Computer assisted surgical anatomy mapping (CASAM) of the distal Posterior Interosseous Nerve (PIN) and its relation to the wrist arthroscopy portals: A cadaver study.

Introduction: The distal Posterior Interosseous Nerve (PIN) plays an important part in the sensory innervation of the wrist joint. Introduction of the arthroscopy portals during wrist arthroscopy might injure the PIN. The anatomic variation in the trajectory of the PIN and the proximity to the dorsal arthroscopy portals have not yet been fully explored. Materials and methods: Computer assisted surgical anatomy mapping (CASAM) is a technique to digitally compute and merge photographic images using anatomic landmarks and visualize variation in anatomy. A standard wrist arthroscopy procedure was carried out on eight cadaver forearms. CASAM was used to map the trajectory of the distal PIN and measure the distance to bony landmarks and the nearest wrist arthroscopy portals. Descriptive statistics were provided for anatomical measurements. Results: CASAM illustrated great variation in the PIN trajectories between the specimens. The mean distance from the PIN to Lister's tubercle was 9 â€‹mm (range 3-14, SD 3.9), the distance to the ulnar styloid was 27 â€‹mm (range 23-32, SD 3.3). None of the nerves showed signs of iatrogenic injury from placement of the arthroscopy portals. The 3-4 portal and the 6R portal were closest to the PIN with a respective mean distance of 9 â€‹mm (range 4-15, SD 3.8) and 19 â€‹mm (range 13-22, SD 3.2). Conclusion: CASAM demonstrated the importance of understanding nerve anatomy variations and offered insight into which arthroscopy portals are most likely to damage the distal PIN. However, we conclude that the overall risk of PIN injury from wrist arthroscopy is low due to the proximity to the portals.

The seroprevalence of SARS-CoV-2-specific antibodies in Australian children: A cross-sectional study.

BACKGROUND: Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated. OBJECTIVE: To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years. METHODS: We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. Spike and nucleocapsid seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework. RESULTS: Blood was collected from 2,046 participants (median age: 6.6 years). The overall adjusted seroprevalence of spike-antibody was 92.1% (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence was similar across geographic remoteness index and socioeconomic quintiles. Nucleocapsid antibody seroprevalence increased with age while the point seroprevalence of the spike antibody seroprevalence decreased in the first year of life and then increased to 97.8 (95% Crl 96.1-99.2) by 12-15 years of age. CONCLUSION: Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia.

Whole-of-Life Inclusion in Bayesian Adaptive Platform Clinical Trials.

Importance: There is a recognized unmet need for clinical trials to provide evidence-informed care for infants, children and adolescents. This Special Communication outlines the capacity of 3 distinct trial design strategies, sequential, parallel, and a unified adult-pediatric bayesian adaptive design, to incorporate children into clinical trials and transform this current state of evidence inequity. A unified adult-pediatric whole-of-life clinical trial is demonstrated through the Staphylococcus aureus Network Adaptive Platform (SNAP) trial. Observations: Bayesian methods provide a framework for synthesizing data in the form of a probability model that can be used in the design and analysis of a clinical trial. Three trial design strategies are compared: (1) a sequential adult-pediatric bayesian approach that involves a separate, deferred pediatric trial that incorporates existing adult trial data into the analysis model to potentially reduce the pediatric trial sample size; (2) a parallel adult-pediatric bayesian trial whereby separate pediatric enrollment occurs in a parallel trial, running alongside an adult randomized clinical trial; and (3) a unified adult-pediatric bayesian adaptive design that supports the enrollment of both children and adults simultaneously in a whole-of-life bayesian adaptive randomized clinical trial. The SNAP trial whole-of-life design uses a bayesian hierarchical model that allows information sharing (also known as borrowing) between trial age groups by linking intervention effects of children and adults, thereby improving inference in both groups. Conclusion and Relevance: Bayesian hierarchical models may provide more precision for estimates of safety and efficacy of treatments in trials with heterogenous populations compared to traditional methods of analysis. They facilitate the inclusion of children in clinical trials and a shift from children deemed therapeutic orphans to the vision of no child left behind in clinical trials to ensure evidence for clinical practice exists across the life course. The SNAP trial provides an example of a bayesian adaptive whole-of-life inclusion design that enhances trial population inclusivity and diversity overall, as well as generalizability and translation of findings into clinical practice.

Scaling up ocean conservation through recognition of key biodiversity areas in the Southern Ocean from multispecies tracking data.

Biodiversity is critical for maintaining ecosystem function but is threatened by increasing anthropogenic pressures. In the Southern Ocean, a highly biologically productive region containing many endemic species, proactive management is urgently needed to mitigate increasing pressures from fishing, climate change, and tourism. Site-based conservation is one important tool for managing the negative impacts of human activities on ecosystems. The Key Biodiversity Area (KBA) Standard is a standardized framework used to define sites vital for the persistence of global biodiversity based on criteria and quantitative thresholds. We used tracking data from 14 species of Antarctic and subantarctic seabirds and pinnipeds from the publicly available Retrospective Analysis of Antarctic Tracking Data (RAATD) data set to define KBAs for a diverse suite of marine predators. We used track2kba, an R package that supports identification of KBAs from telemetry data through identification of highly used habitat areas and estimates of local abundance within sites. We compared abundance estimates at each site with thresholds for KBA criteria A1, B1, and D1 (related to globally threatened species, individual geographically restricted species, and demographic aggregations, respectively). We identified 30 potential KBAs for 13 species distributed throughout the Southern Ocean that were vital for each individual species, population, and life-history stage for which they were determined. These areas were identified as highly used by these populations based on observational data and complement the ongoing habitat modeling and bioregionalization work that has been used to prioritize conservation areas in this region. Although further work is needed to identify potential KBAs based on additional current and future data sets, we highlight the benefits of utilizing KBAs as part of a holistic approach to marine conservation, given their significant value as a global conservation tool.

Ampliación de la conservación oceánica por medio del reconocimiento de áreas importantes de biodiversidad en el Océano Antártico a partir de datos de rastreo de varias especies Resumen La biodiversidad es fundamental para mantener la función de los ecosistemas, pero está amenazada por las crecientes presiones antropogénicas. En el Océano Antártico, una región con mucha producción biológica que contiene numerosas especies endémicas, se necesita urgentemente una gestión proactiva para mitigar las crecientes presiones de la pesca, el cambio climático y el turismo. La conservación basada en el sitio es una herramienta importante para gestionar los efectos negativos de las actividades humanas en los ecosistemas. El Estándar de Áreas Clave para la Biodiversidad (ACB) es un marco estandarizado que se utiliza para definir lugares vitales para la persistencia de la biodiversidad mundial con base en criterios y umbrales cuantitativos. Usamos datos del seguimiento de 14 especies de aves marinas y pinnípedos antárticos y sub­antárticos del conjunto de datos públicos Retrospective Analysis of Antarctic Tracking Data (RAATD) para definir las ACB de un conjunto diverso de depredadores marinos. Utilizamos track2kba, un paquete de R que permite la identificación de ACB a partir de datos telemétricos mediante la identificación de áreas de hábitat altamente utilizadas y estimaciones de abundancia local dentro de los sitios. Comparamos las estimaciones de abundancia en cada lugar con los umbrales de los criterios A1, B1 y D1 de las ACB (relacionados con especies amenazadas a nivel mundial, especies individuales restringidas geográficamente y agregaciones demográficas, respectivamente). Identificamos 30 ACB potenciales para 13 especies distribuidas por todo el Océano Antártico que eran vitales para cada especie individual, población y etapa del ciclo biológico para las que se determinaron. Estas áreas fueron identificadas como muy utilizadas por estas poblaciones con base a datos observacionales y complementan el trabajo en curso de modelos del hábitat y biorregionalización que se ha utilizado para priorizar las áreas de conservación en esta región. Aunque es necesario seguir trabajando para identificar posibles ACB basadas en conjuntos de datos adicionales actuales y futuros, destacamos los beneficios de utilizar las ACB como parte de un enfoque holístico de la conservación marina, dado su importante valor como herramienta de conservación global.

CARDIOVASCULAR AND HEMATOLOGICAL RESPONSES TO A DRY DYNAMIC APNEA IN BREATH HOLD DIVERS.

The mammalian dive reflex, characterized by bradycardia and peripheral vasoconstriction, occurs in all mammals, including humans, in response to apnea. However, the dive reflex to a single, maximal, dry, dynamic apnea (DYN), and how it compares to a time-matched exercise control trial (EX) or dry static apnea (SA), has not been studied. We examined the hypotheses that, compared to EX and SA, the magnitude of the (a) cardiovascular response and (b) hematological response to DYN would be greater. Cardiovascular parameters (heart rate [HR], systolic [SBP], diastolic [DBP], and mean arterial [MAP] blood pressure) were continuously collected in twenty-three (F=6) moderate and elite freedivers, first during a maximal DYN, then during a time-matched SA and EX on a swimming ergometer in randomized order. Venous blood draws were made prior to and following each trial. The change in calculated oxygen saturation (DYN:-17±13%, EX:-2±1%, ΔSA:-2±1%;P<0.05, all comparisons) was greater during DYN compared to EX and SA. During DYN, ΔSBP (DYN:104±31mmHg, EX:38±23mmHg, SA:20±11mmHg), ΔDBP (DYN:45±12mmHg, EX:14±10mmHg, SA:15±8mmHg) and ΔMAP (DYN:65±17mmHg EX:22±13mmHg, SA:16±9mmHg) were increased compared to EX and SA, while ΔHR was greater during EX (DYN:-24±23bpm, EX:33±13bpm, SA:-1±10bpm) than either DYN or SA (P<0.0001, all comparisons). Females had greater pressor response to EX (ΔSBP:59±30mmHg, ΔDBP:24±14mmHg, ΔMAP:35±8mmHg) than males (ΔSBP:31±15mmHg, ΔDBP:11±6mmHg, ΔMAP:18±8mmHg; P<0.01, all comparisons). Together, these data indicate that DYN elicits a distinct, exaggerated cardiovascular response compared to EX or SA alone.

Long-term liver-related outcomes and liver stiffness progression of statin usage in steatotic liver disease.

BACKGROUND: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD). AIM: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD. METHODS: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD. RESULTS: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074). CONCLUSIONS: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD.

Circulating extracellular vesicle-derived miR-1299 disrupts hepatic glucose homeostasis by targeting the STAT3/FAM3A axis in gestational diabetes mellitus.

BACKGROUND: Extracellular vesicles (EVs) are membrane-enclosed structures containing lipids, proteins, and RNAs that play a crucial role in cell-to-cell communication. However, the precise mechanism through which circulating EVs disrupt hepatic glucose homeostasis in gestational diabetes mellitus (GDM) remains unclear. RESULTS: Circulating EVs isolated from human plasma were co-cultured with mammalian liver cells to investigate the potential induction of hepatic insulin resistance by GDM-EVs using glucose output assays, Seahorse assays, metabolomics, fluxomics, qRT-PCR, bioinformatics analyses, and luciferase assays. Our findings demonstrated that hepatocytes exposed to GDM-EVs exhibited increased gluconeogenesis, attenuated energy metabolism, and upregulated oxidative stress. Particularly noteworthy was the discovery of miR-1299 as the predominant miRNA in GDM-EVs, which directly targeting the 3'-untranslated regions (UTR) of STAT3. Our experiments involving loss- and gain-of-function revealed that miR-1299 inhibits the insulin signaling pathway by regulating the STAT3/FAM3A axis, resulting in increased insulin resistance through the modulation of mitochondrial function and oxidative stress in hepatocytes. Moreover, experiments conducted in vivo on mice inoculated with GDM-EVs confirmed the development of glucose intolerance, insulin resistance, and downregulation of STAT3 and FAM3A. CONCLUSIONS: These results provide insights into the role of miR-1299 derived from circulating GDM-EVs in the progression of insulin resistance in hepatic cells via the STAT3/FAM3A axis and downstream metabolic reprogramming.

Glycated haemoglobin is a major predictor of disease severity in patients with NAFLD.

OBJECTIVES: Currently, non-invasive scoring systems to stage the severity of non-alcoholic fatty liver disease (NAFLD) do not consider markers of glucose control (glycated haemoglobin, HbA1c); this study aimed to define the relationship between HbA1c and NAFLD severity in patients with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were obtained from 857 patients with liver biopsy staged NAFLD. Generalized-linear models and binomial regression analysis were used to define the relationships between histological NAFLD severity, age, HbA1c, and BMI. Paired biopsies from interventional studies (n = 421) were used to assess the impact of change in weight, HbA1c and active vs. placebo treatment on improvements in steatosis, non-alcoholic steatohepatitis (NASH), and fibrosis. RESULTS: In the discovery cohort (n = 687), risk of severe steatosis, NASH and advanced fibrosis correlated positively with HbA1c, after adjustment for obesity and age. These data were endorsed in a separate validation cohort (n = 170). Predictive modelling using HbA1c and age was non-inferior to the established non-invasive biomarker, Fib-4, and allowed the generation of HbA1c, age, and BMI adjusted risk charts to predict NAFLD severity. Following intervention, reduction in HbA1c was associated with improvements in steatosis and NASH after adjustment for weight change and treatment, whilst fibrosis change was only associated with weight change and treatment. CONCLUSIONS: HbA1c is highly informative in predicting NAFLD severity and contributes more than BMI. Assessments of HbA1c must be a fundamental part of the holistic assessment of patients with NAFLD and, alongside age, can be used to identify patients with highest risk of advanced disease.

Redefining Cardiac Involvement and Targets of Treatment in Systemic Immunoglobulin AL Amyloidosis.

Importance: Cardiac amyloid infiltration is the key determinant of survival in systemic light-chain (AL) amyloidosis. Current guidelines recommend early switching therapy in patients with a nonoptimal or suboptimal response regardless of the extent of cardiac amyloid infiltration. Objective: To assess the differences between serum biomarkers, echocardiography, and cardiovascular magnetic resonance (CMR) with extracellular volume (ECV) mapping in characterizing cardiac amyloid, the independent prognostic role of these approaches, and the role of ECV mapping to guide treatment strategies. Design, Setting, and Participants: Consecutive patients newly diagnosed with systemic AL amyloidosis (2015-2021) underwent echocardiography, cardiac biomarkers, and CMR with ECV mapping at diagnosis. Data were analyzed from January to June 2024. Main Outcomes and Measures: The primary outcomes of the study were all-cause mortality and hematological response as defined according to validated criteria: no response (NR), partial response (PR), very good partial response (VGPR), and complete response (CR). Secondary outcomes were the depth and speed of hematological response and overall survival according to ECV. Results: Of 560 patients with AL amyloidosis, the median (IQR) age was 68 years (59-74 years); 346 patients were male (61.8%) and 214 female (38.2%). Over a median (IQR) 40.5 months 9-58 months), ECV was independently associated with mortality. In the landmark analysis at 1 month, long-term survival was independent of the achieved hematological response in ECV less than 0.30% and ECV of 0.31% to 0.40%, while it was dependent on the depth of the hematological response in ECV greater than 0.40%. In the landmark analysis at 6 months, survival was independent of the achieved hematological response in ECV less than 0.30% and dependent on achieving at least PR in ECV of 0.31% to 0.40%. Survival was dependent on achieving CR in ECV of 0.41% to 0.50% and ECV greater than 0.50%. Achieving a deep hematological response at 1 month was associated with better survival compared with 6 months in patients with ECV greater than 0.40% but not with ECV less than 0.40%. Conclusions and Relevance: This study found that ECV mapping, in systemic AL amyloidosis, is an independent predictor of prognosis, can help define the hematological response associated with better long-term outcomes for each patient and potentially inform treatment strategies.

Isotopic signature of plutonium accumulated in cryoconite on glaciers worldwide.

Glaciers are recognized as repositories for atmospheric pollutants, however, due to climate change and enhanced melting rates, they are rapidly transitioning from being repositories to secondary sources of such apollutants. Artificial radionuclides are one of the pollutants found on glaciers that efficiently accumulate onto glacier surfaces within cryoconite deposits; a dark, often biogenic sediment. This work provides information about the accumulation, distribution and sources of plutonium (Pu) isotopes in cryoconite samples from glaciers worldwide. Plutonium is an artificial radionuclide spread into the environment in the last decades as a consequence of nuclear test explosions, accidents and nuclear fuel re-processing. Samples collected from 49 glaciers across nine regions of Earth are considered. Activity concentrations of plutonium in cryoconite are orders of magnitude higher than in other environmental matrices typically used for environmental monitoring (e.g. lichens, mosses, soils and sediments), particularly in the Northern Hemisphere. Isotopic ratios indicate that plutonium contamination of cryoconite is dominated by the global signal of stratospheric fallout related to atmospheric nuclear tests. However, specific glaciers in Svalbard reveal a signature compatible with a contribution from the re-entry of the SNAP-9A satellite in 1964, which was equipped with a 238Pu radioisotope thermoelectric generator. Similarly, an excess of 238Pu is observed in cryoconite from the Exploradores Glacier (Chile). This could be associated with the November 1996 crash of the automatic Interplanetary Station "Mars '96" which was carrying a 238Pu thermoelectric generator. This is the first time ever that an isotopic evidence for this event is reported. These findings highlight the role that cryoconite can play in reconstructing the radioactive contamination history of different glaciated regions of the Earth.

Post COVID-19 conditions in an Australian pediatric cohort, 3 months following a Delta outbreak.

BACKGROUND: Pediatric long COVID remains incompletely understood with scant Australian data available. We aimed to assess the impacts of the 2021 Delta variant of SARS-CoV-2 outbreak on symptoms and functioning 12 weeks post-acute infection in a cohort of children and adolescents. METHODS: The parents/carers of 11,864 patients with PCR-confirmed SARS-CoV-2 were invited, via email or text message, to complete an online survey assessing symptoms and functional impairment. FINDINGS: 1731 (17.6%) responded to the survey. 203 (11.7%) reported continued symptoms and/or functional impairment which were flagged for clinical review, all others reported recovery. Of the 169 subsequently clinically reviewed, 63 had already recovered (37.3%) and 17 had exacerbation of pre-existing condition(s) (10.1%); 63 (37.3%) were diagnosed with a Post COVID Condition (PCC). Of these, 21 (12.4%) were considered to have features compatible with the United Kingdom consensus cases definition for Long COVID. INTERPRETATION: During an outbreak of SARS-CoV-2 an online questionnaire with subsequent clinical review revealed self-reported non-recovery at 12 weeks in a minority of cases, with a spectrum of features. Long COVID comprised only a subset of cases with self-reported non-recovery, and is infrequent in children and adolescents, but still comprises a likely significant burden that warrants attention. IMPACT: Our study provides the only comprehensive estimate of the frequency and spectrum of post-COVID conditions in children from Australia. The high frequency of self-reported recovery, and low frequency of Long COVID compatible illness adds to the literature from other settings. Risk factors for post-COVID conditions in children are identified and include: age >11 year, and previous medical co-morbidity.

The attenuation of gut microbiota-derived short-chain fatty acids elevates lipid transportation through suppression of the intestinal HDAC3-H3K27ac-PPAR-γ axis in gestational diabetes mellitus.

Gut flora is considered to modulate lipid transport from the intestine into the bloodstream, and thus may potentially participate in the development of GDM. Although previous studies have shown that the intestinal microbiota influences lipid transport and metabolism in GDM, the precise mechanisms remain elusive. To address this, we used a high-fat diet (HFD)-induced GDM mouse model and conducted 16s rRNA sequencing and fecal metabolomics to assess gut microbial community shifts and associated metabolite changes. Western blot, ELISA, and chromatin immunoprecipitation (ChIP) were utilized to elucidate how gut microbiota affect intestinal lipid transport and the insulin sensitivity of hepatic, adipose, and skeletal muscle tissues. We found that HFD impaired the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) in pregnant mice. 16s rRNA sequencing demonstrated profound compositional changes, especially in the relative abundances of Firmicutes and Bacteroidetes. Metabolomics analysis presented a decline in the concentration of short-chain fatty acids (SCFAs) in the GDM group. Western blot analyses showed an upregulation of HDAC3 and a concurrent reduction in H3K27 acetylation in the intestine. ChIP-qPCR showed that PPAR-γ was inhibited, which in turn activated lipid-transporter CD36. ELISA and insulin signaling pathway detection in insulin-target organs showed high concentrations of circulating fatty acids and triglycerides and insulin resistance in insulin-target organs. Our results suggest that gut microbiota is closely associated with the development of GDM, partly because decreased gut flora-associated SCFAs activate CD36 by suppressing the HDAC3-H3K27ac-PPAR-γ axis to transport excessive fatty acids and triglycerides into blood circulation, thereby dysregulating the insulin sensitivity of insulin target organs.

Evidence for direct CO2 -mediated alterations in cerebral oxidative metabolism in humans.

AIM: How the cerebral metabolic rates of oxygen and glucose utilization (CMRO2 and CMRGlc, respectively) are affected by alterations in arterial PCO2 (PaCO2) is equivocal and therefore was the primary question of this study. METHODS: This retrospective analysis involved pooled data from four separate studies, involving 41 healthy adults (35 males/6 females). Participants completed stepwise steady-state alterations in PaCO2 ranging between 30 and 60 mmHg. The CMRO2 and CMRGlc were assessed via the Fick approach (CBF × arterial-internal jugular venous difference of oxygen or glucose content, respectively) utilizing duplex ultrasound of the internal carotid artery and vertebral artery to calculate cerebral blood flow (CBF). RESULTS: The CMRO2 was altered by 0.5 mL × min-1 (95% CI: -0.6 to -0.3) per mmHg change in PaCO2 (p < 0.001) which corresponded to a 9.8% (95% CI: -13.2 to -6.5) change in CMRO2 with a 9 mmHg change in PaCO2 (inclusive of hypo- and hypercapnia). The CMRGlc was reduced by 7.7% (95% CI: -15.4 to -0.08, p = 0.045; i.e., reduction in net glucose uptake) and the oxidative glucose index (ratio of oxygen to glucose uptake) was reduced by 5.6% (95% CI: -11.2 to 0.06, p = 0.049) with a + 9 mmHg increase in PaCO2. CONCLUSION: Collectively, the CMRO2 is altered by approximately 1% per mmHg change in PaCO2. Further, glucose is incompletely oxidized during hypercapnia, indicating reductions in CMRO2 are either met by compensatory increases in nonoxidative glucose metabolism or explained by a reduction in total energy production.

ADRB2 and ADCY9 Sequence Variations in Brazilian Asthmatic Patients.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The ß2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

The impact of stigma on quality of life and liver disease burden among patients with nonalcoholic fatty liver disease.

Background & Aims: Patients with nonalcoholic fatty liver disease (NAFLD)/metabolic dysfunction-associated steatotic liver disease (MASLD) face a multifaceted disease burden which includes impaired health-related quality of life (HRQL) and potential stigmatization. We aimed to assess the burden of liver disease in patients with NAFLD and the relationship between experience of stigma and HRQL. Methods: Members of the Global NASH Council created a survey about disease burden in NAFLD. Participants completed a 35-item questionnaire to assess liver disease burden (LDB) (seven domains), the 36-item CLDQ-NASH (six domains) survey to assess HRQL and reported their experience with stigmatization and discrimination. Results: A total of 2,117 patients with NAFLD from 24 countries completed the LDB survey (48% Middle East and North Africa, 18% Europe, 16% USA, 18% Asia) and 778 competed CLDQ-NASH. Of the study group, 9% reported stigma due to NAFLD and 26% due to obesity. Participants who reported stigmatization due to NAFLD had substantially lower CLDQ-NASH scores (all p <0.0001). In multivariate analyses, experience with stigmatization or discrimination due to NAFLD was the strongest independent predictor of lower HRQL scores (beta from -5% to -8% of score range size, p <0.02). Experience with stigmatization due to obesity was associated with lower Activity, Emotional Health, Fatigue, and Worry domain scores, and being uncomfortable with the term "fatty liver disease" with lower Emotional Health scores (all p <0.05). In addition to stigma, the greatest disease burden as assessed by LDB was related to patients' self-blame for their liver disease. Conclusions: Stigmatization of patients with NAFLD, whether it is caused by obesity or NAFLD, is strongly and independently associated with a substantial impairment of their HRQL. Self-blame is an important part of disease burden among patients with NAFLD. Impact and implications: Patients with nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic dysfunction-associated steatotic liver disease (MASLD), may experience impaired health-related quality of life and stigmatization. Using a specifically designed survey, we found that stigmatization of patients with NAFLD, whether it is caused by obesity or the liver disease per se, is strongly and independently associated with a substantial impairment of their quality of life. Physicians treating patients with NAFLD should be aware of the profound implications of stigma, the high prevalence of self-blame in the context of this disease burden, and that providers' perception may not adequately reflect patients' perspective and experience with the disease.

Liver Disease as a Potential Risk Factor for Colorectal Cancer: A Community Hospital Experience.

BACKGROUND: Liver disease (LD) is a common pathology worldwide. Many patients remain asymptomatic and undiagnosed. Colorectal cancer (CRC) is a prevalent neoplasm and a leading cause of cancer-related deaths globally. Multiple studies suggest that inflammation in the liver could drive the initiation of colorectal cancer. METHODS: This five-year (2018-2022) case-control study included 274 patients diagnosed with CRC and adenomas at a community hospital in Houston, Texas. Each patient's medical record was reviewed for pre-existing LD, including steatosis, cirrhosis, primary biliary cirrhosis, and Hepatitis B and C infections. This study aims to investigate the association between LD and CRC risk and assess differences by gender, race, and ethnicity. The study cohort comprised 124 (45.3%) women and 150 (54.7%) men. Data were compared and analyzed using a Chi-squared test for independence and binomial logistic regression. A p-value of < 0.05 was considered statistically significant.  Results: Patients with LD had a two-fold increase in the odds of developing CRC compared to those without LD, in both univariate and multivariate analyses (OR 2.13 {95% CI 1.30-3.49}, p = 0.003 / OR 2.30 {95% CI 1.37-3.87}, p = 0.002, respectively). The chi-square test revealed that the association between CRC and LD was stronger in women than in men (p = 0.018 and p = 0.056, respectively). CONCLUSION: Our study establishes a positive correlation between LD and CRC development, suggesting LD is a potential risk factor for CRC, particularly in women. Future research directions include exploring the underlying mechanisms of this association, evaluating the utility of early CRC screening in individuals with LD, and assessing the impact of interventions targeting LD on CRC incidence and mortality.

Randomized controlled trial of intermittent hypoxia in Parkinson's disease: study rationale and protocol.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disease for which no disease-modifying therapies exist. Preclinical and clinical evidence suggest that repeated exposure to intermittent hypoxia might have short- and long-term benefits in PD. In a previous exploratory phase I trial, we demonstrated that in-clinic intermittent hypoxia exposure is safe and feasible with short-term symptomatic effects on PD symptoms. The current study aims to explore the safety, tolerability, feasibility, and net symptomatic effects of a four-week intermittent hypoxia protocol, administered at home, in individuals with PD. METHODS/DESIGN: This is a two-armed double-blinded randomized controlled trial involving 40 individuals with mild to moderate PD. Participants will receive 45 min of normobaric intermittent hypoxia (fraction of inspired oxygen 0.16 for 5 min interspersed with 5 min normoxia), 3 times a week for 4 weeks. Co-primary endpoints include nature and total number of adverse events, and a feasibility-tolerability questionnaire. Secondary endpoints include Movement Disorders Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part II and III scores, gait tests and biomarkers indicative of hypoxic dose and neuroprotective pathway induction. DISCUSSION: This trial builds on the previous phase I trial and aims to investigate the safety, tolerability, feasibility, and net symptomatic effects of intermittent hypoxia in individuals with PD. Additionally, the study aims to explore induction of relevant neuroprotective pathways as measured in plasma. The results of this trial could provide further insight into the potential of hypoxia-based therapy as a novel treatment approach for PD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05948761 (registered June 20th, 2023).

Response rates to second-line treatment with daratumumab bortezomib dexamethasone (DVD) in relapsed/refractory light chain amyloidosis (AL) after initial Bortezomib-based regime.

Bortezomib is regularly used as frontline therapy for systemic AL amyloidosis. We assess the efficacy of second-line daratumumab-bortezomib-dexamethasone (DVD) in AL amyloidosis in bortezomib-exposed patients. A total of 116 patients treated with second-line DVD were identified from a prospective observational study of newly diagnosed AL amyloidosis (ALchemy). DVD was initiated in both the relapsed setting or where there was an inadequate response defined as very good partial response (VGPR) or VGPR with organ progression/lack of organ improvement. A complete response (CR)/VGPR to second-line DVD was achieved in 81 (69.8%) patients. A CR/VGPR was achieved in 67 (79.7%) in those who achieved a VGPR/CR to first line versus 14/32 (43.8%) in those who did not. Where DVD was initiated due to an inadequate response to first line (vs. at relapse), the median event-free survival (EFS) was 18 vs. 34 months (p = 0.002). If a CR/VGPR was achieved to DVD, the 2-year EFS was still lower in those with prior inadequate response 54% vs. 66% (p = 0.062). DVD is an efficacious second-line treatment in systemic AL amyloidosis in a bortezomib-exposed population. However, the response to DVD is poorer in those with an inadequate response to first-line bortezomib.

A Phase 2 Randomized Trial of Survodutide in MASH and Fibrosis.

BACKGROUND: Dual agonism of glucagon receptor and glucagon-like peptide-1 (GLP-1) receptor may be more effective than GLP-1 receptor agonism alone for treating metabolic dysfunction-associated steatohepatitis (MASH). The efficacy and safety of survodutide (a dual agonist of glucagon receptor and GLP-1 receptor) in persons with MASH and liver fibrosis are unclear. METHODS: In this 48-week, phase 2 trial, we randomly assigned adults with biopsy-confirmed MASH and fibrosis stage F1 through F3 in a 1:1:1:1 ratio to receive once-weekly subcutaneous injections of survodutide at a dose of 2.4, 4.8, or 6.0 mg or placebo. The trial had two phases: a 24-week rapid-dose-escalation phase, followed by a 24-week maintenance phase. The primary end point was histologic improvement (reduction) in MASH with no worsening of fibrosis. Secondary end points included a decrease in liver fat content by at least 30% and biopsy-assessed improvement (reduction) in fibrosis by at least one stage. RESULTS: A total of 293 randomly assigned participants received at least one dose of survodutide or placebo. Improvement in MASH with no worsening of fibrosis occurred in 47% of the participants in the survodutide 2.4-mg group, 62% of those in the 4.8-mg group, and 43% of those in the 6.0-mg group, as compared with 14% of those in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63% of the participants in the survodutide 2.4-mg group, 67% of those in the 4.8-mg group, 57% of those in the 6.0-mg group, and 14% of those in the placebo group; improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events that were more frequent with survodutide than with placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%); serious adverse events occurred in 8% with survodutide and 7% with placebo. CONCLUSIONS: Survodutide was superior to placebo with respect to improvement in MASH without worsening of fibrosis, warranting further investigation in phase 3 trials. (Funded by Boehringer Ingelheim; 1404-0043 ClinicalTrials.gov number, NCT04771273; EudraCT number, 2020-002723-11.).