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BackgroundHepatocellular cancer (HCC) is associated with high mortality, and early diagnosis leads to better survival. Patients with cirrhosis, especially due to nonalcoholic fatty liver disease and viral hepatitis, are at higher risk of developing HCC and form the main screening group. The current screening methods for HCC (6-monthly screening with serum alpha fetoprotein and ultrasound liver) have low sensitivity; hence, there is a need for better screening markers for HCC. ObjectiveOur study, TENDENCY, aims to validate the novel screening markers (methylated septin 9, urinary volatile organic compounds, and urinary peptides) for HCC diagnosis and study these noninvasive biomarkers in liver disease. MethodsThis is a multicenter, nested case-control study, which involves comparing the plasma levels of methylated septin 9 between confirmed HCC cases and patients with cirrhosis (control group). It also includes the comparison of urine samples for the detection of HCC-specific volatile organic compounds and peptides. Based on the findings of a pilot study carried out at University Hospital Coventry & Warwickshire, we estimated our sample size to be 308 (n=88, 29% patients with HCC; n=220, 71% patients with cirrhosis). Urine and plasma samples will be collected from all participants and will be frozen at –80 °C until the end of recruitment. Gas chromatography–mass spectrometry will be used for urinary volatile organic compounds detection, and capillary electrophoresis–mass spectrometry will be used for urinary peptide identification. Real-time polymerase chain reaction will be used for the qualitative detection of plasma methylated septin 9. The study will be monitored by the Research and Development department at University Hospital Coventry & Warwickshire. ResultsThe recruitment stage was completed in March 2023. The TENDENCY study is currently in the analysis stage, which is expected to finish by November 2023. ConclusionsThere is lack of effective screening tests for hepatocellular cancer despite higher mortality rates. The application of more sensitive plasma and urinary biomarkers for hepatocellular cancer screening in clinical practice will allow us to detect the disease at earlier stages and hence, overall, improve HCC outcomes. International Registered Report Identifier (IRRID)DERR1-10.2196/44264

Germline pathogenic genetic variants in the BRCA1 and BRCA2 genes are the most frequent causes of familial breast and ovarian cancer. Contrasting BRCA2, epimutations in the BRCA1 gene are frequently detected in tissue from triple‐negative breast (TNBC) and high‐grade serous ovarian cancers (HGSOC). While studies over the last decade have reported BRCA1 epimutations in white blood cells (WBC) from breast and ovarian cancer patients, the potential hazard ratio for incident TNBC and HGSOC was not formally assessed until recently. Conducting a prospective nested case‐control study on women participating in the American Women's Health Initiative Study, we provided firm evidence that mosaic WBC BRCA1 epimutations, even at allele frequencies < 0.1%, are associated with a significantly increased risk of both incident HGSOC and TNBC > 5 years after WBC collection. In a second study assessing BRCA1 epimutations in WBC and matched tumor samples from TNBC, our results indicated such epimutations to be the underlying cause of around 20% of TNBC, far exceeding the percentage of cases carrying BRCA1 germline pathogenic genetic variants. We detected primary constitutional BRCA1 epimutations in tissues derived from all three germ layers. They occur independently of BRCA1 promoter haplotypes but are present on the same allele in all WBC within affected individuals. Moreover, epimutations are consistently found on the same allele in normal and tumor breast tissue as well as in WBC. This finding, together with BRCA1 epimutations detected in WBC from newborns, strongly indicates an early embryonic event with clonal expansion affecting all germ layers. Future work in the field must lead to an understanding of exactly when and how the BRCA1 epimutations occur and, most importantly, whether primary constitutional epimutations in genes other than BRCA1 may cause an elevated risk of other cancer types. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to compare the outcomes of pediatric LT with left liver grafts, obtained either from a living donor (LD) or a split deceased donor (sDD). Methods: Retrospective single‐center study from 2002 to 2022. All pediatric LT with left liver grafts (not including middle hepatic vein) from LD or sDD were included. Reduced grafts were not included. Results: A total of 112 pediatric LT were performed: 58 with LD grafts and 54 with sDD grafts (17 split ex situ and 37 in situ). Donor characteristics were similar, apart from donor age (33 years in LD vs. 30 years in sDD, p = 0.03). Indications were similar with 55% biliary atresia in each group. Retransplantation was more frequently performed in the sDD group (2% vs. 15%, p = 0.01). Recipient age, weight, and PELD score at transplant were not significantly different between groups. Cold ischemia time was longer for sDD (158 min in LD vs. 390 min in sDD; p < 0.0001). Posttransplant peak ALT was higher with sDD grafts (1470 vs. 1063, p = 0.018), and hospital stay was longer with sDD grafts (27 vs. 21 days, p = 0.005). However, there was no difference between groups in terms of major morbidity (Dindo‐Clavien grade ≥3), vascular and biliary complications, and 90‐day mortality. Patient survival at 10 years was 93.1% for LD and 92.8% for sDD (p = 0.807). Graft survival at 10 years was 89.7% for LD and 83.1% for sDD (p = 0.813). Conclusions: Technically similar LD and sDD grafts achieve very similar postoperative and long‐term outcomes with excellent patient and graft survival. [ABSTRACT FROM AUTHOR]

Abstract Objective: We evaluated the impact of an asymptomatic bacteriuria (ASB) assessment protocol on the number of antibiotics prescribed for ASB after discharge from the emergency department (ED). Design: Single-center, before-and-after, retrospective cohort study. Setting: The study was conducted at a large community health system in North Carolina. Patients: Eligible patients were discharged from an ED without an antibiotic prescription and had a positive urine culture result after discharge from May through July 2021 (preimplementation group) and October through December 2021 (postimplementation group). Methods: Patient records were reviewed to determine the number of antibiotic prescriptions for ASB on follow-up call before and after implementation of an ASB assessment protocol. Secondary outcomes included 30-day admissions, 30-day ED visits, 30-day UTI-related encounters, and projected antibiotic days of therapy. Results: The study included 263 patients: 147 in the preimplementation group and 116 in the postimplementation group). There were significantly fewer antibiotic prescriptions for ASB in the postimplementation group (50% vs 8%; P < .0001). There were no differences in the incidence of 30-day admissions (7% vs 8%; P = .9761), 30-day ED visits (14% vs 16%; P = .7805), or 30-day UTI-related encounters (0% vs 0%, NA). Conclusions: Implementation of an ASB assessment protocol for patients discharged from the ED significantly reduced the number of antibiotic prescriptions for ASB on follow-up call without an increase in 30-day admissions, ED visits, or UTI-related encounters.

BackgroundThe SARS-CoV-2 pandemic has caused an unprecedented strain on healthcare systems worldwide, including the United Kingdom National Health Service (NHS). We conducted an observational cohort study of SARS-CoV-2 infection in frontline healthcare workers (HCW) working in an acute NHS Trust during the first wave of the pandemic, to answer emerging questions surrounding SARS-CoV-2 infection, diagnosis, transmission and control.MethodsUsing self-collected weekly saliva and twice weekly combined oropharyngeal/nasopharyngeal (OP/NP) samples, in addition to self-assessed symptom profiles and isolation behaviours, we retrospectively compared SARS-CoV-2 detection by RT-qPCR of saliva and OP/NP samples. We report the association with contemporaneous symptoms and isolation behaviour.ResultsOver a 12-week period from 30th March 2020, 40·0% (n = 34/85, 95% confidence interval 31·3-51·8%) HCW had evidence of SARS-CoV-2 infection by surveillance OP/NP swab and/or saliva sample. Symptoms were reported by 47·1% (n = 40) and self-isolation by 25·9% (n = 22) participants. Only 44.1% (n = 15/34) participants with SARS-CoV-2 infection reported any symptoms within 14 days of a positive result and only 29·4% (n = 10/34) reported self-isolation periods. Overall agreement between paired saliva and OP/NP swabs was 93·4% (n = 211/226 pairs) but rates of positive concordance were low. In paired samples with at least one positive result, 35·0% (n = 7/20) were positive exclusively by OP/NP swab, 40·0% (n = 8/20) exclusively by saliva and in only 25·0% (n = 5/20) were the OP/NP and saliva result both positive.ConclusionsHCW are a potential source of SARS-CoV-2 transmission in hospitals and symptom screening will identify the minority of infections. Without routine asymptomatic SARS-CoV-2 screening, it is likely that HCW with SARS-CoV-2 infection would continue to attend work. Saliva, in addition to OP/NP swab testing, facilitated ascertainment of symptomatic and asymptomatic SARS-CoV-2 infections. Combined saliva and OP/NP swab sampling would improve detection of SARS-CoV-2 for surveillance and is recommended for a high sensitivity strategy.

We report on a family with ornithine transcarbamylase (OTC) deficiency, an X-linked urea cycle disorder, with variable disease severity and tailored management strategies based on each family member's biochemical profile and clinical presentation. Our primary patient is a female monozygotic twin who presented to medical care at 10 months of age with acute liver failure, gastrointestinal symptoms, altered mental status, hypoglycemia, and hyperammonemia. The patient's older brother, known to have hemizygous OTC deficiency, died at 8 months of age from cardiac arrest after complications secondary to his diagnosis. Despite her family history, manifestation of symptoms of heterozygous (partial) OTC deficiency went unrecognized by multiple providers based on misconceptions regarding a female's risk for X-linked disease. Despite barriers related to the family's low socioeconomic status, follow-up care by a multidisciplinary metabolic care team, including moderate protein restriction and nitrogen scavenger therapy, led to positive outcomes for the patient. Her twin sister and mother are also heterozygous for variants in OTC and remain controlled on moderate protein restriction. This case illustrates the importance of genotyping all individuals with genetic risk factors for OTC deficiency and the variability in disease manifestation that necessitates tailored treatment approaches for individuals with partial OTC deficiency.

Abstract Previous studies have suggested that the pneumococcal niche changes from the nasopharynx to the oral cavity with age. We use an Experimental Human Pneumococcal Challenge model to investigate pneumococcal colonisation in different anatomical niches with age. Healthy adults (n = 112) were intranasally inoculated with Streptococcus pneumoniae serotype 6B (Spn6B) and were categorised as young 18–55 years (n = 57) or older > 55 years (n = 55). Colonisation status (frequency and density) was determined by multiplex qPCR targeting the lytA and cpsA-6A/B genes in both raw and culture-enriched nasal wash and oropharyngeal swab samples collected at 2-, 7- and 14-days post-exposure. For older adults, raw and culture-enriched saliva samples were also assessed. 64% of NW samples and 54% of OPS samples were positive for Spn6B in young adults, compared to 35% of NW samples, 24% of OPS samples and 6% of saliva samples in older adults. Many colonisation events were only detected in culture-enriched samples. Experimental colonisation was detected in 72% of young adults by NW and 63% by OPS. In older adults, this was 51% by NW, 36% by OPS and 9% by saliva. The nose, as assessed by nasal wash, is the best niche for detection of experimental pneumococcal colonisation in both young and older adults.

Introduction Despite widely available vaccinations, Streptococcus pneumoniae (SPN) remains a major cause of morbidity and mortality worldwide, causing community-acquired pneumonia, meningitis, otitis media, sinusitis and bacteraemia. Here, we summarise an ethically approved protocol for a double-blind, randomised controlled trial investigating the effect of the 13-valent pneumococcal conjugate vaccine (PCV13) and the 23-valent pneumococcal polysaccharide vaccine (PPV23) on pneumococcal nasopharyngeal colonisation acquisition, density and duration using experimental human pneumococcal challenge (EHPC).Methods and analysis Healthy adult participants aged 18–50 years will be randomised to receive PCV13, PPV23 or placebo and then undergo one or two EHPCs involving intranasal administration of SPN at 1-month post-vaccination with serotype 3 (SPN3) and 6 months with serotype 6B (SPN6B). Participants randomised to PCV13 and placebo will also be randomised to one of two clinically relevant SPN3 strains from distinct lineages within clonal complex 180, clades Ia and II, creating five study groups. Following inoculation, participants will be seen on days 2, 7, 14 and 23. During the follow-up period, we will monitor safety, colonisation status, density and duration, immune responses and antigenuria. The primary outcome of the study is comparing the rate of SPN3 acquisition between the vaccinated (PCV13 or PPV23) and unvaccinated (placebo) groups as defined by classical culture. Density and duration of colonisation, comparison of acquisition rates using molecular methods and evaluation of the above measurements for individual SPN3 clades and SPN6B form the secondary objectives. Furthermore, we will explore the immune responses associated with these vaccines, their effect on colonisation and the relationship between colonisation and urinary pneumococcal antigen detection.Ethics and dissemination The study is approved by the NHS Research and Ethics Committee (Reference: 20/NW/0097) and by the Medicines and Healthcare products Regulatory Agency (Reference: CTA 25753/0001/001–0001). Findings will be published in peer-reviewed journals.Trial registration number ISRCTN15728847, NCT04974294.

Background Although recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses.Methods Here, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus.Results In both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients.Conclusion Our findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection.Trial registration ISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study).

BackgroundIn 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016.MethodsEight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS.ResultsComplete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019.ConclusionThrough effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets.

BACKGROUND. Although recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses. METHODS. Here, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus. RESULTS. In both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients. CONCLUSION. Our findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection. TRIAL REGISTRATION. ISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study)., Introduction Despite the widespread global effects of the coronavirus disease 2019 (COVID-19) pandemic, few reports have assessed potential interactions between upper airway bacterial colonization and severe acute respiratory syndrome coronavirus [...]

The authors reflect on the relationship between antidepressant use and impulse control disorder (ICD) in people suffering from Parkinson's disease (PD). Also cited are the studies showing several risk factors for ICD in PD like dopaminergic medication exposure, smoking, depression, male sex, and longer disease duration.

X-linked adrenoleukodystrophy (X-ALD) is a genetic neurodegenerative disorder with an approximate incidence of 1 in 14,700 births. Both males and females are affected. Approximately one-third of affected males develop childhood cerebral adrenoleukodystrophy, which progresses rapidly to severe disability and death. In these cases, early surveillance and treatment can be lifesaving, but only if initiated before the onset of neurologic symptoms. Therefore, X-ALD was added to the Recommended Uniform Screening Panel. We report outcomes of the initial screening of approximately 276,000 newborns in Illinois. The lipid C26:0 lysophosphatidylcholine (C26:0-LPC) was measured in dried blood spots (DBS) using liquid chromatography with tandem mass spectrometry. Results ≥ 0.28 µmol/L were considered screen positive. Of 18 screen positive results detected, 12 cases were confirmed. Results were reported as borderline if initial and repeat analyses were ≥0.18 and

Lynch syndrome is characterized by predisposition to colorectal cancer and mutations in genes involved in mismatch repair. Here, the authors use whole genome sequencing and immunohistochemistry of mismatch repair proteins to show a high prevalence of Lynch syndrome in the Icelandic population.

Children with hearing loss, and those with language disorders, can have excellent speech recognition in quiet, but still experience unique challenges when listening to speech in noisy environments. However, little is known about how speech-in-noise (SiN) perception relates to individual differences in cognitive and linguistic abilities in these children. The present study used the Norwegian version of the Hearing in Noise Test (HINT) to investigate SiN perception in 175 children aged 5.5–12.9 years, including children with cochlear implants (CI, n = 64), hearing aids (HA, n = 37), developmental language disorder (DLD, n = 16) and typical development (TD, n = 58). Further, the study examined whether general language ability, verbal memory span, non-verbal IQ and speech perception of monosyllables and sentences in quiet were predictors of performance on the HINT. To allow comparisons across ages, scores derived from age-based norms were used for the HINT and the tests of language and cognition. There were significant differences in SiN perception between all the groups except between the HA and DLD groups, with the CI group requiring the highest signal-to-noise ratios (i.e., poorest performance) and the TD group requiring the lowest signal-to-noise ratios. For the full sample, language ability explained significant variance in HINT performance beyond speech perception in quiet. Follow-up analyses for the separate groups revealed that language ability was a significant predictor of HINT performance for children with CI, HA, and DLD, but not for children with TD. Memory span and IQ did not predict variance in SiN perception when language ability and speech perception in quiet were taken into account. The finding of a robust relation between SiN perception and general language skills in all three clinical groups call for further investigation into the mechanisms that underlie this association.

ObjectiveImmune therapy with the PD1 inhibitor pembrolizumab has been approved to treat unresectable/metastatic solid tumours exhibiting mismatch repair (MMR) deficiency. Lynch syndrome (LS), caused by autosomal dominant germline mutations of a MMR gene, predisposes to the development of MMR-deficient cancers. We report a case of MSH2-LS with an MMR-intact pancreatic ductal adenocarcinoma (PDAC) ineligible for treatment with pembrolizumab.DesignImmunohistochemistry of MMR proteins was performed in each malignancy developed in a MSH2-LS patient to determine MMR status.ResultsThe patient carried a pathogenic MSH2 germline mutation and had a history of LS-type cancers, including endometrial carcinoma, colorectal adenocarcinoma, urothelial carcinoma of the bladder and PDAC. Three malignancies (endometrial, colorectal, urothelial) lacked MSH2 and MSH6 expression, consistent with MSH2-associated tumorigenesis. However, MSH2 and MSH6 expression were intact in the PDAC, suggesting the sporadic occurrence of the pancreatic tumour unrelated to the germline MSH2 mutation. These inconsistent MMR statuses among the tumours rendered the patient ineligible for the immunotherapy pembrolizumab.ConclusionTesting for MMR protein expression is recommended for each tumour in patients with LS, especially pancreatic, as discordant results may have profound effects on treatment opportunities. To our knowledge, this is the first documented case of MMR-intact PDAC in a patient with MSH2-LS.

Purpose: The purpose of this paper is to examine current approaches to interpretation of student evaluation data and present an innovative approach to developing benchmark targets for the effective and efficient use of these data. Design/Methodology/Approach: This article discusses traditional approaches to gathering and using student feedback across the tertiary sector. The limitations of the customary use of the statistical mean as a quality measure of performance are presented and examined. An alternative method of interpreting student evaluation data is proposed and examples given. Findings: The traditional use of the statistical mean to interpret student evaluation data has limitations. Focusing on data at the macro level provides subject teaching staff and managers with a clearer indication of student satisfaction. The use of a percentage satisfied and percentage dissatisfied metric to classify and rank subjects is presented as an efficient alternative to the traditional approach, while recognising the value of the statistical mean to interpret data at the micro level. Originality/Value: In light of the important role student feedback plays in determining university ranking, prioritising staff development and its potential function as an academic performance indicator, the effective interpretation of student evaluation data is critical. As economic factors become increasingly important to higher education providers, the role of evaluation data obtained from students will continue to gain traction. The identification of methods to fully capitalise on the value of these data, such as the one proposed in this article, is therefore crucial.