP), which in turn increases the risk of cardiovascular diseases. We found that the increase in leptin levels seen in diet-induced obesity (DIO) drives an increase in BP in rodents, an effect that was not seen in animals deficient in leptin or leptin receptors (LepR). Furthermore, humans with loss-of-function mutations in leptin and the LepR have low BP despite severe obesity. Leptin's effects on BP are mediated by neuronal circuits in the dorsomedial hypothalamus (DMH), as blocking leptin with a specific antibody, antagonist, or inhibition of the activity of LepR-expressing neurons in the DMH caused a rapid reduction of BP in DIO mice, independent of changes in weight. Re-expression of LepRs in the DMH of DIO LepR-deficient mice caused an increase in BP. These studies demonstrate that leptin couples changes in weight to changes in BP in mammalian species.

Mapping carbon accumulation potential from global natural forest regrowth.

To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide1,2. Regrowing natural forests is a prominent strategy for capturing additional carbon3, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates2,3. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)4,5 may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported3 owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy.

Phylogeographic analysis of the Bantu language expansion supports a rainforest route.

The Bantu expansion transformed the linguistic, economic, and cultural composition of sub-Saharan Africa. However, the exact dates and routes taken by the ancestors of the speakers of the more than 500 current Bantu languages remain uncertain. Here, we use the recently developed "break-away" geographical diffusion model, specially designed for modeling migrations, with "augmented" geographic information, to reconstruct the Bantu language family expansion. This Bayesian phylogeographic approach with augmented geographical data provides a powerful way of linking linguistic, archaeological, and genetic data to test hypotheses about large language family expansions. We compare four hypotheses: an early major split north of the rainforest; a migration through the Sangha River Interval corridor around 2,500 BP; a coastal migration around 4,000 BP; and a migration through the rainforest before the corridor opening, at 4,000 BP. Our results produce a topology and timeline for the Bantu language family, which supports the hypothesis of an expansion through Central African tropical forests at 4,420 BP (4,040 to 5,000 95% highest posterior density interval), well before the Sangha River Interval was open.

A global analysis of matches and mismatches between human genetic and linguistic histories.

Human history is written in both our genes and our languages. The extent to which our biological and linguistic histories are congruent has been the subject of considerable debate, with clear examples of both matches and mismatches. To disentangle the patterns of demographic and cultural transmission, we need a global systematic assessment of matches and mismatches. Here, we assemble a genomic database (GeLaTo, or Genes and Languages Together) specifically curated to investigate genetic and linguistic diversity worldwide. We find that most populations in GeLaTo that speak languages of the same language family (i.e., that descend from the same ancestor language) are also genetically highly similar. However, we also identify nearly 20% mismatches in populations genetically close to linguistically unrelated groups. These mismatches, which occur within the time depth of known linguistic relatedness up to about 10,000 y, are scattered around the world, suggesting that they are a regular outcome in human history. Most mismatches result from populations shifting to the language of a neighboring population that is genetically different because of independent demographic histories. In line with the regularity of such shifts, we find that only half of the language families in GeLaTo are genetically more cohesive than expected under spatial autocorrelations. Moreover, the genetic and linguistic divergence times of population pairs match only rarely, with Indo-European standing out as the family with most matches in our sample. Together, our database and findings pave the way for systematically disentangling demographic and cultural history and for quantifying processes of shifts in language and social identities on a global scale.

Total neoadjuvant therapy in oesophageal and gastro-oesophageal junctional adenocarcinoma.

Adenocarcinoma of the oesophagus and gastro-oesophageal junction represent a large burden of cancer death in the Western World with an increasing incidence. In the past two decades, the overall survival of patients on a potentially curative treatment pathway has more than doubled due to the addition of perioperative oncological therapies to surgery. However, patients often fail to respond to oncological treatment or struggle to complete their treatment after surgery. In this review, we discuss the current evidence for total neoadjuvant therapy and options for assessment of treatment response.

Endoscopic Approaches to Obesity Management.

The field of endoscopic bariatric and metabolic therapy has rapidly evolved from offering endoscopic treatment of weight regain following bariatric surgery to providing primary weight loss options as alternatives to pharmacologic and surgical interventions. Gastric devices and remodeling procedures were initially designed to work through a mechanism of volume restriction, leading to earlier satiety and reduced caloric intake. As the field continues to grow, small bowel interventions are evolving that may have some effect on weight loss but focus on the treatment of obesity-related comorbidities. Future implementation of combination therapy that utilizes both gastric and small bowel interventions offers an exciting option to further augment weight loss and alleviate metabolic disease. This review considers gastric devices and techniques including space-occupying intragastric balloons, aspiration therapy, endoscopic tissue suturing, and plication interventions, followed by a review of small bowel interventions including endoluminal bypass liners, duodenal mucosal resurfacing, and endoscopically delivered devices to create incisionless anastomoses.

Early life adversity reduces affiliative behavior with a stressed cagemate and leads to sex-specific alterations in corticosterone responses in adult mice.

Experiencing early life adversity (ELA) alters stress physiology and increases the risk for developing psychiatric disorders. The social environment can influence dynamics of stress responding and buffer and/or transfer stress across individuals. Yet, the impact of ELA on sensitivity to the stress of others and social behavior following stress is unknown. Here, to test the impact of ELA on social and physiological responses to stress, circulating blood corticosterone (CORT) and social behaviors were assessed in adult male and female mice reared under limited bedding and nesting (LBN) or control conditions. To induce stress, one cagemate of a pair-housed cage underwent a footshock paradigm and was then returned to their unshocked partner. CORT was measured in both groups of mice 20 or 90 min after stress exposure, and social behaviors were recorded and analyzed. ELA rearing influenced the CORT response to stress in a sex-specific manner. In males, both control and ELA-reared mice exhibited similar stress transfer to unshocked cagemates and similar CORT dynamics. In contrast, ELA females showed a heightened stress transfer to unshocked cagemates, and sustained elevation of CORT relative to controls, indicating enhanced stress contagion and a failure to terminate the stress response. Behaviorally, ELA females displayed decreased allogrooming and increased investigative behaviors, while ELA males showed reduced huddling. Together, these findings demonstrate that ELA influenced HPA axis dynamics, social stress contagion and social behavior. Further research is needed to unravel the underlying mechanisms and long-term consequences of ELA on stress systems and their impact on behavioral outcomes.

Late Ordovician eurypterid preserves oldest euchelicerate musculature in pyrite.

Pyritization of soft tissues of invertebrates is rare in the fossil record. In New York State, it occurs in black shales of the Lorraine Group (Late Ordovician), the best-known example of which is Beecher's Trilobite Bed. Exceptional preservation at the quarry where this bed is exposed allowed detailed examination of trilobite and ostracod soft-tissue anatomy. Here, we present the first example of a eurypterid (sea scorpion) currently ascribed to Carcinosomatidae from this deposit that also preserves the first evidence for mesosomal musculature in eurypterids. This specimen demonstrates that eurypterid musculature can be preserved in pyrite and evidences the oldest example of euchelicerate muscles within the fossil record. Sulfur isotope data illustrate that pyrite rapidly replicated muscle tissue in the early burial environment, prior to the pyritization of biomineralized exoskeleton and cuticular trilobite limbs. This discovery therefore expands the limited fossil record of euchelicerate musculature, while extending the taphonomic scope for preservation of detailed internal structures, more broadly, within arthropods.

Efficacy and Safety of Gastric Per-Oral Endoscopic Myotomy (G-POEM): A Systematic Review and Meta-Analysis.

BACKGROUND: Gastric per-oral endoscopic myotomy (G-POEM) is an innovative treatment that has become increasingly utilized for patients with refractory gastroparesis. The aim of this systematic review and meta-analysis was to evaluate the safety and effectiveness of G-POEM for the treatment of gastroparesis. METHODS: Individualized search strategies were developed through February 2021 in accordance with the PRISMA and MOOSE guidelines. This meta-analysis was performed by calculating pooled proportions and mean difference preprocedure and postprocedure with rates estimated using random effects models. Measured outcomes included technical success, clinical success, improvement in gastroparesis cardinal symptom index (GCSI), change in gastric emptying rate, alterations in impedance planimetry (functional lumen imaging probe [FLIP]) assessment, and adverse events. RESULTS: A total of 20 studies (n=797 patients; 67.41% female) were included. The mean age was 48.92±11.61 y, with an average duration of 4.24±1.11 y since gastroparesis diagnosis. Technical success was 98.47% [(95% CI: 97.14, 99.19);I2=0.00] with a mean myotomy length of 3.78±1.16 cm. In terms of clinical success, mean preprocedure GCSI scores were 3.38±0.37 and improved significantly postprocedure [weighted mean difference -1.56 (95% CI: -1.89 to -1.24); I2=82.53; P<0.001]. Gastric retention after 4 hours demonstrated ~50% improvement (preprocedure 43.08±9.24% versus postprocedure 22.97±10.19%; P<0.001). FLIP assessment with 40 mL and 50 mL balloons demonstrated a significant increase in diameter, distensibility index, and cross-sectional area postprocedure (all P<0.05). Procedure-associated adverse events occurred among 10.92% [(95% CI 5.09 to 19.32); I2=82.85] of patients. CONCLUSION: G-POEM appears safe and highly effective for the treatment of patients with refractory gastroparesis regardless of symptom predominance or etiology.

Evidence for cryptic molting behavior in the trilobite Toxochasmops vormsiensis from the Upper Ordovician Katian Kõrgessaare Formation, Estonia.

Documentation of cryptic trilobite behavior has presented important insights into the paleoecology of this fully extinct arthropod group. One such example is the preservation of trilobites inside the remains of larger animals. To date, evidence for trilobites within cephalopods, gastropods, hyoliths, and other trilobites has been presented. Importantly, most of these interactions show trilobite molts, suggesting that trilobites used larger animals for protection during molting. To expand the record of molted trilobites within cephalopods, we present a unique case of a Toxochasmops vormsiensis trilobite within the body chamber of a Gorbyoceras textumaraneum nautiloid from the Upper Ordovician Kõrgessaare Formation of Estonia. By examining this material, we present new insights into the ecology of pterygometopid trilobites, highlighting how these forms used large cephalopods as areas to successfully molt.

Real World Clinical Effectiveness and Safety of Ozanimod in the Treatment of Ulcerative Colitis: 1-Year Follow-Up from a Tertiary Center.

BACKGROUND: Ozanimod is a first-in-class Sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. AIM: To provide 1-year follow-up results of our UC patient cohort treated with ozanimod. METHODS: This prospective, observational cohort study includes consecutive patients who initiated ozanimod at the University of Chicago IBD Center between 5/2021 and 12/2022. We collected demographic, clinical, and laboratory data. Clinical disease activity was prospectively assessed using the Simple Clinical Colitis Activity Index. RESULTS: Forty-five patients with UC initiated ozanimod therapy and were included in the effectiveness analysis. The median age was 35 years (interquartile range (IQR) 28-52), median disease duration of 6 years (IQR 3-13), 26 (58%) were male, 23 (51%) had extensive colitis, 34 (76%) had previous advanced therapy exposure. Thirty-four patients had clinically active UC at the time of ozanimod initiation; week 10 clinical response and remission rates were 58% and 53%, respectively. By week 52, the rates were 25% for both clinical response and remission. In the 12 (39%) patients with a > 75% reduction in absolute lymphocyte count, numerically greater induction clinical response and remission rates were observed (80% vs 54%, p = 0.4 and 75% vs 53%, p = 0.4, respectively). There were no episodes of symptomatic bradycardia and no other new safety signals. CONCLUSION: Ozanimod effectively induced clinical response and remission patients with largely treatment refractory UC, however, had modest long-term effectiveness. The safety profile was favorable with no new signals.

Defining the Core Content for Transport Physician Training Programs.

In many parts of the world, emergency medical services (EMS) clinical care is traditionally delivered by different levels or types of EMS clinicians, such as emergency medical technicians and paramedics. In some areas, physicians are also included among the cadre of professionals administering EMS-based care. This is especially true in the interfacility transport (IFT) setting. Though there is significant overlap between the knowledge and skills necessary to safely and effectively provide care in the IFT and prehospital settings, the IFT care environment requires physicians to develop several additional competencies beyond those that are expected of traditional EMS clinicians. NAEMSP first published recommendations regarding what some of these competencies should be in 1983 and subsequently updated those recommendations in 2002. This document is an updated work, given the evolution of the field.

Novel estimation of African swine fever transmission parameters within smallholder villages in Lao P.D.R.

African Swine Fever (ASF) disease transmission parameters are crucial for making response and control decisions when faced with an outbreak, yet they are poorly quantified for smallholder and village contexts within Southeast Asia. Whilst disease-specific factors - such as latent and infectious periods - should remain reasonably consistent, host, environmental and management factors are likely to affect the rate of disease spread. These differences are investigated using Approximate Bayesian Computation with Sequential Monte-Carlo methods to provide disease parameter estimates in four naïve pig populations in villages of Lao People's Democratic Republic. The villages represent smallholder pig farmers of the Northern province of Oudomxay and the Southern province of Savannakhet, and the model utilised field mortality data to validate the transmission parameter estimates over the course of multiple model generations. The basic reproductive number between-pigs was estimated to range from 3.08 to 7.80, whilst the latent and infectious periods were consistent with those published in the literature for similar genotypes in the region (4.72 to 6.19 days and 2.63 to 5.50 days, respectively). These findings demonstrate that smallholder village pigs interact similarly to commercial pigs, however the spread of disease may occur slightly slower than in commercial study groups. Furthermore, the findings demonstrated that despite diversity across the study groups, the disease behaved in a consistent manner. This data can be used in disease control programs or for future modelling of ASF in smallholder contexts.

Risankizumab Effectiveness and Safety in Crohn's Disease: Real-world Data From a Large Tertiary Center.

L23 is a recognized cytokine involved in the pathogenesis of inflammatory bowel diseases (IBDs).1 The first IL23-targeting agent that became available for clinical use in IBD was Ustekinumab, a monoclonal antibody that targets p40, a shared subunit of both IL23 and IL12.2,3 Risankizumab (Skyrizi; Abbvie) is a humanized IgG1 monoclonal antibody which binds to the p19 subunit and therefore selectively inhibits IL23.4 In June 2022, it was approved by the United States Food and Drug Administration for the treatment of moderately to severely active Crohn's disease (CD). Here, we describe the effectiveness and safety of risankizumab throughout the induction period in a real-world setting of a large tertiary center.

Ozanimod in the Treatment of Ulcerative Colitis: Initial Real-World Data From a Large Tertiary Center.

Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon and rectum. Long-term therapy is generally required to achieve and maintain disease control.1 In May 2021 the US Food and Drug Administration approved the use of ozanimod in patients with moderate to severe UC. We describe the first report of the use of ozanimod in real-world clinical practice.

Upadacitinib Is Effective and Safe in Both Ulcerative Colitis and Crohn's Disease: Prospective Real-World Experience.

BACKGROUND & AIMS: Upadacitinib is a novel selective Janus kinase 1 inhibitor that has shown efficacy in the treatment of moderate to severe ulcerative colitis (UC) and Crohn's disease (CD), and has received Food and Drug Administration approval for UC. We report a large real-world experience with upadacitinib in UC and CD. METHODS: We performed a prospective analysis of clinical outcomes on upadacitinib in patients with UC and CD using predetermined intervals at weeks 0, 2, 4, and 8 as part of a formalized treatment protocol at our institution. We used the Simple Clinical Colitis Activity Index and the Harvey-Bradshaw index, as well as C-reactive protein and fecal calprotectin to assess efficacy, and also recorded treatment-related adverse events and serious adverse events. RESULTS: A total of 105 patients were followed up for 8 weeks on upadacitinib, 84 of whom (44 UC patients, 40 CD patients) were initiated because of active luminal or perianal disease and included in the analysis. One hundred percent previously received anti-tumor necrosis factor therapy, and 89.3% had received 2 or more advanced therapies. At 4 and 8 weeks of treatment for UC, 19 of 25 (76.0%) and 23 of 27 (85.2%) achieved clinical response and 18 of 26 (69.2%) and 22 of 27 (81.5%) achieved clinical remission, respectively. Of those who previously were tofacitinib-exposed, 7 of 9 (77.8%) achieved clinical remission by 8 weeks. In CD, 13 of 17 (76.5.%) achieved clinical response and 12 of 17 (70.6%) achieved clinical remission by 8 weeks. Of those with increased fecal calprotectin and C-reactive protein levels, 62% and 64% normalized by week 8, respectively. Results were seen as early as week 2 in both UC and CD, with clinical remission rates of 36% and 56.3.%, respectively. Acne was the most commonly reported adverse event, occurring in 24 of 105 patients (22.9%). CONCLUSIONS: In this large real-world experience in medically resistant patients with UC or CD, we report that upadacitinib is rapidly effective and safe, including in those who had prior tofacitinib exposure. This study was approved by the Institutional Review Board at the University of Chicago (IRB20-1979).

Prospective Cohort Study to Investigate the Safety of Preoperative Tumor Necrosis Factor Inhibitor Exposure in Patients With Inflammatory Bowel Disease Undergoing Intra-abdominal Surgery.

BACKGROUND & AIMS: Whether preoperative treatment of inflammatory bowel disease (IBD) with tumor necrosis factor inhibitors (TNFis) increases the risk of postoperative infectious complications remains controversial. The primary aim of this study was to determine whether preoperative exposure to TNFis is an independent risk factor for postoperative infectious complications within 30 days of surgery. METHODS: We conducted a multicenter prospective observational study of patients with IBD undergoing intra-abdominal surgery across 17 sites from the Crohn's & Colitis Foundation Clinical Research Alliance. Infectious complications were categorized as surgical site infections (SSIs) or non-SSIs. Current TNFi exposure was defined as use within 12 weeks of surgery, and serum was collected for drug-level analyses. Multivariable models for occurrence of the primary outcome, any infection, or SSI were adjusted by predefined covariates (age, sex, preoperative steroid use, and disease type), baseline variables significantly associated (P < .05) with any infection or SSI separately, and TNFi exposure status. Exploratory models used TNFi exposure based on serum drug concentration. RESULTS: A total of 947 patients were enrolled from September 2014 through June 2017. Current TNFi exposure was reported by 382 patients. Any infection (18.1% vs 20.2%, P = .469) and SSI (12.0% vs 12.6%, P = .889) rates were similar in patients currently exposed to TNFis and those unexposed. In multivariable analysis, current TNFi exposure was not associated with any infection (odds ratio, 1.050; 95% confidence interval, 0.716-1.535) or SSI (odds ratio, 1.249; 95% confidence interval, 0.793-1.960). Detectable TNFi drug concentration was not associated with any infection or SSI. CONCLUSIONS: Preoperative TNFi exposure was not associated with postoperative infectious complications in a large prospective multicenter cohort.

Raptorial appendages of the Cambrian apex predator Anomalocaris canadensis are built for soft prey and speed.

The stem-group euarthropod Anomalocaris canadensis is one of the largest Cambrian animals and is often considered the quintessential apex predator of its time. This radiodont is commonly interpreted as a demersal hunter, responsible for inflicting injuries seen in benthic trilobites. However, controversy surrounds the ability of A. canadensis to use its spinose frontal appendages to masticate or even manipulate biomineralized prey. Here, we apply a new integrative computational approach, combining three-dimensional digital modelling, kinematics, finite-element analysis (FEA) and computational fluid dynamics (CFD) to rigorously analyse an A. canadensis feeding appendage and test its morphofunctional limits. These models corroborate a raptorial function, but expose inconsistencies with a capacity for durophagy. In particular, FEA results show that certain parts of the appendage would have experienced high degrees of plastic deformation, especially at the endites, the points of impact with prey. The CFD results demonstrate that outstretched appendages produced low drag and hence represented the optimal orientation for speed, permitting acceleration bursts to capture prey. These data, when combined with evidence regarding the functional morphology of its oral cone, eyes, body flaps and tail fan, suggest that A. canadensis was an agile nektonic predator that fed on soft-bodied animals swimming in a well-lit water column above the benthos. The lifestyle of A. canadensis and that of other radiodonts, including plausible durophages, suggests that niche partitioning across this clade influenced the dynamics of Cambrian food webs, impacting on a diverse array of organisms at different sizes, tiers and trophic levels.

Diagnosis, treatment, and outcome of patients with oesophagogastric cancer during the COVID-19 pandemic: national study.

BACKGROUND: The national response to COVID-19 has had a significant impact on cancer services. This study investigated the effect of national lockdown on diagnosis, management, and outcomes of patients with oesophagogastric cancers in Scotland. METHODS: This retrospective cohort study included consecutive new patients presenting to regional oesophagogastric cancer multidisciplinary teams in National Health Service Scotland between October 2019 and September 2020. The study interval was divided into before and after lockdown, based on the first UK national lockdown. Electronic health records were reviewed and results compared. RESULTS: Some 958 patients with biopsy-proven oesophagogastric cancer in 3 cancer networks were included: 506 (52.8 per cent) before and 452 (47.2 per cent) after lockdown. Median age was 72 (range 25-95) years and 630 patients (65.7 per cent) were men. There were 693 oesophageal (72.3 per cent) and 265 gastric (27.7 per cent) cancers. Median time to gastroscopy was 15 (range 0-337) days before versus 19 (0-261) days after lockdown (P < 0.001). Patients were more likely to present as an emergency after lockdown (8.5 per cent before versus 12.4 per cent after lockdown; P = 0.005), had poorer Eastern Cooperative Oncology group performance status, were more symptomatic, and presented with a higher stage of disease (stage IV: 49.8 per cent before versus 58.8 per cent after lockdown; P = 0.04). There was a shift to treatment with non-curative intent (64.6 per cent before versus 77.4 per cent after lockdown; P < 0.001). Median overall survival was 9.9 (95 per cent c.i. 8.7 to 11.4) months before and 6.9 (5.9 to 8.3) months after lockdown (HR 1.26, 95 per cent c.i. 1.09 to 1.46; P = 0.002). CONCLUSION: This national study has highlighted the adverse impact of COVID-19 on oesophagogastric cancer outcomes in Scotland. Patients presented with more advanced disease and a shift towards treatment with non-curative intent was observed, with a subsequent negative impact on overall survival.