Cost burden of cirrhosis and liver disease progression in metabolic dysfunction-associated steatohepatitis: A US cohort study.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis, is characterized by fat accumulation and inflammation of the liver and may result in progression to cirrhosis and liver-related events. OBJECTIVE: To characterize the impact of cirrhosis and progression to liver-related events on costs and health care resource use (HCRU) among MASH patients in the United States. METHODS: The study cohort included patients with diagnosed nonalcoholic steatohepatitis (International Classification of Diseases, Tenth Revision, Clinical Modification code K75.81) in Optum's deidentified Clinformatics Data Mart Database (October 2015 to December 2022) and were stratified by baseline cirrhosis status. Among those without cirrhosis at baseline, patients were further stratified by status of progression to cirrhosis during follow-up. Total HCRU and costs per-person per-year (PPPY) were estimated and compared descriptively between the cohorts. In addition, gamma generalized linear models were used to compare costs PPPY between those with vs without cirrhosis at baseline, as well as with vs without progression during follow-up, while adjusting for baseline patient and disease characteristics. Annual costs per person were also longitudinally modeled using gamma generalized linear mixed models to understand longitudinal changes in costs PPPY while accounting for time correlations within individual patients. Lastly, a series of sensitivity analyses were conducted to assess the impact of study design features and clinical variations of total costs PPPY. RESULTS: A total of 28,576 adults were included, and 9,157 (32.0%) had baseline cirrhosis; of the 19,419 without baseline cirrhosis, a total of 4,235 (21.8%) progressed over follow-up. Mean (SD) HCRU and costs PPPY were higher among patients with cirrhosis ($110,403 [$226,037]) than without ($28,340 [$61,472]; P < 0.01) and among those with progression ($58,128 [$102,626]) than without ($20,031 [$39,740]; P < 0.01). Costs remained significantly greater when adjusted for covariates, with a risk ratio (95% CI) of 1.99 (1.89-2.09) when comparing with vs without baseline cirrhosis and 2.28 (2.15-2.42) when comparing with vs without progression over follow-up. Costs increased with each subsequent year, to 21% by year 6 among those with cirrhosis at baseline and 49% among those without baseline cirrhosis who progressed. CONCLUSIONS: The financial burden of MASH is substantial and significantly greater among those with cirrhosis or disease progression. Although patients without cirrhosis incur lower burden, the increase over time is greater and associated with progression. Therapies that slow progression may help alleviate the financial burden, and strategies are needed to identify patients with MASH at risk of progressing to cirrhosis.

Utility of exercise testing to assess athletes for post COVID-19 myocarditis.

Purpose: This study assessed a functional protocol to identify myocarditis or myocardial involvement in competitive athletes following SARS-CoV2 infection. Methods: We prospectively evaluated competitive athletes (n = 174) for myocarditis or myocardial involvement using the Multidisciplinary Inquiry of Athletes in Miami (MIAMI) protocol, a median of 18.5 (IQR 16-25) days following diagnosis of COVID-19 infection. The protocol included biomarker analysis, ECG, cardiopulmonary stress echocardiography testing with global longitudinal strain (GLS), and targeted cardiac MRI for athletes with abnormal findings. Patients were followed for median of 148 days. Results: We evaluated 52 females and 122 males, with median age 21 (IQR: 19, 22) years. Five (2.9%) had evidence of myocardial involvement, including definite or probable myocarditis (n = 2). Three of the 5 athletes with myocarditis or myocardial involvement had clinically significant abnormalities during stress testing including ventricular ectopy, wall motion abnormalities and/or elevated VE/VCO2, while the other two athletes had resting ECG abnormalities. VO2max, left ventricular ejection fraction and GLS were similar between those with or without myocardial involvement. No adverse events were reported in the 169 athletes cleared to exercise at a median follow-up of 148 (IQR108,211) days. Patients who were initially restricted from exercise had no adverse sequelae and were cleared to resume training between 3 and 12 months post diagnosis. Conclusions: Screening protocols that include exercise testing may enhance the sensitivity of detecting COVID-19 related myocardial involvement following recovery from SARS-CoV2 infection.

Multidisciplinary team management of tracheostomy procedures in neurocritical care patients: our experience over 17 years in a quaternary centre.

OBJECTIVE: Tracheostomy in the neurocritical care population is associated with poorer outcomes. This study hypothesised that a multidisciplinary approach to tracheostomy care can improve outcomes. METHODS: This study was a prospective longitudinal study of all tracheostomised patients in the neurocritical care units of a quaternary centre over 17 years. All patients were managed by a tracheostomy team with a constant core membership of an intensive care consultant, speech and language therapist, and physiotherapist with consultant ENT input. RESULTS: A total of 51 per cent of patients were decannulated in hospital at an average of 48 (neuromedical) and 57.6 (neurosurgical) days. Of the 42 per cent of patients transferred to another facility with a tracheostomy tube in situ, 37.5 per cent were at an advanced stage of tracheostomy weaning. Complication rates were low at 4.8 per cent with no tracheostomy associated mortalities. CONCLUSION: A multidisciplinary approach can enable good outcomes in the neurocritical care population. Consistency of care spanning the step-down from critical to ward-level care is crucial to improving outcomes.

Union of the European Phoniatricians' position statement on the exit strategy of phoniatric and laryngological services: staying safe and getting back to normal after the peak of coronavirus disease 2019 (issued on 25th May 2020).

BACKGROUND: The following position statement from the Union of the European Phoniatricians, updated on 25th May 2020 (superseding the previous statement issued on 21st April 2020), contains a series of recommendations for phoniatricians and ENT surgeons who provide and/or run voice, swallowing, speech and language, or paediatric audiology services. OBJECTIVES: This material specifically aims to inform clinical practices in countries where clinics and operating theatres are reopening for elective work. It endeavours to present a current European view in relation to common procedures, many of which fall under the aegis of aerosol generating procedures. CONCLUSION: As evidence continues to build, some of the recommended practices will undoubtedly evolve, but it is hoped that the updated position statement will offer clinicians precepts on safe clinical practice.

Intravenous stem cell dose and changes in quantitative lung fibrosis and DLCO in the AETHER trial: a pilot study.

OBJECTIVE: Our purpose was to compare quantitative CT-derived changes in lung fibrosis with pulmonary function, including DLCO, in human subjects with idiopathic pulmonary fibrosis who received an injection of one of two different intravenous doses of human bone-marrow-derived mesenchymal stem cells. PATIENTS AND METHODS: Two three-subject cohorts from the AETHER trial (Allogeneic Human Cells in subjects with Idiopathic Pulmonary Fibrosis via Intravenous Delivery) underwent high-resolution CT and clinical testing at baseline, 24 weeks, and 48 weeks after injection. Cohort 1 received 2x107 stem cells, and cohort 2 received 1x108 stem cells. CT scans were quantitatively analyzed for lung fibrosis using 510K cleared validated software. The percent predicted DLCO and other pulmonary function studies were obtained. RESULTS: The cohorts were well matched in lung fibrosis at baseline as assessed by CT scan and lung function. The mean QLF in cohort 1 increased from 13.1% at baseline to 17.1% at 48 weeks, while mean QLF in cohort 2 increased from 15.4% at baseline to 16.5% at 48 weeks. The subjects in cohort 2 progressed more slowly in whole lung fibrosis by a mean of 2.87% compared with cohort 1 (p=0.001 with adjustment of baseline covariates) during the baseline to the 48-week interval. The baseline DLCO was lower in cohort 2 than in cohort 1 (p<0.0001). Over 48 weeks of the study, cohort 2 subjects demonstrated a mean DLCO decline of only 2% compared with a decline of 17% in cohort 1 subjects (p=0.02). CONCLUSIONS: In this pilot study, the subjects receiving 1x108 stem cells demonstrated slower progression in quantitative lung fibrosis and a smaller decrease in DLCO than subjects receiving 2x107 stem cells.

Rhinological interventions for obstructive sleep apnoea - a systematic review and descriptive meta-analysis.

OBJECTIVES: Obstructive sleep apnoea is a common chronic sleep disorder characterised by collapse of the upper airway during sleep. The nasal airway forms a significant part of the upper airway and any obstruction is thought to have an impact on obstructive sleep apnoea. A systematic review was performed to determine the role of rhinological surgical interventions in the management of obstructive sleep apnoea. METHODS: A systematic review of current literature was undertaken; studies were included if they involved comparison of a non-surgical and/or non-rhinological surgical intervention with a rhinological surgical intervention for treatment of obstructive sleep apnoea. RESULTS: Sixteen studies met the selection criteria. The pooled data suggest that there are reductions in the apnoea/hypopnea index and respiratory disturbance index following nasal surgery. However, the current body of studies is too heterogeneous for statistically significant meta-analysis to be conducted. CONCLUSION: Nasal surgery may have limited benefit for a subset of patients based on current evidence.

Prolonged Survival Following Pig-to-Primate Liver Xenotransplantation Utilizing Exogenous Coagulation Factors and Costimulation Blockade.

Since the first attempt of pig-to-primate liver xenotransplantation (LXT) in 1968, survival has been limited. We evaluated a model utilizing α-1,3-galactosyltransferase knockout donors, continuous posttransplant infusion of human prothrombin concentrate complex, and immunosuppression including anti-thymocyte globulin, FK-506, methylprednisone, and costimulation blockade (belatacept, n = 3 or anti-CD40 mAb, n = 1) to extend survival. Baboon 1 remained well until postoperative day (POD) 25, when euthanasia was required because of cholestasis and plantar ulcers. Baboon 2 was euthanized following a seizure on POD 5, despite normal liver function tests (LFTs) and no apparent pathology. Baboon 3 demonstrated initial stable liver function but was euthanized on POD 8 because of worsening LFTs. Pathology revealed C4d positivity, extensive hemorrhagic necrosis, and a focal cytomegalovirus inclusion. Baboon 4 was clinically well with stable LFTs until POD29, when euthanasia was again necessitated by plantar ulcerations and rising LFTs. Final pathology was C4d negative and without evidence of rejection, inflammation, or thrombotic microangiopathy. Thus, nearly 1-mo rejection-free survival has been achieved following LXT in two of four consecutive recipients, demonstrating that the porcine liver can support life in primates for several weeks and has encouraging potential for clinical application as a bridge to allotransplantation for patients with acute-on-chronic or fulminant hepatic failure.

Infection in Organ Transplantation.

The prevention, diagnosis, and management of infectious disease in transplantation are major contributors to improved outcomes in organ transplantation. The risk of serious infections in organ recipients is determined by interactions between the patient's epidemiological exposures and net state of immune suppression. In organ recipients, there is a significant incidence of drug toxicity and a propensity for drug interactions with immunosuppressive agents used to maintain graft function. Thus, every effort must be made to establish specific microbiologic diagnoses to optimize therapy. A timeline can be created to develop a differential diagnosis of infection in transplantation based on common patterns of infectious exposures, immunosuppressive management, and antimicrobial prophylaxis. Application of quantitative molecular microbial assays and advanced antimicrobial therapies have advanced care. Pathogen-specific immunity, genetic polymorphisms in immune responses, and dynamic interactions between the microbiome and the risk of infection are beginning to be explored. The role of infection in the stimulation of alloimmune responses awaits further definition. Major hurdles include the shifting worldwide epidemiology of infections, increasing antimicrobial resistance, suboptimal assays for the microbiologic screening of organ donors, and virus-associated malignancies. Transplant infectious disease remains a key to the clinical and scientific investigation of organ transplantation.

Tropospheric Emissions: Monitoring of Pollution (TEMPO).

TEMPO was selected in 2012 by NASA as the first Earth Venture Instrument, for launch between 2018 and 2021. It will measure atmospheric pollution for greater North America from space using ultraviolet and visible spectroscopy. TEMPO observes from Mexico City, Cuba, and the Bahamas to the Canadian oil sands, and from the Atlantic to the Pacific, hourly and at high spatial resolution (~2.1 km N/S×4.4 km E/W at 36.5°N, 100°W). TEMPO provides a tropospheric measurement suite that includes the key elements of tropospheric air pollution chemistry, as well as contributing to carbon cycle knowledge. Measurements are made hourly from geostationary (GEO) orbit, to capture the high variability present in the diurnal cycle of emissions and chemistry that are unobservable from current low-Earth orbit (LEO) satellites that measure once per day. The small product spatial footprint resolves pollution sources at sub-urban scale. Together, this temporal and spatial resolution improves emission inventories, monitors population exposure, and enables effective emission-control strategies. TEMPO takes advantage of a commercial GEO host spacecraft to provide a modest cost mission that measures the spectra required to retrieve ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), formaldehyde (H2CO), glyoxal (C2H2O2), bromine monoxide (BrO), IO (iodine monoxide),water vapor, aerosols, cloud parameters, ultraviolet radiation, and foliage properties. TEMPO thus measures the major elements, directly or by proxy, in the tropospheric O3 chemistry cycle. Multi-spectral observations provide sensitivity to O3 in the lowermost troposphere, substantially reducing uncertainty in air quality predictions. TEMPO quantifies and tracks the evolution of aerosol loading. It provides these near-real-time air quality products that will be made publicly available. TEMPO will launch at a prime time to be the North American component of the global geostationary constellation of pollution monitoring together with the European Sentinel-4 (S4) and Korean Geostationary Environment Monitoring Spectrometer (GEMS) instruments.

A systematic review of the surgical techniques for the treatment of internal nasal valve collapse: where do we stand?

BACKGROUND: A myriad of interventions have been described to address the restoration or preservation of the internal nasal valve, the narrowest portion of nasal airway. OBJECTIVE OF REVIEW: To review systematically available knowledge and evidence about management options of the collapse of the internal nasal valve area. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: A MEDLINE, EMBASE, Cochrane Library and CENTRAL database search, followed by extensive hand searching for the identification of relevant studies. EVALUATION METHOD: Review of all English-language studies addressing the treatment of the internal nasal valve collapse. RESULTS: Fifty-three studies were eventually identified and systematically reviewed. The majority (50 of 53) of the included articles are graded as level IV evidence and only one randomised trial was identified. The included randomised study reported no significant difference in improvement between the intervention group (autospreader flap) and placebo arms. The majority of the included studies presented in this systematic review provide level IV evidence concerning the optimal approach for cases of nasal valve collapse. Current research is driven more by reports of techniques than patient outcomes. CONCLUSIONS: Proper evaluation and identification of the cause of the internal nasal valve collapse is paramount prior to selection of the preferred surgical solution. The three-dimensional construction of the nasal valve implies that many pathologies cannot be restored by a single solution. Treatment approaches should be directed at specific involved sites. Present systematic review of the literature revealed that the available evidence is based on low-level studies and focuses more on the description of various surgical techniques rather than on patient-reported outcome measures. Future studies are needed, including homogenous patient groups, comparing different surgical techniques and incorporating patient-reported outcome measures.

The Cell Biology of Cytomegalovirus: Implications for Transplantation.

Interpretation of clinical data regarding the impact of cytomegalovirus (CMV) infection on allograft function is complicated by the diversity of viral strains and substantial variability of cellular receptors and viral gene expression in different tissues. Variation also exists in nonspecific (monocytes and dendritic cells) and specific (NK cells, antibodies) responses that augment T cell antiviral activities. Innate immune signaling pathways and expanded pools of memory NK cells and γδ T cells also serve to amplify host responses to infection. The clinical impact of specific memory T cell anti-CMV responses that cross-react with graft antigens and alloantigens is uncertain but appears to contribute to graft injury and to the abrogation of allograft tolerance. These responses are modified by diverse immunosuppressive regimens and by underlying host immune deficits. The impact of CMV infection on the transplant recipient reflects cellular changes and corresponding host responses, the convergence of which has been termed the "indirect effects" of CMV infection. Future studies will clarify interactions between CMV infection and allograft injury and will guide interventions that may enhance clinical outcomes in transplantation.

How advances in light technology have shaped ENT.

The development of light technologies, allowing anatomical visualisation of otherwise hidden structures, led to significant advances in ENT in the nineteenth and twentieth centuries. Natural light from the sun, and from candles, was initially harnessed using mirrors. Later, the invention of limelight and electricity preceded the emergence of the modern-day endoscope, which, in tandem with the discovery of coherent fibre-optics in the 1950s, significantly expanded the surgical repertoire available to otolaryngologists. This study aimed to trace the rich history of ENT through the specialty's use of light.

Mitotic phosphorylation of Bloom helicase at Thr182 is required for its proteasomal degradation and maintenance of chromosomal stability.

Mutations in Bloom helicase (BLM) lead to Bloom Syndrome (BS). BS is characterized by multiple clinical manifestations including predisposition to a wide spectrum of cancers. Studies have revealed the mechanism of BLM recruitment after stalled replication and its role during the repair of DNA damage. We now provide evidence that BLM undergoes K48-linked ubiquitylation and subsequent degradation during mitosis due to the E3 ligase, Fbw7α. Fbw7α carries out its function after GSK3ß- and CDK2/cyclin A2-dependent phosphorylation events on Thr171 and Ser175 of BLM which lies within a well-defined phosphodegron, a sequence which is conserved in all primates. Phosphorylation on BLM Thr171 and Ser175 depends on prior phosphorylation at Thr182 by Chk1/Chk2. Thr182 phosphorylation not only controls BLM ubiquitylation and degradation during mitosis but is also a determinant for its localization on the ultrafine bridges. Consequently lack of Thr182 phosphorylation leads to multiple manifestations of chromosomal instability including increased levels of DNA damage, lagging chromatin, micronuclei formation, breaks and quadriradials. Hence Thr182 phosphorylation on BLM has two functions-it regulates BLM turnover during mitosis and also helps to maintain the chromosomal stability.

Estimating surface NO2 and SO2 mixing ratios from fast-response total column observations and potential application to geostationary missions.

Total-column nitrogen dioxide (NO2) data collected by a ground-based sun-tracking spectrometer system (Pandora) and an photolytic-converter-based in-situ instrument collocated at NASA's Langley Research Center in Hampton, Virginia were analyzed to study the relationship between total-column and surface NO2 measurements. The measurements span more than a year and cover all seasons. Surface mixing ratios are estimated via application of a planetary boundary-layer (PBL) height correction factor. This PBL correction factor effectively corrects for boundary-layer variability throughout the day, and accounts for up to ≈75 % of the variability between the NO2 data sets. Previous studies have made monthly and seasonal comparisons of column/surface data, which has shown generally good agreement over these long average times. In the current analysis comparisons of column densities averaged over 90 s and 1 h are made. Applicability of this technique to sulfur dioxide (SO2) is briefly explored. The SO2 correlation is improved by excluding conditions where surface levels are considered background. The analysis is extended to data from the July 2011 DISCOVER-AQ mission over the greater Baltimore, MD area to examine the method's performance in more-polluted urban conditions where NO2 concentrations are typically much higher.

Regenerative medicine in otorhinolaryngology.

BACKGROUND: Tissue engineering using biocompatible scaffolds, with or without cells, can permit surgeons to restore structure and function following tissue resection or in cases of congenital abnormality. Tracheal regeneration has emerged as a spearhead application of these technologies, whilst regenerative therapies are now being developed to treat most other diseases within otolaryngology. METHODS AND RESULTS: A systematic review of the literature was performed using Ovid Medline and Ovid Embase, from database inception to 15 November 2014. A total of 561 papers matched the search criteria, with 76 fulfilling inclusion criteria. Articles were predominantly pre-clinical animal studies, reflecting the current status of research in this field. Several key human research articles were identified and discussed. CONCLUSION: The main issues facing research in regenerative surgery are translation of animal model work into human models, increasing stem cell availability so it can be used to further research, and development of better facilities to enable implementation of these advances.

Clinical Implications of Basic Science Discoveries: Immune Homeostasis and the Microbiome-Dietary and Therapeutic Modulation and Implications for Transplantation.

Links between the human microbiome and the innate and adaptive immune systems and their impact on autoimmune and inflammatory diseases are only beginning to be recognized. Characterization of the complex human microbial community is facilitated by culture-independent nucleic acid sequencing tools and bioinformatics systems. Specific organisms and microbial antigens are linked with initiation of innate immune responses that, depending on the context, may be associated with tolerogenic or effector immune responses. Further complexity is introduced by preclinical data that demonstrate the impacts of dietary manipulation on the prevention of genetically determined, systemic autoimmune disorders and on gastrointestinal microbiota. Investigation of interactions of complex microbial populations with the human immune system may provide new targets for clinical management in allotransplantation.