Glycan-Tailored Glycoproteomic Analysis Reveals Serine is the Sole Residue Subjected to O-Linked Glycosylation in Acinetobacter baumannii.

Protein glycosylation is a ubiquitous process observed across all domains of life. Within the human pathogen Acinetobacter baumannii, O-linked glycosylation is required for virulence; however, the targets and conservation of glycosylation events remain poorly defined. In this work, we expand our understanding of the breadth and site specificity of glycosylation within A. baumannii by demonstrating the value of strain specific glycan electron-transfer/higher-energy collision dissociation (EThcD) triggering for bacterial glycoproteomics. By coupling tailored EThcD-triggering regimes to complementary glycopeptide enrichment approaches, we assessed the observable glycoproteome of three A. baumannii strains (ATCC19606, BAL062, and D1279779). Combining glycopeptide enrichment techniques including ion mobility (FAIMS), metal oxide affinity chromatography (titanium dioxide), and hydrophilic interaction liquid chromatography (ZIC-HILIC), as well as the use of multiple proteases (trypsin, GluC, pepsin, and thermolysis), we expand the known A. baumannii glycoproteome to 33 unique glycoproteins containing 42 glycosylation sites. We demonstrate that serine is the sole residue subjected to glycosylation with the substitution of serine for threonine abolishing glycosylation in model glycoproteins. An A. baumannii pan-genome built from 576 reference genomes identified that serine glycosylation sites are highly conserved. Combined this work expands our knowledge of the conservation and site specificity of A. baumannii O-linked glycosylation.

Streptococcus dysgalactiae subsp. equisimilis infection and its intersection with Streptococcus pyogenes.

SUMMARYStreptococcus dysgalactiae subsp. equisimilis (SDSE) is an increasingly recognized cause of disease in humans. Disease manifestations range from non-invasive superficial skin and soft tissue infections to life-threatening streptococcal toxic shock syndrome and necrotizing fasciitis. Invasive disease is usually associated with co-morbidities, immunosuppression, and advancing age. The crude incidence of invasive disease approaches that of the closely related pathogen, Streptococcus pyogenes. Genomic epidemiology using whole-genome sequencing has revealed important insights into global SDSE population dynamics including emerging lineages and spread of anti-microbial resistance. It has also complemented observations of overlapping pathobiology between SDSE and S. pyogenes, including shared virulence factors and mobile gene content, potentially underlying shared pathogen phenotypes. This review provides an overview of the clinical and genomic epidemiology, disease manifestations, treatment, and virulence determinants of human infections with SDSE with a particular focus on its overlap with S. pyogenes. In doing so, we highlight the importance of understanding the overlap of SDSE and S. pyogenes to inform surveillance and disease control strategies.

Spinal column radiological factors associated with increased spinal cord intramedullary signal intensity - A study evaluating aging spinal cord's relation to spinal disc degeneration.

PURPOSE: Increased intramedullary signal intensity (IISI) on T2 weighted MRI scan (T2WI) can be a radiological feature of spinal cord degeneration. However, the association of IISI to degeneration of the spinal column that protects the spinal cord remains unclear. The purpose of this study was to determine the prevalence of IISI and analyze the independent relationship between IISI and cervical degenerative parameters on X-ray and magnetic resonance imaging (MRI). METHODS: A retrospective review of MRI, X-ray, and radiology data (n = 144) adult patients with both cervical MRI and X-ray scans was conducted. A total of 39 (27 %) patients with IISI was identified. The remaining 105 patients without IISI made up the control group. RESULTS: IISI was most frequent in C6-C7 cervical levels. The likelihood of having IISI was 1.947 (Exp(B) 1.947, 95 %CI [1.004-3.776]) times higher in segmental levels with facet joint degeneration. There was an increased likelihood of IISI within the spinal cord with increasing age (Exp(B) 1.034, 95 %CI [1.008-1.060]), maximum spinal cord compression (MSCC) (Exp(B) 1.038, 95 %CI [1.003-1.075]), rotational angle (Exp(B) 1.082, 95 %CI [1.020-1.148]) and posterior disc herniation width (Exp(B) 1.333, 95 %CI [1.017-1.747]) and decreasing Torg-Pavlov ratio (Exp(B) 0.010, 95 %CI [0.001-0.068]). CONCLUSION: IISI was independently associated with increased age, facet joint degeneration, MSCC, rotational angle, posterior herniation width and decreasing Torg-Pavlov angle. Radiologicaldegenerative changesassociated with IISI indicates a potential for identifying predictors of age related spinal cord morphological changes in DCM, which may allow for early intervention strategies in the future.

Influence of a Novel Morphology-Driven Classification on Limb Salvage after Isolated Tibial Intervention for Chronic Limb Threatening Ischemia.

BACKGROUND: Infra-popliteal interventions for chronic limb-threatening ischemia (CLTI) can be impacted by the morphology of the tibial vessels. The aim of this study was to examine the impact of a novel morphology-driven classification on the outcomes of isolated tibial intervention for CLTI. METHODS: A database of patients undergoing isolated tibial interventions for CLTI at a single center between 2010 and 2020 was retrospectively queried. Patients with isolated Infra-popliteal disease were identified, and their anatomy was scored as present or absent for lesion calcification (1 point), target vessel diameter<3.0 mm (1 point), lesion length>300mm (1 point) and poor pedal runoff score (1 point). Patients were then divided into three groups: low-risk (0 or 1 points), moderate-risk (2 points), and high-risk (3 or 4 points). Intention to treat analysis by the patient was performed. Limb-based patency (the absence of reintervention, occlusion, critical stenosis (>70%), or hemodynamic compromise with ongoing symptoms of CLTI as it related to the patency of the preoperatively determined target artery pathway) was assessed. Patient-orientated outcomes of amputation-free survival (AFS; survival without major amputation) and freedom from major adverse limb events (MALE; Above ankle amputation of the index limb or major re-intervention (new bypass graft, jump/interposition graft revision) were evaluated. RESULTS: 1607 patients (55% male, average age 60 years, 3846 vessels) underwent tibial intervention for CLTI. The majority of the patients were diabetic and of Hispanic. origin Morphologically, 27%, 31%, and 42% of the vessels were categorized as low risk, moderate risk, and high risk, respectively. There was a significant worsening of the infra-popliteal Global Limb Anatomic Staging System (GLASS) grading as the morphological risk increased. The 30-day major adverse cardiac events (MACE) were equivalent across the groups and were under the stated objective performance goal (OPG) of ≤10%. In contrast, both the 30-day MALE and the 30-day Major Amputations were significantly different across the groups, with the low-risk group remaining under the OPG of ≤9% and ≤4%, respectively, while the moderate-risk and high-risk exceeded the goal threshold. For the OPG. Freedom from MALE was 60±5%, 46±5%, and 22±9% at 5 years for low-, moderate-, and high-risk groups, respectively (mean ± SEM; p =0.008. Overall amputation-free survival (AFS) was 55±5%, 37±6%, and 18±7% at 5 years for low-, moderate-, and high-risk groups, respectively (mean ± SEM; p=0.003). CONCLUSIONS: Tibial anatomic morphology impacts isolated tibial endovascular intervention with adverse morphology associated with poorer short and long-term outcomes. Risk stratification based on anatomic predictors should be an additional consideration as one intervenes on infra-popliteal vessels for CLTI.

Comparative Analysis of Response to Cardiac Resynchronisation Therapy Upgrades in Patients with Implantable Cardioverter-Defibrillators and Pacemakers.

Introduction: The efficacy of de novo cardiac resynchronisation therapy (CRT) in patients with heart failure (HF), left ventricular systolic dysfunction (LVSD), and a broad QRS morphology is well established. However, the optimal stage for upgrading patients with existing pacemakers (PPMs) or implantable cardioverter-defibrillators (ICDs) and HF with high-burden right ventricular (RV) pacing remains uncertain. Thus, this multicentre retrospective analysis compared patients with pre-existing PPMs or ICDs who underwent CRT upgrades to investigate the appropriate stage for CRT implantation in these patients and to assess the validity of treating both PPM and ICD recipients under the same recommendation level in the current guidelines. Materials and Methods: A total of 151 participants underwent analysis in this study, comprising 93 upgrades to cardiac resynchronisation therapy with pacemaker (CRT-P) and 58 upgrades to cardiac resynchronisation therapy with defibrillator (CRT-D) across three centres in the UK. The aim of the study was to investigate the safety and efficacy of upgrading to CRT from an existing conventional pacemaker or an ICD in the context of high-burden RV pacing. The analysis was conducted separately for each group, assessing changes in echocardiographic parameters, functional New York Heart Association (NYHA) class, and procedure-related complications. Results: The PPM group had a higher percentage RVP burden compared to the ICD group. Post-upgrade, NYHA functional class and EF and LV volumes improved in both groups; however, the response to an upgrade from a pacemaker was greater compared to an upgrade from an ICD. Post-procedural complication risks were similar across the two subgroups but significantly higher compared to de novo implantation. Conclusions: Within the CRT-P subgroup, participants exhibited better responses than their CRT-D counterparts, evident both in echocardiographic improvements and clinical outcomes. Furthermore, patients with non-ischemic cardiomyopathy (NICM) were better responders than those with ischaemic cardiomyopathy. These findings suggest that international guidelines should consider approaching each subgroup separately in the future.

The PARTNER trial of neoadjuvant olaparib with chemotherapy in triple-negative breast cancer.

PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer1,2, who were germline BRCA1 and BRCA2 wild type3. Here we report the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)4, and secondary end points included event-free survival (EFS) and overall survival (OS)5. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .

Incidence of avascular necrosis of native femur following hip transposition surgery for periacetabular malignancies: a single-centre experience.

BACKGROUND: Hip transposition surgery after surgical resection of large pelvic tumours is a well-established alternate to endoprosthetic reconstruction. The major goals of surgery are to ensure adequate resection margins with limb salvation, albeit with acceptable levels of morbidity. While surveillance is aimed at diagnosing local recurrence or distant metastasis primarily, other complications may occasionally be seen.The aim of this study was to assess incidence of avascular necrosis (AVN) in the preserved native femoral heads after hip transposition surgery for periacetabular malignancies, also known as hanging hip surgery. PATIENTS AND METHODS: Patient records and follow-up imaging of 22 patients who had undergone hanging hip surgery from 1999 to 2020 were retrospectively analysed to assess for any probable causes of AVN. RESULTS: Of the 22 patients, 5 (22.7%) had developed AVN on follow-up with a mean time of onset of about 10.5 months from surgery (5 months-2 years). A review of the patient demographics, surgical notes, preoperative management did not offer any clues as to the cause of AVN in these patients. Osteopenia was the most common radiological finding (59%) in most patients, but this also did not herald AVN onset. CONCLUSIONS: The theory that loss of major vascular supply to the femoral head from capsular disruption during hip transposition surgery would lead to AVN in most patients did not hold true as AVN occurred in a small number of patients.

Overlapping Streptococcus pyogenes and Streptococcus dysgalactiae subspecies equisimilis household transmission and mobile genetic element exchange.

Streptococcus dysgalactiae subspecies equisimilis (SDSE) and Streptococcus pyogenes share skin and throat niches with extensive genomic homology and horizontal gene transfer (HGT) possibly underlying shared disease phenotypes. It is unknown if cross-species transmission interaction occurs. Here, we conduct a genomic analysis of a longitudinal household survey in remote Australian First Nations communities for patterns of cross-species transmission interaction and HGT. Collected from 4547 person-consultations, we analyse 294 SDSE and 315 S. pyogenes genomes. We find SDSE and S. pyogenes transmission intersects extensively among households and show that patterns of co-occurrence and transmission links are consistent with independent transmission without inter-species interference. We identify at least one of three near-identical cross-species mobile genetic elements (MGEs) carrying antimicrobial resistance or streptodornase virulence genes in 55 (19%) SDSE and 23 (7%) S. pyogenes isolates. These findings demonstrate co-circulation of both pathogens and HGT in communities with a high burden of streptococcal disease, supporting a need to integrate SDSE and S. pyogenes surveillance and control efforts.

Recombinational exchange of M-fibril and T-pilus genes generates extensive cell surface diversity in the global group A Streptococcus population.

Among genes present in all group A streptococci (GAS), those encoding M-fibril and T-pilus proteins display the highest levels of sequence diversity, giving rise to the two primary serological typing schemes historically used to define strain. A new genotyping scheme for the pilin adhesin and backbone genes is developed and, when combined with emm typing, provides an account of the global GAS strain population. Cluster analysis based on nucleotide sequence similarity assigns most T-serotypes to discrete pilin backbone sequence clusters, yet the established T-types correspond to only half the clusters. The major pilin adhesin and backbone sequence clusters yield 98 unique combinations, defined as "pilin types." Numerous horizontal transfer events that involve pilin or emm genes generate extensive antigenic and functional diversity on the bacterial cell surface and lead to the emergence of new strains. Inferred pilin genotypes applied to a meta-analysis of global population-based collections of pharyngitis and impetigo isolates reveal highly significant associations between pilin genotypes and GAS infection at distinct ecological niches, consistent with a role for pilin gene products in adaptive evolution. Integration of emm and pilin typing into open-access online tools (pubmlst.org) ensures broad utility for end-users wanting to determine the architecture of M-fibril and T-pilus genes from genome assemblies.IMPORTANCEPrecision in defining the variant forms of infectious agents is critical to understanding their population biology and the epidemiology of associated diseases. Group A Streptococcus (GAS) is a global pathogen that causes a wide range of diseases and displays a highly diverse cell surface due to the antigenic heterogeneity of M-fibril and T-pilus proteins which also act as virulence factors of varied functions. emm genotyping is well-established and highly utilized, but there is no counterpart for pilin genes. A global GAS collection provides the basis for a comprehensive pilin typing scheme, and online tools for determining emm and pilin genotypes are developed. Application of these tools reveals the expansion of structural-functional diversity among GAS via horizontal gene transfer, as evidenced by unique combinations of surface protein genes. Pilin and emm genotype correlations with superficial throat vs skin infection provide new insights on the molecular determinants underlying key ecological and epidemiological trends.

Pedal medial arterial calcification influences the outcomes of isolated infra-malleolar interventions for chronic limb-threatening ischemia.

OBJECTIVE: Inframalleolar disease is present in most diabetic patients presenting with tissue loss. Inframalleolar (pedal) artery disease and pedal medial arterial calcification (pMAC) are associated with major amputation in patients with chronic limb-threatening ischemia (CLTI). This study aimed to examine the impact of pMAC on the outcomes after isolated inframalleolar (pedal artery) interventions. METHODS: A database of lower extremity endovascular intervention for patients with tissue loss between 2007 and 2022 was retrospectively queried. Patients with CLTI were selected, and those undergoing isolated inframalleolar intervention on the dorsalis pedis and medial and lateral tarsal arteries and who had foot x-rays were identified. X-rays were assessed blindly for pMAC and scored on a scale of 0 to 5. Patients with concomitant superficial femoral artery and tibial interventions were excluded. Intention to treat analysis by the patient was performed. Amputation-free survival (survival without major amputation) was evaluated. RESULTS: A total of 223 patients (51% female; 87% Hispanic; average age, 66 years; 323 vessels) underwent isolated infra-malleolar intervention for tissue loss. All patients had diabetes, 96% had hypertension, 79% had hyperlipidemia, and 63% had chronic renal insufficiency (55% of these were on hemodialysis). Most of the patients had Wound, Ischemia, and foot Infection (WIfI) stage 3 disease and had various stages of pMAC: severe (score = 5) in 48%, moderate (score = 2-4) in 31%, and mild (score = 0-1) in 21% of the patients. Technical success was 94%, with a median of one vessel treated per patient. All failures were in severe pMAC. Overall, major adverse cardiovascular events was 0.9% at 90 days after the procedure. Following the intervention, most patients underwent a planned forefoot amputation (single digit, multiple digits, ray amputation, or trans-metatarsal amputation). WIfI ischemic grade was improved by 51%. Wound healing at 3 months was 69%. Those not healing underwent below-knee amputations. The overall 5-year amputation-free survival rate was 35% ± 9%. The severity of pMAC was associated with decreased AFS. CONCLUSIONS: Increasing severity of pMAC influences the technical and long-term outcomes of infra-malleolar intervention in diabetes. Severe pMAC is associated with amputation and should be considered as a variable in the shared decision-making of diabetic patients with CLTI.

Extracorporal Membrane Oxygenation in Massive Pulmonary Embolism.

BACKGROUND: Massive pulmonary embolism (MPE) carries significant 30-day mortality risk, and a change in societal guidelines has promoted the increasing use of extracorporeal membrane oxygenation (ECMO) in the immediate management of MPE-associated cardiovascular shock. This narrative review examines the current status of ECMO in MPE. METHODS: A literature review was performed from 1982 to 2022 searching for the terms "Pulmonary embolism" and "ECMO," and the search was refined by examining those publications that covered MPE. RESULTS: In the patient with MPE, veno-arterial ECMO is now recommended as a bridge to interventional therapy. It can reliably decrease right ventricular overload, improve RV function, and allow hemodynamic stability and restoration of tissue oxygenation. The use of ECMO in MPE has been associated with lower mortality in registry reviews, but there has been no significant difference in outcomes between patients treated with and without ECMO in meta-analyses. Applying ECMO is also associated with substantial multisystem morbidity due to systemic inflammatory response, bleeding with coagulopathy, hemorrhagic stroke, renal dysfunction, and acute limb ischemia, which must be factored into the outcomes. CONCLUSIONS: The application of ECMO in MPE should be combined with an aggressive interventional pulmonary interventional program and should strictly adhere to the current selection criteria.

Management of depth to achieve timely arteriovenous fistula utilization.

OBJECTIVE: Failure to achieve timely arteriovenous fistulae (AVFs) utilization due to excessive depth (>6 mm) remains an ongoing concern for dialysis access. This study evaluates the outcomes of radiocephalic (RCF) and brachiocephalic (BCF) fistula elevation required for access utilization. METHODS: A retrospective review of all patients undergoing first-time autologous access over 10 years was undertaken. RCF and BCF were analyzed, and cases of initial access failure due to depth alone were selected for study. Primary and staged brachio-basilic AVF were excluded. Outcomes of early thrombosis, line placement, maturation (successful progression to hemodialysis [HD), reintervention, and functional dialysis (continuous HD for 3 consecutive months) were examined. RESULTS: From January 2012 to December 2022, 1733 patients (67% female; mean age, 61 ± 14 years) underwent autologous AVF placement. Of these, 298 patients (17%) had depth-related AVF access issues (BCF, 71% and RCF, 29%). Nineteen percent of these AVFs underwent a primary balloon-assisted maturation (BAM), and 2% had side branch coil embolization before consideration for elevation. The average time to intervention for depth was 11 ± 4 weeks after primary creation. During elevation, side branch ligation occurred in 38% of cases, and 15% underwent intraoperative BAM, The pre-elevation depth was 8.2 ± 3.1 mm, and the mean post-elevation depth was 4.7 ± 2.9 mm (P = .002). Early thrombosis (<18 days) occurred in 4% of cases. There was no mortality, and the 30-day major adverse cardiac event rate was 2%, with a 30-day morbidity of 5%, which was driven by wound issues. Six percent of the AVFs underwent follow-up BAM within 3 months. Mean maturation of the AVFs was 74% ± 3% vs 72% ± 3% (P = .58) for the elevation vs no-elevation groups at 24 weeks, respectively. However, there was an increase in tunneled central line placement in pre-emptive fistula patients due to the delay in maturation (elevation, 17% vs no-elevation, 8%; P = .008). There was a mean successful access time of 6 ± 3 weeks after elevation (16 ± 4 weeks after access creation). There was a median of 2.4 secondary interventions per year after elevation compared with a median of 2.7 secondary interventions per year without elevation. Mean access functionality was 68% ± 8% vs 75% ± 8% at 3 years for the elevation vs no-elevation groups, respectively (P = .25). CONCLUSIONS: Elevation of deep BCF and RCF occurs late after placement but can be successfully achieved with low morbidity and satisfactory long-term functionality. It results in an increase in tunneled central line placement in pre-emptive fistula patients. Elevation is a valuable adjunct to AVF maturation and enhances an autologous access policy.

Endovascular management of acute and subacute venous thoracic outlet syndrome.

Approximately 3% of all patients presenting with Thoracic Outlet Syndrome have a venous etiology (vTOS), which is considered "effort thrombosis". These patients will present with symptomatic deep venous thrombosis or focal subclavian vein (SCV) stenosis. Endovascular management of vTOS occurs in several phases: diagnostic, preoperative therapeutic intervention before decompression, postoperative interventions after decompression, and delayed interventions in the follow-up after decompression. In the diagnostic phase, dynamic SCV venography can establish functional vTOS. Approximately 4,000 patients have been treated for vTOS and reported in the literature since 1970. Declotting of the SCV was followed by surgical decompression in 53% of patients, while in the remainder, surgical decompression alone (18%), endovascular intervention alone (15%), or conservative therapy with anticoagulation (15%) was performed. The initial intervention was predominantly catheter-directed thrombolysis, with <10% of cases undergoing concomitant balloon angioplasty. 93% of cases were successful. In the postoperative phase, balloon angioplasty was performed to correct residual intrinsic SCV disease after vTOS decompression in under 15% of cases. Stents were rarely deployed. Symptom relief was reported as 94 ± 12% (mean ± SD) and 90 ± 23%, respectively for declotting with decompression and declotting alone. In the delayed phase, balloon angioplasty was performed in under 15% of cases to re-establish patency.

Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis.

Streptococcus dysgalactiae subsp. equisimilis (SDSE) is an emerging cause of human infection with invasive disease incidence and clinical manifestations comparable to the closely related species, Streptococcus pyogenes. Through systematic genomic analyses of 501 disseminated SDSE strains, we demonstrate extensive overlap between the genomes of SDSE and S. pyogenes. More than 75% of core genes are shared between the two species with one third demonstrating evidence of cross-species recombination. Twenty-five percent of mobile genetic element (MGE) clusters and 16 of 55 SDSE MGE insertion regions were shared across species. Assessing potential cross-protection from leading S. pyogenes vaccine candidates on SDSE, 12/34 preclinical vaccine antigen genes were shown to be present in >99% of isolates of both species. Relevant to possible vaccine evasion, six vaccine candidate genes demonstrated evidence of inter-species recombination. These findings demonstrate previously unappreciated levels of genomic overlap between these closely related pathogens with implications for streptococcal pathobiology, disease surveillance and prevention.

Counting the lifetime cost of obesity: Analysis based on national England data.

AIM: Obesity has a significant impact on all-cause mortality rate and overall health care resource use (HCRU). These outcomes are also strongly linked to age, sex and local deprivation of the population. We aimed to establish the lifetime costs of obesity by demographic group/geographic area using published mortality rates and HCRU use for integrated care boards (ICB) in England in the context of costs of therapeutic intervention. METHODS: Population and expected mortality rates by age, sex and deprivation were obtained from national data. Obesity class prevalence was taken from the health of the nation study. The published impact of obesity by age, group, sex and deprivation on mortality and HCRU were applied to estimate life years lost and lifetime HCRU [by sex, age band and body mass index (BMI) class for each ICB]. The year 2019 was chosen as the study basis data to avoid influences of COVID-19 pandemic on obesity rates with application of 2022/23 HCRU values. Outcomes including prevalence, deaths, life years lost, HCRU and lifetime HCRU were compared by age and sex groups across four BMI classes normal/underweight (BMI <25 kg/m2 ), overweight (25-29.9 kg/m2 ), obese class I and II (30-39.9 kg/m2 ), and obese class III (≥40), with benchmarking being set against all population being BMI <25 kg/m2 overall and by each of the 42 ICBs. We also associated future life with deaths to provide an estimate of 'future life years lost' occurring each year. RESULTS: Total population aged >16 years was 45.4 million (51% female). PREVALENCE: 13.7 million (28% of the total adult population) had a BMI ≥30 mg/m2 and BMI ≥40 kg/m2 were 1.50 million (12%) of these 1.0 million (68%) were female and of these 0.6 million 40% were women aged 16-49 years. In addition, 35% of those with a BMI ≥40 kg/m2 were in the top deprivation quintile (i.e. overall 20%). Mortality was based on expected deaths of 518K/year, and modelling suggested that if a BMI <25 kg/m2 was achieved in all individuals, the death rate would fall by 63K to 455K/year for the English population (12% reduction). For those with a BMI ≥40 kg/m2 the predicted reduction was 12K deaths (54% lower); while in those aged 16-49 years with a BMI ≥40 kg/m2 72% of deaths were linked to obesity. For future life years lost, we estimated 2.5 years were lost in people with BMI 30-39.9 kg/m2 6.7 years when BMI ≥40 kg/m2 . However, for those aged 16-49 years with a BMI ≥40 kg/m2 , 8.3 years were lost. HCRU, for weight reduction, the annual HCRU decrease from BMI ≥40 kg/m2 to BMI 30-39.9 kg/m2 was £342 per person and from BMI 30-39.9 to 25-29.9 kg/m2 the reduction was £316/person. However, lifetime costs were similar because of reduced life expectancy for obese individuals. In quality adjusted life years (QALY), overall, 791 689 future life years were lost (13.1% of all) in people with BMI ≥25 kg/m2 and were related to excess weight. When the NICE £30 000 per QALY value was applied to the estimated total 791 689 future life years lost then the potential QALY value reduction lost was equivalent to £24 billion/year or £522/person in the obese population. For morbidly obese men and women the potential QALY value lost was £2864/person/year. Regarding geography, across the 42 ICBs, we observed significant variation in the prevalence of BMI ≥40 (1.8%-4.3%), excess mortality (11.6%-15.4%) and HCRU linked to higher BMI (7.2%-8.8%). The areas with the greatest impact on HCRU were in the north-west, north-east and Midlands of England, while the south shows less impact. CONCLUSION: The expected increases in annual HCRU because of obesity, when considered over a lifetime, are being mitigated by the increased mortality of obese individuals. Our data suggest that simple short-term HCRU reduction brought about through BMI reduction will be insufficient to fund additional specialist weight reduction interventions. The HRCUs associated with BMI are not in most cases related to short-term health conditions. They are a cumulative result over a number of years, so for age 16-49 years reducing BMI from ≥40 to 30-39.9 kg/m2 might show an annual decrease in HCRU/person by £325/year for women and £80/year for men but this might not have immediately occurred within that year. For those aged >70 years reducing BMI from ≥40 to 30-39.9 kg/m2 might show an annual decrease in HCRU/person by £777/year for women and £796/year for men but also may not be manifest within that year. However, for the morbidly obese men and women, the potential QALY value lost was £2864 per person per year with the potential for these funds to be applied to intensive weight management programmes, including pharmacotherapy.

Molecular characterization of the interaction between human IgG and the M-related proteins from Streptococcus pyogenes.

Group A Streptococcal M-related proteins (Mrps) are dimeric α-helical-coiled-coil cell membrane-bound surface proteins. During infection, Mrp recruit the fragment crystallizable region of human immunoglobulin G via their A-repeat regions to the bacterial surface, conferring upon the bacteria enhanced phagocytosis resistance and augmented growth in human blood. However, Mrps show a high degree of sequence diversity, and it is currently not known whether this diversity affects the Mrp-IgG interaction. Herein, we report that diverse Mrps all bind human IgG subclasses with nanomolar affinity, with differences in affinity which ranged from 3.7 to 11.1 nM for mixed IgG. Using surface plasmon resonance, we confirmed Mrps display preferential IgG-subclass binding. All Mrps were found to have a significantly weaker affinity for IgG3 (p < 0.05) compared to all other IgG subclasses. Furthermore, plasma pulldown assays analyzed via Western blotting revealed that all Mrp were able to bind IgG in the presence of other serum proteins at both 25 °C and 37 °C. Finally, we report that dimeric Mrps bind to IgG with a 1:1 stoichiometry, enhancing our understanding of this important host-pathogen interaction.

Outbreak of Diarrhea Caused by a Novel Cryptosporidium hominis Subtype During British Military Training in Kenya.

Background: We report clinical, epidemiological, and laboratory features of a large diarrhea outbreak caused by a novel Cryptosporidium hominis subtype during British military training in Kenya between February and April 2022. Methods: Data were collated from diarrhea cases, and fecal samples were analyzed on site using the multiplex polymerase chain reaction (PCR) BioFire FilmArray. Water was tested using Colilert kits (IDEXX, UK). DNA was extracted from feces for molecular characterization of Cryptosporidium A135, Lib13, ssu rRNA, and gp60 genes. Results: One hundred seventy-two of 1200 (14.3%) personnel at risk developed diarrhea over 69 days. One hundred six primary fecal samples were tested, and 63/106 (59.4%; 95% CI, 0.49%-0.69%) were positive for Cryptosporidium spp. Thirty-eight had Cryptosporidium spp. alone, and 25 had Cryptosporidium spp. with ≥1 other pathogen. A further 27/106 (25.5%; 95% CI, 0.18%-0.35%) had non-Cryptosporidium pathogens only, and 16/106 (15.1%; 95% CI, 0.09%-0.23%) were negative. C. hominis was detected in 58/63 (92.1%) Cryptosporidium spp.-positive primary samples, but the others were not genotypable. Twenty-seven C. hominis specimens were subtypable; 1 was gp60 subtype IeA11G3T3, and 26 were an unusual subtype, ImA13G1 (GenBank accession OP699729), supporting epidemiological evidence suggesting a point source outbreak from contaminated swimming water. Diarrhea persisted for a mean (SD) of 7.6 (4.6) days in Cryptosporidium spp. cases compared with 2.3 (0.9) days in non-Cryptosporidium cases (P = .001). Conclusions: Real-time multiplex PCR fecal testing was vital in managing this large cryptosporidiosis outbreak. The etiology of a rare C. hominis gp60 subtype emphasizes the need for more genotypic surveillance to identify widening host and geographic ranges of novel C. hominis subtypes.

Quantifying the Value of Reduced Health Disparities: Low-Dose Computed Tomography Lung Cancer Screening of High-Risk Individuals Within the United States.

OBJECTIVE: This study aimed to measure the value of increasing lung cancer screening rates for high-risk individuals and its impact on health disparities. METHODS: The model estimated changes in health economic outcomes if low-dose computed tomography screening increased from current to 100% compliance, following clinical guidelines. Current low-dose computed tomography screening rates were estimated by income, education, and race, using 2017-2019 Behavioral Risk Factor Surveillance System data. The model contained a decision tree module to segment the population by screening outcomes and a Markov chain module to estimate cancer progression over time. Model parameters included information on survival, quality of life, and costs related to cancer diagnosis, treatment, and adverse events. Distributional cost-effectiveness analysis estimated the net monetary value from reduced health disparities-measured using quality-adjusted life expectancy-across income, education, and race groups. Outcomes were assessed over 30 years. RESULTS: Lung cancer screening eligibility using US Preventive Services Task Force guidelines was higher for individuals with income <$15 000 (47.2%) and without a high-school education (46.1%) than individuals with income >$50 000 (16.6%) and with a college degree (13.5%), respectively. Increasing lung cancer screening to 100% compliance was cost-effective ($64 654 per quality-adjusted life-year) and produced economic value by up to $560 per person ($182.1 billion for United States overall). Up to 32.2% of the value was due to reductions in health disparities. CONCLUSIONS: Significant value in increasing lung cancer screening rates derived from reducing health disparities. Policy makers and clinicians may not be appropriately prioritizing cancer screening if value from reducing health disparities is unconsidered.

Outcomes of one-stage and two-stage aneurysm repair in arteriovenous fistulae.

OBJECTIVE: Maintenance of long-term arteriovenous access is important in long-term care for patients with end-stage renal disease. Arteriovenous access is associated in the long term with the development of fistula aneurysms (FAs). This study aims to evaluate the outcomes of staged FA treatment in dialysis access arteriovenous fistulae (AVF). METHODS: A retrospective review of all patients over a 12-year period with primary autogenous AVF was undertaken at a single center. Patients undergoing elective open aneurysm repair were identified and were categorized into three groups: single FA repair (single, control group) and staged and unstaged repair of two FAs (staged and unstaged). A staged repair was a procedure in which the initial intent was to treat both aneurysms in the AVF and in which the most symptomatic aneurysm was treated first. When the incision from the first surgery had healed, the second symptomatic aneurysm in the AVF was treated. An unstaged repair was a procedure in which the initial intent was to repair both symptomatic aneurysms simultaneously. All patients had a fistulogram before the FA repair. Thirty-day outcomes, cannulation failure, line placement, reintervention, and functional dialysis (continuous hemodialysis for 3 consecutive months) were examined. RESULTS: Five hundred twenty-seven patients presented with FA that met requirements for open intervention; 44% underwent single FA repair, whereas the remaining 34% and 22% underwent staged and unstaged repair of two FAs, respectively. The majority of patients were diabetic and Hispanic. Ninety-one percent of the patients required percutaneous interventions of the outflow tract (37%) and the central veins (54%). Thirty-day major adverse cardiovascular events were equivalent across all modalities. Thirty-day morbidity and early thrombosis (<18 days) were significantly higher in the unstaged group (4.3%) compared with the two other groups (1.3% and 2.1%, single and staged, respectively), which led to an increased need for a short-term tunneled catheter (8.9%) compared with the two other groups (3.4% and 4.4%, single and staged, respectively), Unstaged repair resulted in an increased incidence of secondary procedures (5.0%) compared with the two other groups (2.6% and 3.1%, single and staged, respectively). Functional dialysis at 5 years was equivalent in the single and staged groups but was significantly decreased in the unstaged group. CONCLUSIONS: Open interventions are successful therapeutic modalities for FAs, but unstaged rather than staged repair of two concurrent FAs results in a higher early thrombosis, an increased secondary intervention rate, and a need for a short-term tunneled central line. Staged and single FA repairs have equivalent results. In the setting of two symptomatic FAs, staged repair is recommended.

Current Quality of Videos on Colorectal Cancer Screening for General Public.

BACKGROUND: One-third of American adults encompassed by current colorectal cancer screening guidelines fail to obtain recommended screening evaluations. Educational videos are a valuable medium through which to educate and encourage recommended health behaviors in patients. METHODS: A cross-sectional study reviewing the quality of patient education videos addressing colorectal cancer screening. Video quality was assessed in 3 domains: accountability, content, and production. RESULTS: Forty-four videos met inclusion criteria. Out of 33 possible points, videos scored a median of 15.0 (interquartile range 12.9-16.6). Videos scored 1.0 (interquartile range .8-1.0) out of 4.0 for accountability, 6.0 (interquartile range 4.4-8.0) out of 20 for content, and 8.0 (interquartile range 7.4-8.0) out of 9.0 for production. Colonoscopy was the most frequently discussed method of screening (38, 86%). While 13 (34%) videos discussed the risk of colorectal cancer in the general population and 15 (32%) discussed the risk in those with a family history, few videos addressed those with other risk factors. Most (31, 70%) videos discussed the medical consequences of not receiving screening, but only 1 (2%) video discussed the social consequences. Similarly, medical benefits were discussed in 34 (77%) videos while other benefits were not discussed by any video. Only one-fifth of the videos address three or more barriers to screening. CONCLUSIONS: Videos on colorectal cancer screening have excellent production quality but need improvement in the domains of accountability and content. The videos included in this analysis did not adequately address the concerns of viewers nor the benefits of colorectal cancer screening.