Meta-analytic findings on reading in children with cochlear implants This meta-analysis study aims to quantify the group differences in reading skills between children with cochlear implants and their hearing peers and between children with cochlear implants and children with hearing aids (aged between 3 to 18 years old). Of the 5,642 articles screened, 47 articles met predetermined inclusion criteria (published between 2002 and 2019). The robust variance estimation based meta-analysis models were used to synthesize all the effect sizes. Children with cochlear implants scored significantly lower than their hearing peers in phonological awareness (g = - 1.62, p < .001), vocabulary (g = -1.50, p < .001), decoding (g = -1.24, p < .001), and reading comprehension (g = -1.39, p < .001), but not for fluency (g = -.67, p = .054). Compared to children with hearing aids, children with cochlear implants scored significantly lower in phonological awareness (g = -.30, p = .028). The percentage of unilateral cochlear implant negatively impacts the group difference between children with cochlear implants and their hearing peers. Findings from this study confirm a positive shift in reading outcomes for profoundly deaf children due to cochlear implantation. Some children with cochlear implants may need additional supports in educational settings.
The effect of stimulus duration on preferences for gain adjustments when listening to speech ObjectivesIn the personalisation of hearing aid fittings, gain is often adjusted to suit patient preferences using live speech. When using brief sentences as stimuli, the minimum gain adjustments necessary to elicit consistent preferences ( preference thresholds) were previously found to be much greater than typical adjustments in current practice. The current study examined the role of duration on preference thresholds.

DesignParticipants heard 2, 4 and 6-s segments of a continuous monologue presented successively in pairs. The first segment of each pair was presented at each individuals real-ear or prescribed gain. The second segment was presented with a {+/-}0-12 dB gain adjustment in one of three frequency bands. Participants judged whether the second was "better", "worse" or "no different" from the first.

Study SampleTwenty-nine adults, all with hearing-aid experience.

ResultsThe minimum gain adjustments needed to elicit "better" or "worse" judgments decreased with increasing duration for most adjustments. Inter-participant agreement and intra-participant reliability increased with increasing duration up to 4 s, then remained stable.

ConclusionsProviding longer stimuli improves the likelihood of patients providing reliable judgments of hearing-aid gain adjustments, but the effect is limited, and alternative fitting methods may be more viable for effective hearing-aid personalisation.
Investigating trends in those who experience menstrual bleeding changes after SARS-CoV-2 vaccination Early in 2021, many people began sharing that they experienced unexpected menstrual bleeding after SARS-CoV-2 inoculation. We investigated this emerging phenomenon of changed menstrual bleeding patterns among a convenience sample of currently and formerly menstruating people using a web-based survey. In this sample, 42% of people with regular menstrual cycles bled more heavily than usual while 44% reported no change after being vaccinated. Among respondents who typically do not menstruate, 71% of people on long-acting reversible contraceptives, 39% of people on gender-affirming hormones, and 66% of post-menopausal people reported breakthrough bleeding. We found increased/breakthrough bleeding was significantly associated with age, systemic vaccine side effects (fever, fatigue), history of pregnancy or birth, and ethnicity. Generally, changes to menstrual bleeding are not uncommon nor dangerous, yet attention to these experiences is necessary to build trust in medicine.

TeaserIncreased bleeding can occur post SARS-CoV-2 vaccines; this study investigates patterns in who experiences these changes. Substance Use Onset in High-Risk 9-13 Year-Olds in the ABCD Study AimA key aim of the Adolescent Brain Cognitive DevelopmentSM (ABCD) Study is to document substance use onset, patterns, and sequelae across adolescent development. However, substance use misreporting obscures accurate drug use characterization. Hair toxicology tests provide objective historical substance use data, but are rarely investigated in youth. Here, we compare objective hair toxicology results with self-reported substance use in youth.

MethodsA literature-based substance use risk algorithm identified 696 ABCD Study(R) participants for hair sample collections between baseline and 2-year follow-up (spanning ages 9-13) for laboratory analysis. Chi-square and t-tests assessed differences between participants demographics, positive and negative hair tests, risk algorithm scores, and self-reported substance use.

ResultsHair testing confirmed that 17% of at-risk 9-13 year-olds had evidence of past 3-month use of one (n=99), two (n=17), three (n=3), or four (n=2) drug classes. After considering prescribed medication use, 11% had a positive test incongruent with self- or parent-report. No participant with a positive result self-reported substance use consistent with their toxicology results. Participants with positive tests under-reported use (p<.001), reported less sipping of alcohol (p<.001), and scored higher on the risk algorithm (p<.001) than those with negative hair toxicology.

ConclusionsAn alarming 11% of tested samples in at-risk 9-13 year-olds were positive for at least one unreported substance, suggesting underreporting in this population when participating in a national healthy development study. The degree of underreporting cannot yet be calculated, as at-risk samples were prioritized for assays. Expanded toxicology testing is key to characterize substance use in youth. Longitudinal determination of mRNA-vaccination induced strongly binding SARS-CoV-2 IgG antibodies in a cohort of Romanian healthcare workers Mass vaccination against the disease caused by the novel coronavirus (COVID-19) was a crucial step in slowing the spread of SARS-CoV-2 in 2021. Even in the face of new variants, it still remains extremely important for reducing hospitalizations and COVID-19 deaths. Only limited data exists about the short- and long-term dynamics of humoral immune response. We present a longitudinal analysis of post-vaccination IgG levels in a cohort of 166 healthcare workers vaccinated with BNT162b2 with weekly follow-up until 35 days past the first dose and monthly follow-up up to 6 months post-vaccination. A subset of the patients continued with follow-up after 6 months and either received a booster dose or got infected during the Delta wave in Romania. Tests were carried out on 1697 samples using a CE-marked IgG ELISA assay developed in-house, containing S1 and N antigens of the wild type virus.

Participants infected with SARS-CoV-2 before vaccination mount a quick immune response, reaching peak IgG levels two weeks after the first dose, while IgG levels of previously uninfected participants mount gradually, increasing abruptly after the second dose. Overall higher IgG levels are maintained for the previously infected group 35-70 days after vaccination. The decrease of IgG levels is gradual, with lower overall values in the infection naive cohort even 7-8 months after vaccination, compared to the previously infected cohort. Administration of a booster dose yielded higher average IgG antibody levels than post second dose in the infection naive group and comparable levels in the previously infected group. Preterm outcomes following COVID-19 lockdowns, Melbourne, Australia BackgroundCommunity lockdowns during the COVID-19 pandemic may influence preterm birth rates, but mechanisms are unclear.

MethodsWe compared neonatal outcomes of preterm infants born to mothers exposed to community lockdowns in 2020 (exposed group) to those born in 2019 (control group). Main outcome studied was composite of significant neonatal morbidity or death.

ResultsMedian gestational age was 35+4 weeks (295 infants, exposed group) vs. 35+0 weeks (347 infants, control group) (p = 0.108). The main outcome occurred in 36/295 (12.2%) infants in exposed group vs. 46/347 (13.3%) in control group (p = 0.69). Continuous positive airway pressure (CPAP) use, jaundice requiring phototherapy, hypoglycaemia requiring treatment, early neonatal white cell and neutrophil counts were significantly reduced in the exposed group.

ConclusionsCOVID-19 community lockdowns did not alter composite neonatal outcomes in preterm infants, but reduced rates of some common outcomes, and early white cell and neutrophil counts. Sequencing individual genomes with recurrent genomic disorder deletions reveals genes for autosomal recessive traits In medical genetics, discovery and characterization of disease trait contributory genes and alleles depends on genetic reasoning, study design, and patient ascertainment; we now suggest a segmental haploid genetics approach to enhance gene discovery and molecular diagnostics. We present novel genomic insights to enhance discovery in the challenging context of autosomal recessive (AR) traits and bi-allelic variation. We demonstrate computationally that new mutation mediated by nonallelic homologous recombination (NAHR), involving recurrent deletions at 30 genomic regions, likely drives recessive disease burden for over 70% of loci within these segmental deletions or at least 2% of loci genome wide. Meta-analyses of literature-reported patients implicate that NAHR-deletions are depleted from the ascertained pool of AR trait alleles. Exome reanalysis of personal genomes from subjects harboring recurrent deletions uncovered new disease-contributing variants in genes including COX10, ERCC6, PRRT2 and OTUD7A. Our data demonstrate that genomic sequencing of personal genomes with NAHR-deletions could dramatically foment allele and gene discovery, enhance clinical molecular diagnosis, and could potentially enable human haploid genetics screens as an approach to disease biology. Factors affecting first return to work following arthroscopic rotator cuff repair: A retrospective observational study in an occupational medicine clinic and single-surgeon practice BackgroundReturn to work (RTW) following arthroscopic rotator cuff repair (aRCR) within New South Wales (NSW), Australia, under compensable schemes has not been reported.

AimsDetermine factors affecting RTW status and time in patients treated with aRCR under state-based compensation schemes, compared to those outside such schemes.

MethodsPatients undergoing aRCR by one surgeon with minimum 1-year follow-up were grouped into those under (CP) or outside (non-CP) workers or vehicle accident compensation schemes, matched by age and gender. RTW status and time were assessed using chi-square analysis and multivariable linear regression.

ResultsOf 1054 available patients, 90 CP patients were identified with 29 consented and matched to non-CP (N=29). A higher proportion of CP patients (17.2 vs 0%, P<0.001) never returned to work and a lower proportion resumed pre-injury duties at first RTW (3 vs 52%, P<0.01). Median time to first RTW did not differ between CP and non-CP groups (5.1 vs 4.4, P=0.86). Smoking (P=0.007) and post-injury activity level (P=0.004) were significantly associated with longer time to first RTW, whereas compensation status was not.

ConclusionsCP patients undergoing aRCR in NSW are at risk of not returning to work. For those that return, there is no significant difference compared to non-CP in time to first RTW. Particularly, patient and management factors associated with extended time to first RTW have been identified. Interventions aimed at modifiable factors such as smoking cessation and increasing preoperative activity may improve future outcomes.

What is already known about this subjectO_LIWork-related injury and disease present a significant financial burden to the Australian economy ($AUD61.8billion per annum), with shoulder conditions due to body stressing accounting for 7% of this total cost (>$AUD4.2billion)
C_LIO_LIPatients receiving compensation appear to have poorer outcomes and take longer to return to work than their non-compensated counterparts, but the degree to which this occurs is variably reported in the literature
C_LIO_LIThe effect of modifiable factors on return to work status and time remain unclear, and have not previously been reported for the Australian population under the New South Wales workers compensation scheme
C_LI

What this study addsO_LIPatients receiving arthroscopic rotator cuff repair under a compensable scheme in New South Wales are at increased risk of not returning to work compared to patients presenting outside of a compensable scheme and patients in equivalent schemes internationally
C_LIO_LIPatients reporting a longer duration of symptoms and smokers are at increased risk of extended time to first return to work
C_LI

What impact this may have on practice or policyO_LIThe study has identified smoking and pre-surgery activity levels as key targets for intervention in patients receiving arthroscopic rotator cuff repair under a workers compensation scheme in New South Wales
C_LIO_LIBy further investigating whether interventions designed to modify these factors are able to favourably affect patient outcomes, there is potential to return patients to their preoperative level of work sooner
C_LI Prevalence of vitamin D is not associated with the COVID-19 epidemic in Europe. A critical update of the existing evidence. BackgroundCOVID-19 has emerged as a global pandemic, affecting nearly 104 million people worldwide as of February 4th 2021. In previous published studies, the association between the mean Vit D status of each country and COVID-19 infection rate, and mortality among the adult population in European countries was examined. The aim of this study was to re-examine the relationship between the Vit D status of each country and COVID-19 infection, recovery, and mortality using updated data and a different methodological approach.

MethodsInformation only form the last decade on Vit D concentration/deficiency for each country was retrieved through literature search on PubMed(R) database. As of February, 4th 2021, COVID-19 infections and mortalities per one million population as well as total recoveries were extracted from the Worldometer website. The association between vitamin D deficiency and COVID-19 infection, recovery, and mortality were explored using correlation coefficients and scatterplots.

FindingsThe prevalence of vitamin D deficiency among European countries ranged from 6.0 (Finland) to 75.5% (Turkey), with several countries facing more than 50% of vitamin D deficiency among their population. Non-significant correlations were observed between the number of COVID-19 infections (r=0.190; p=0.374), recoveries (rs=0.317, p=0.131), and mortalities (r=0.129; p=0.549) per one million population, with the prevalence of vitamin D deficiency.

InterpretationPrevalence of vitamin D deficiency was not significantly associated with either number of infections, recoveries or mortality rate of COVID-19 among European countries. Thus, it is an important parameter to be considered when implementing preventive measures to face COVID-19.

FundingNone Shorter serial intervals in SARS-CoV-2 cases with Omicron BA.1 variant compared to Delta variant in the Netherlands, 13 - 26 December 2021 The SARS-CoV-2 Omicron variant has a growth advantage over the Delta variant, due to higher transmissibility, immune evasion, or a shorter serial interval. Using S-gene target failure (SGTF) as indication for Omicron BA.1, we identify 908 SGTF and 1621 non-SGTF serial intervals in the same period. Within households, we find that the mean serial interval for SGTF cases is 0.2-0.6 days shorter than for non-SGTF cases. This suggests that the growth advantage of Omicron is partly due to a shorter serial interval. COVID-19 vaccine-associated cerebral venous thrombosis in Germany ObjectiveReports of cerebral sinus and venous thrombosis (CVT) after ChAdOx1 vaccination against SARS-CoV-2 have raised safety concerns. We aimed to estimate the incidence of CVT within one month from first dose administration and the frequency of vaccine-induced immune thrombotic thrombocytopenia (VITT) as the underlying mechanism after vaccination with BNT162b2, ChAdOx1, and mRNA-1273, in Germany.

MethodsA web-based questionnaire was e-mailed to all Departments of Neurology. We asked to report cases of CVT within one month of a COVID-19 vaccination. Other cerebral events could also be reported. Incidence rates of CVT were calculated by using official statistics of nine German States.

ResultsA total of 45 CVT cases were reported. In addition, 9 primary ischemic strokes, 4 primary intracerebral hemorrhages, and 4 other neurological events were recorded. Of the CVT patients, 35 (77.8%) were female, and 36 (80.0%) were below the age of 60 years. Fifty-three events were observed after vaccination with ChAdOx1 (85.5%), 9 after BNT162b2 (14.5%), and none after mRNA-1273 vaccination. After 7,126,434 first vaccine doses, the incidence rate of CVT within one month from first dose administration was 6.5 (95% CI, 4.4-9.2) per 100,000 person-years for all vaccines and 17.9 (11.8-26.1) for ChAdOx1 (after 2,320,535 ChAdOx1 first doses). The adjusted incidence rate ratio was 9.68 (3.46-34.98) for ChAdOx1 compared to mRNA-based vaccines and 3.14 (1.22-10.65) for women compared to non-women. In 26/45 patients with CVT (57.8%), VITT was graded highly probable.

ConclusionsGiven an incidence of 0.22-1.75 per 100,000 person-years for CVT in the general population, these findings point towards a higher risk for CVT after ChAdOx1 vaccination, especially for women. Surgical interventions targeting the nucleus caudalis for craniofacial pain: a systematic and historical review. IntroductionChronic facial pain is a prevalent group of conditions and when refractory to common treatments poses a social and economic burden. The last decade has seen a multitude of advancements in the multimodal management of pain. Ablative or neuromodulatory interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex is one such treatment that has remained underutilized.

MethodsHere we present a systematic review of the literature and historical perspective regarding interventions targeting the NC. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome reporting scheme was devised to allow comparison between studies using differing outcome reporting methods.

ResultsA review of the literature revealed 49 retrospective studies published over the last 80 years, reporting on 858 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy (n=515, 60.0%); however, there has been an emergence of novel approaches such as endoscopic (n=6, 0.7%) and spinal cord stimulation (n=20, 2.3%) in the last 10 years. Regardless of intervention technique or preoperative diagnosis, 90.4% of patients demonstrated some improvement from treatment.

ConclusionThis systematic review highlights recent advancements in NC intervention technique and the wide range of facial pain syndromes for which these interventions show promising efficacy. New and less invasive techniques continue to emerge, however prospective studies remain absent in the literature. Future work should address efficacy comparisons between intervention type and preoperative diagnosis. Background rates of five thrombosis with thrombocytopenia syndromes of special interest for COVID-19 vaccine safety surveillance: incidence between 2017 and 2019 and patient profiles from 25.4 million people in six European countries BackgroundThrombosis with thrombocytopenia syndrome (TTS) has been reported among individuals vaccinated with adenovirus-vectored COVID-19 vaccines. In this study we describe the background incidence of TTS in 6 European countries.

MethodsElectronic medical records from France, Netherlands, Italy, Germany, Spain, and the United Kingdom informed the study. Incidence rates of cerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), deep vein thrombosis (DVT), pulmonary embolism (PE), and stroke, all with concurrent thrombocytopenia, were estimated among the general population between 2017 to 2019. A range of additional adverse events of special interest for COVID-19 vaccinations were also studied in a similar manner.

FindingsA total of 25,432,658 individuals were included. Background rates ranged from 1.0 (0.7 to 1.4) to 8.5 (7.4 to 9.9) per 100,000 person-years for DVT with thrombocytopenia, from 0.5 (0.3 to 0.6) to 20.8 (18.9 to 22.8) for PE with thrombocytopenia, from 0.1 (0.0 to 0.1) to 2.5 (2.2 to 2.7) for SVT with thrombocytopenia, and from 0.2 (0.0 to 0.4) to 30.9 (28.6 to 33.3) for stroke with thrombocytopenia. CVST with thrombocytopenia was only identified in one database, with incidence rate of 0.1 (0.1 to 0.2) per 100,000 person-years. The incidence of TTS increased with age, with those affected typically having more comorbidities and greater medication use than the general population. TTS was also more often seen in men than women. A sizeable proportion of those affected were seen to have been taking antithrombotic and anticoagulant therapies prior to their TTS event.

InterpretationAlthough rates vary across databases, TTS has consistently been seen to be a very rare event among the general population. While still very rare, rates of TTS are typically higher among older individuals, and those affected were also seen to generally be male and have more comorbidities and greater medication use than the general population.

FundingThis study was funded by the European Medicines Agency (EMA/2017/09/PE Lot 3). Impact of tozinameran (BNT162b2) mRNA vaccine on kidney transplant and chronic dialysis patients: 3-5 months followup BackgroundDetermining the humoral immunogenicity of tozinameran (BNT162b2) vaccine in patients requiring chronic renal replacement therapy, and its impact on COVID-19 morbidity several months after vaccination, will guide risk assessment and subsequent changes in vaccination policy.

MethodsIn a prospective post-vaccination cohort study with up to 5 months follow-up we studied outpatient dialysis and kidney transplant patients and respective healthcare teams. Outcomes were anti S1/S2 antibody response to vaccine or infection and infection rate during followup.

Results175 dialysis patients (40% women, 65{+/-}15 years), 252 kidney transplant patients (33% women, 54{+/-}14 years) and 71 controls (65% women, 44{+/-}14 years) were followed. Three months or longer after vaccination we detected anti S1/S2 IgG antibodies in 80% of dialysis patients, 44% of transplant recipients and 100% of controls, whereas respective rates after infection were 94%, 75% and 100%. Predictors of non-response were older age, diabetes, history of cancer, lower lymphocyte count and lower vitamin-D levels. Factors associated with lower titers in dialysis patients were modality (hemodialysis vs peritoneal) and high serum ferritin levels. In transplant patients, hypertension and higher calcineurin or mTOR inhibitor drug levels were linked with diminished antibody response. Vaccination associated with fewer subsequent infections (HR=0.23, p<0.05). Moreover, higher antibody titers associated with fewer events, HR 0.41 for each unit increased in log10titer (p<0.05).

ConclusionsDialysis patients, and more so kidney transplant recipients, mounted reduced antibody response to COVID-19 mRNA vaccination, and lesser humoral response associated with more infections. Measures to identify and protect non-responsive patients are urgently required.

SignificanceReports on the humoral immunogenicity of SARS-CoV-2 mRNA vaccines in patients with end stage renal disease are scarce, and association with subsequent COVID-19 morbidity is unknown. In this cohort study that included 175 patients treated with dialysis, 252 kidney transplant recipients and 71 control volunteers, the proportion achieving an antibody response was time- and group-dependent, reaching 80%, 44% and 100% at 3 months post prime inoculation. Personal history of vaccination, positive antibody responses and antibody titers associated with significantly lower risk of COVID-19 infection. Thus, in patients with end stage renal disease, SARS-CoV-2 antibody testing may be warranted after vaccination, to identify non-responders at higher risk for disease. The effect of hypersensitivity pneumonitis guideline on pathologic diagnosis of interstitial pneumonia Hypersensitivity pneumonitis (HP) and interstitial pneumonia (IP) have several overlapping characteristics, and a high diagnostic concordance rate of HP is rarely obtained. New guideline, highly influenced by pathology, were devised for its diagnosis. We recently reported that the 2020 HP guideline may result in a possible overdiagnosis of fibrotic HP (fHP) through multidisciplinary discussion. Here, we attempted to investigate the impact of the 2020 HP guideline on the pathological diagnosis of cases previously diagnosed as IP. We classified 247 cases with fibrotic IP diagnoses sourced from 2014-2019 into three categories according to the 2020 HP guideline: typical, probable, and indeterminate HP. The original pathological diagnosis and categorization based on the 2020 HP guideline were compared. The clinical data including serum data and pulmonary function tests were compared among groups. The number of cases that changed to HP from an original diagnosis other than HP based on the guideline was 56 (23%). The clinical data of these cases bore a greater resemblance to cases diagnosed as indeterminate for HP than those diagnosed as typical or probable. The ratio of typical and probable HP to the total cases was significantly lower when using a transbronchial lung cryobiopsy (TBLC). Based on the new guideline, the pathological diagnosis of HP efficiently excluded HP cases but increased the rate of HP diagnosis for cases with fibrotic IP that may not suit an HP diagnosis. Thus, a TBLC may not be useful when imparting findings for fibrotic HP diagnosis using the new criteria.

Key messagesO_LIWhat is the key question? >
Does the 2020 HP Guideline improve pathological diagnosis?
C_LIO_LIWhat is the bottom line? >
By applying the new guideline, about 1/4 of the pathological diagnoses were changed from not chronic HP to probable or typical fHP, but most of the changed cases showed a clinical picture closer to not chronic HP.
C_LIO_LIWhy read on? >
To understand that simple application of the pathological criteria of the HP guideline may cause a misleading diagnosis.
C_LI Caffeine and Methylliberine: A Human Pharmacokinetic Interaction Study Methylliberine and theacrine are methylurates found in the leaves of various Coffea species and Camellia assamica var. kucha, respectively. We previously demonstrated that the methylxanthine caffeine increased theacrines oral bioavailability in humans. Consequently, we conducted a double-blind, placebo-controlled study pharmacokinetic study in humans administered methylliberine, theacrine, and caffeine to determine methylliberines pharmacokinetic interaction potential with either caffeine or theacrine. Subjects (n = 12) received an oral dose of either methylliberine (25 or 100 mg), caffeine (150 mg), methylliberine (100 mg) plus caffeine (150 mg), or methylliberine (100 mg) plus theacrine (50 mg) using a randomized, double-blind, crossover design. Blood samples were collected over 24 hours and analyzed for methylliberine, theacrine, and caffeine using UPLC-MS/MS. Methylliberine exhibited linear pharmacokinetics that were unaffected by co-administration of either caffeine or theacrine. However, methylliberine co-administration resulted in decreased oral clearance (41.9 {+/-} 19.5 vs. 17.1 {+/-} 7.80 L/hr) and increased half-life (7.2 {+/-} 5.6 versus 15 {+/-} 5.8 hrs) of caffeine. Methylliberine had no impact on caffeines maximum concentration (440 {+/-} 140 vs. 458 {+/-} 93.5 ng/mL) or oral volume of distribution (351 {+/-} 148 vs. 316 {+/-} 76.4 L). We previously demonstrated theacrine bioavailability was enhanced by caffeine, however, caffeine pharmacokinetics were unaffected by theacrine. Herein, we found that methylliberine altered caffeine pharmacokinetics without a reciprocal interaction, which suggests caffeine may interact uniquely with different methylurates. Understanding the mechanism(s) of interaction between methylxanthines and methylurates is of critical importance in light of the recent advent of dietary supplements containing both purine alkaloid classes. A User Preference Analysis Of Commercial Breath Ketone Sensors To Inform The Development Of Portable Breath Ketone Sensors For Diabetes Management In Young People BackgroundPortable breath ketone sensors may help people with Type 1 Diabetes Mellitus (T1DM) avoid episodes of diabetic ketoacidosis; however the design features preferred by users have not been studied. We aimed to elucidate breath analysis and design preferences associated with commercial breath ketone devices among young people with T1DM aged 12-16 years and their parents in order to inform the development of a breath ketone sensor prototype for diabetes management.

Research Designs and MethodsTwo commercially available breath ketone sensors, designed for ketogenic diet monitoring, were explored over one week by ten young people with T1DM to get an insight into breath measurements. Participants interacted with the devices at least twice daily for five days, taking breath ketone, blood ketone and blood glucose measurements. Semi-structured interviews were conducted post-testing with the young participants and their caregivers to elicit preferences related to breath analysis and to inform the co-design of a diabetes breath ketone sensor prototype. To validate the results from a professional healthcare perspective, we interviewed two diabetes educators working in pediatric care about their perspective of young people using breath ketone sensors.

ResultsParticipants acknowledged the non-invasiveness of breath sensors as compared to blood testing. Affordability, reliability and accuracy were identified as prerequisites for breath ketone sensors used for diabetes management. Design features valued by young people included portability, ease of use, sustainability, readability and suitability for use in public. The time required to use breath sensors was similar to that for blood testing. The requirement to maintain a 10-second breath exhalation posed a challenge for users. Diabetes educators highlighted the ease of use of breath devices especially for young people with insufficient blood ketone testing.

ConclusionsBreath ketone sensors for diabetes management bear potential to facilitate ketone testing in young people. Our study affirms features for young people that drive usability of breath sensors among this population, and provides a model of user preference assessment.

Highlights/new findingsO_LIPortable breath ketone sensors potentially offer a non-invasive alternative to blood ketone testing in diabetes management, especially for young people with diabetes.
C_LIO_LIA user preference assessment of portable non-medical breath ketone devices among young people with Type 1 Diabetes Mellitus demonstrates the key values associated with breath ketone devices for diabetes management.
C_LIO_LIThe time to test for breath ketones was similar to that of blood ketone testing.
C_LIO_LIYoung people can and should be engaged in co-creation of medical devices that they will use.
C_LI Strain-resolved analysis in a randomized trial of antibiotic pretreatment and maintenance dose delivery mode with fecal microbiota transplant for ulcerative colitis Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2x2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after six weeks of treatment, versus 2 of 11 non-pretreated patients (odds ratio: 1.69, 95% confidence interval: -0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer. Global reports of takotsubo (stress) cardiomyopathy following COVID-19 vaccination: a systematic review and meta-analysis Background and aimsConcerns have been raised recently about takotsubo cardiomyopathy after receiving COVID-19 vaccines, particularly the messenger RNA (mRNA) vaccines. The goal of this study was to compile case reports in order to provide a comprehensive overview of takotsubo cardiomyopathy associated with COVID-19 vaccines.

MethodsFrom inception until March 10, 2022, a systematic literature search was conducted in PubMed and Google Scholar. The study included individuals who developed cardiac takotsubo cardiomyopathy as a result of receiving COVID-19 vaccinations, regardless of the type of vaccine or dose.

ResultsEight studies, including 8 cases, participated in the current systematic review. The median age was 61.6 years; 87.5% were female, while 12.5% were male. 75% of the patients received the mRNA COVID-19 vaccines, while 25% received other types. In addition, takotsubo cardiomyopathy occurred in 62.5% of patients after receiving the first dose and another 25% after the second dose of COVID-19 vaccines. Moreover, the mean number of days to the onset of symptoms was 2.62 days. All cases had an elevated troponin test and abnormal ECG findings. The left ventricular ejection fraction (LVEF) was above 50% among all cases. In terms of the average length of stay in the hospital, 62.5% stayed for 10.2 days, and all cases recovered from their symptoms.

ConclusionTakotsubo (stress) cardiomyopathy complications that are associated with COVID-19 vaccination are rare, they can be life-threatening. Chest pain should be considered an alarming symptom, especially in those who had received a second dose of the vaccine in the last 3 days. For diagnosis, CK-MB and troponin are better biomarkers to confirm myocarditis than CRP, ESR, and NT-proBNP. All of cases completely recovered. What delirium detection tools are used in routine clinical practice in the United Kingdom? Survey results from 91% of acute healthcare organisations. PurposeOur aim was to collect information on delirium assessment processes and pathways in non-intensive care settings in the United Kingdom (UK).

MethodsWe sent a Freedom of Information request to 169 UK National Health Service (NHS) hospitals, trusts and health boards (units) in July 2020 to obtain data on usage of delirium assessment tools in clinical practice and delirium pathways or guidelines.

ResultsWe received responses from 154/169 units (91% response rate). Of these, 146/154 (95%) units reported use of formal delirium assessment processes and 131/154 (85%) units had guidelines or pathways in place. The 4  As Test (4AT) was the most widely used tool, with 117/146 (80%) units reporting use. The Confusion Assessment Method was used in 65/146 (45%) units, and the Single Question to identify Delirium (SQiD) in 52/146 (36%) units.

ConclusionsOur findings show that the 4AT is the most commonly used tool in the UK, with 80% of units reporting use. This study adds to our knowledge of real-world uptake of delirium detection methods at scale. Future studies should evaluate real-world implementation of delirium assessment tools further via (i) tool completion rates and (ii) rates of positive scores against the expected prevalence delirium in the clinical population concerned.

KEY SUMMARY POINTSO_ST_ABSAimC_ST_ABSTo seek information on delirium assessment processes and pathways in non-intensive clinical care settings in the United Kingdom (UK), and to assess usage of specific delirium assessment tools: the 4  As Test (4AT), Confusion Assessment Method and Single Question to identify Delirium (SQiD).

FindingsIn total, 95% of National Health Service (NHS) units (hospitals, trusts and health boards) reported use of formal delirium assessment processes and 85% of units had guidelines or pathways in place. The 4AT was the most widely used tool, with 80% of units reporting use; the Confusion Assessment Method was reportedly used in 45% of units and the SQiD in 36% of units.

MessageThis study shows real-world, large-scale uptake of delirium detection methods and delirium guidelines in UK hospitals, which contributes to ongoing efforts to improve delirium care. Distinct temporal characteristics of circulating alveolar epithelial and endothelial injury markers in ARDS with COVID-19: a preliminary retrospective report The time course and specific contributions of alveolar epithelial and endothelial injury to the pathogenesis of acute respiratory distress syndrome (ARDS) with coronavirus disease (COVID-19) remain unclear. Here, we evaluated the characteristics of circulating markers of alveolar epithelial and endothelial injury in serum samples from eleven ARDS patients and ten non-ARDS patients, all with COVID-19. Our results indicates that the alveolar epithelial injury at the very early disease stage and the endothelial injury which continues to exacerbate during the later disease stage seem to be the hallmarks of ARDS with COVID-19. Three-dimensional cephalometric landmarking and Frankfort horizontal plane construction: reproducibility of conventional and novel landmarks ObjectivesTo assess manual landmarking repeatability and reproducibility (R&R) of a set of three-dimensional (3D) landmarks and to evaluate R&R of vertical cephalometric measurements using two Frankfort Horizontal (FH) planes as references for horizontal 3D imaging reorientation.

MethodsThirty-three landmarks, divided into "conventional", "foraminal" and "dental", were manually located twice by 3 experienced operators on 20 computed tomography (CT) scans of orthognathic surgery patients. R&R of the landmark localization were computed according to the ISO 5725 standard. These landmarks were then used to construct 2 FH planes: a conventional FH plane (orbitale left, porion right and left) and a newly proposed FH plane (midinternal acoustic foramen, orbitale right and left). R&R of vertical cephalometric measurements were computed using these 2 FH planes as horizontal references for CT reorientation.

ResultsLandmarks showing a 95% confidence interval (CI) of repeatability and/or reproducibility > 2mm were found exclusively in the "conventional" landmarks group. Vertical measurements showed excellent R&R (95% CI < 1mm) with either FH plane as horizontal reference. However, the 2 FH planes were not found to be parallel (absolute angular difference of 2.41{degrees}, SD 1.27{degrees}). The average time needed to landmark one CT scan was 14 {+/-} 3 minutes.

ConclusionsThe "dental" and "foraminal" landmarks tended to be more reliable than the "conventional" landmarks. Despite the poor overall reliability of the landmarks orbitale and porion, the construction of the conventional FH plane using 3 landmarks provided a reliable horizontal reference for 3D craniofacial CT scan reorientation. The effect of D-cycloserine on brain processing of breathlessness over pulmonary rehabilitation - an experimental medicine study BackgroundPulmonary rehabilitation is the best treatment for chronic breathlessness in COPD but there remains an unmet need to improve efficacy. Pulmonary rehabilitation has strong parallels with exposure-based cognitive behavioural therapies (CBT), both clinically and in terms of brain activity patterns. The partial NMDA-receptor agonist, D-cycloserine has shown promising results in enhancing efficacy of CBT, thus we hypothesised that it would similarly augment the effects of pulmonary rehabilitation in the brain. Positive findings would support further development in phase 3 clinical trials.

Methods72 participants with mild-to-moderate COPD were recruited to a double-blind pre-registered (ID: NCT01985750) experimental medicine study running parallel to a pulmonary rehabilitation course. Participants were randomised to 250mg D-cycloserine or placebo, administered immediately prior to the first four sessions of pulmonary rehabilitation. Primary outcome measures were differences between D-cycloserine and placebo in brain activity in the anterior insula, posterior insula, anterior cingulate cortices, amygdala and hippocampus following completion of pulmonary rehabilitation. Secondary outcomes included the same measures at an intermediate time point and voxel-wise difference across wider brain regions.

ResultsNo difference between D-cycloserine and placebo groups was observed across the primary or secondary outcome measures. Questionnaire and measures of respiratory function showed no group difference.

ConclusionsThis is the first study testing brain-active drugs in pulmonary rehabilitation. Rigorous trial methodology and validated surrogate end-points maximised statistical power. Although increasing evidence supports therapeutic modulation of NMDA pathways to treat symptoms, we conclude that a phase 3 clinical trial of D-cycloserine would not be worthwhile.

Key MessagesO_ST_ABSWhat is the key question?C_ST_ABSDoes the partial NMDA-receptor agonist, D-cycloserine, augment the effects of pulmonary rehabilitation on breathlessness related brain activity?

What is the bottom line?Rigorous trial methodology and validated surrogate end-points revealed no effect of D-cycloserine on breathlessness related brain activity across pulmonary rehabilitation.

Why read on?This study highlights both the value of functional magnetic resonance imaging in "de-risking" expensive clinical trials and provides detailed investigation of brain-targeted points for pharmacological treatments of breathlessness. Evaluating a first fully automated interview grounded in Multiple Mini Interview (MMI) methodology: results from a feasibility study ObjectivesGlobal, Covid-driven restrictions around face-to-face interviews for healthcare student selection have forced admissions staff to rapidly adopt adapted online systems before supporting evidence is available. We have developed, what we believe is, the first fully automated interview grounded in Multiple Mini-Interview (MMI) methodology. This study aimed to explore test re-test reliability, acceptability and usability of the system.

Design, setting and participantsmixed-methods feasibility study in Physician Associate (PA) programmes from two UK and one US university during 2019 - 2020.

Primary, secondary outcomesFeasibility measures (test retest reliability acceptability and usability) were assessed using intra-class correlation (ICC), descriptive statistics, thematic and content analysis.

MethodsVolunteers took (T1), then repeated (T2), the automated MMI, with a seven-day interval (+/- 2) then completed an evaluation questionnaire. Admissions staff participated in focus group discussions.

ResultsSixty-two students and seven admission staff participated; 34 students and four staff from UK and 28 students and three staff from US universities.

Good-excellent test-retest reliability was observed with T1 and T2 ICC between 0.62-0.81 (p<0.001) when assessed by individual total scores (range 80.6-119), station total scores 0.6-0.91, p<0.005, individual site (all ICC[&ge;] 0.76 p<0.001) and mean test retest across sites 0.82 p<0.001 (95% CI 0.7-0.9).

Admissions staff reported potential to reduce resource costs and bias through a more objective screening tool for pre-selection or to replace some MMI stations in a  hybrid model. Maintaining human interaction through  touch points was considered essential.

Users positively evaluated the system, stating it was intuitive with an accessible interface. Concepts chosen for dynamic probing needed to be appropriately tailored.

ConclusionThese preliminary findings suggest that the system is reliable, generating consistent scores for candidates and is acceptable to end-users provided human touchpoints are maintained. Thus, there is evidence for the potential of such an automated system to augment healthcare student selection processes. Statistical modeling for quality risk assessment of clinical trials: follow-up at the era of remote auditing BackgroundAs investigator site audits have largely been conducted remotely during the COVID-19 pandemic, remote quality monitoring has gained some momentum. To further facilitate the conduct of remote Quality Assurance (QA) activities for clinical trials, we developed new quality indicators, building on a previously published statistical modeling methodology.

MethodsWe modeled the risk of having an audit or inspection finding using historical audits and inspections data from 2011 - 2019. We used logistic regression to model finding risk for 4 clinical impact factor (CIF) categories: Safety Reporting, Data Integrity, Consent and Protecting Endpoints.

ResultsWe could identify 15 interpretable factors influencing audit finding risk of 4 out of 5 CIF categories. They can be used to realistically predict differences in risk between 25 and 43% for different sites which suffice to rank sites by audit and inspection finding risk.

ConclusionContinuous surveillance of the identified risk factors and resulting risk estimates could be used to complement remote QA strategies for clinical trials and help to manage audit targets and audit focus also in post-pandemic times. Hepatic resection versus transarterial chemoembolization for the intermediate stage hepatocellular carcinoma：A cohort study BackgroundThe selection criterion for hepatic resection(HR) in intermediate-stage(IM) hepatocellular carcinoma(HCC) is still controversial. We used real-world data to evaluate the overall survival (OS) treated with HR or TACE.

MethodsIn all, 942 patients with IM-HCC were categorized in HR and TACE groups. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score- matched (PSM) analyses. The smooth curve was performed through the generalized additive model. The interaction test was performed to evaluate the HR impact on OS concerning risk factors. Also, we used multiple imputation to deal with the missing data.

ResultsTotally, 23.0% (n=225) of patients received HR. At a median overall survival of 23.7 months, HR was associated with the improved OS on multivariate analysis (hazard ratio, 0.45; 95%CI: 0.35, 0.58; after PSM: 0.56; 95%CI: 0.41, 0.77). Landmark analyses limited to long-term survivors of [&ge;] 6 months, [&ge;] 1, and [&ge;] 2 years demonstrated better OS with HR in all subsets (all P<0.05). After PSM analysis, however, HR increased 20% risk of death (HR, 1.20; 95%CI: 0.67, 2.15) in the subgroup of LDH [&le;]192 U/L (P for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and the HR with respect to 1-, 3-, and 5-year observed survival rate (all P<0.05).

ConclusionHepatic resection was superior to TACE for intermediate-stage HCC in the range of LDH level > 192 U/L. Moreover, TACE might be suitable for patients with LDH level [&le;] 192 U/L.

SynopsisO_LIHepatectomy was superior to TACE for BCLC-B HCC.
C_LIO_LIHepatectomy increased 20% risk of death for LDH < 192 U/L after matching.
C_LIO_LIA significant interaction was robust between LDH and with respect to hepatectomy the 1-, 3-, and 5-year observed survival rate.
C_LI