DNA damage reduces heterogeneity and coherence of chromatin motions.

Chromatin motions depend on and may regulate genome functions, in particular the DNA damage response. In yeast, DNA double-strand breaks (DSBs) globally increase chromatin diffusion, whereas in higher eukaryotes the impact of DSBs on chromatin dynamics is more nuanced. We mapped the motions of chromatin microdomains in mammalian cells using diffractive optics and photoactivatable chromatin probes and found a high level of spatial heterogeneity. DNA damage reduces heterogeneity and imposes spatially defined shifts in motions: Distal to DNA breaks, chromatin motions are globally reduced, whereas chromatin retains higher mobility at break sites. These effects are driven by context-dependent changes in chromatin compaction. Photoactivated lattices of chromatin microdomains are ideal to quantify microscale coupling of chromatin motion. We measured correlation distances up to 2 µm in the cell nucleus, spanning chromosome territories, and speculate that this correlation distance between chromatin microdomains corresponds to the physical separation of A and B compartments identified in chromosome conformation capture experiments. After DNA damage, chromatin motions become less correlated, a phenomenon driven by phase separation at DSBs. Our data indicate tight spatial control of chromatin motions after genomic insults, which may facilitate repair at the break sites and prevent deleterious contacts of DSBs, thereby reducing the risk of genomic rearrangements.

Respiratory carriage of hypervirulent Klebsiella pneumoniae by indigenous populations of Malaysia.

Klebsiella pneumoniae is a Gram-negative Enterobacteriaceae that is classified by the World Health Organisation (WHO) as a Priority One ESKAPE pathogen. South and Southeast Asian countries are regions where both healthcare associated infections (HAI) and community acquired infections (CAI) due to extended-spectrum ß-lactamase (ESBL)-producing and carbapenem-resistant K. pneumoniae (CRKp) are of concern. As K. pneumoniae can also exist as a harmless commensal, the spread of resistance genotypes requires epidemiological vigilance. However there has been no significant study of carriage isolates from healthy individuals, particularly in Southeast Asia, and specially Malaysia. Here we describe the genomic analysis of respiratory isolates of K. pneumoniae obtained from Orang Ulu and Orang Asli communities in Malaysian Borneo and Peninsular Malaysia respectively. The majority of isolates were K. pneumoniae species complex (KpSC) 1 K. pneumoniae (n = 53, 89.8%). Four Klebsiella variicola subsp. variicola (KpSC3) and two Klebsiella quasipneumoniae subsp. similipneumoniae (KpSC4) were also found. It was discovered that 30.2% (n = 16) of the KpSC1 isolates were ST23, 11.3% (n = 6) were of ST65, 7.5% (n = 4) were ST13, and 13.2% (n = 7) were ST86. Only eight of the KpSC1 isolates encoded ESBL, but importantly not carbapenemase. Thirteen of the KpSC1 isolates carried yersiniabactin, colibactin and aerobactin, all of which harboured the rmpADC locus and are therefore characterised as hypervirulent. Co-carriage of multiple strains was minimal. In conclusion, most isolates were KpSC1, ST23, one of the most common sequence types and previously found in cases of K. pneumoniae infection. A proportion were hypervirulent (hvKp) however antibiotic resistance was low.

Risk factors and outcomes of bloodstream infection from a urinary source in kidney transplant recipients.

BACKGROUND: Bacteriuria is common among kidney transplant recipients (KTR). Risk factors and outcomes associated with bloodstream infection due to a urinary source (BSIU) in KTR are poorly understood. METHODS: This single center case-control study from 2010 to 2022 compared KTR with BSIU to those with bacteria without bloodstream infection (BU). Multivariable logistic regression identified BSIU risk factors, and Cox models assessed its impact on graft failure. RESULTS: Among 3435 patients, who underwent kidney transplantation at Emory Hospital, 757 (22%) developed bacteriuria, among whom 142 (18.8%) were BSIU. Male sex, presence of Escherichia coli, Klebsiella pneumoniae, or Pseudomonas species in urine culture, urethral stricture, neuromuscular bladder disorder, and history of diabetes-induced renal failure were independently associated with increased odds of BSIU (Male sex: aOR 2.29, 95% CI 1.52, 3.47, E. coli: aOR 5.14, 95% CI 3.02, 9.13; K. pneumoniae aOR 3.19, 95% CI 1.65, 6.27, Pseudomonas spp aOR 3.06, 95% CI 1.25, 7.18; urethral stricture: 4.10, 95% CI 1.63, 10.3, neuromuscular bladder disorder aOR 1.98, 95% CI 1.09, 3.53, diabetes: aOR 1.64, 95% CI 1.08, 2.49). BSIU was associated with increased hazard of graft failure (HR 1.52, 95% CI 1.05, 2.20). CONCLUSION: Close monitoring is warranted for male KTR with bacteriuria, those with urine cultures positive for Pseudomonas spp, K. pneumoniae, or E. coli, as well as KTR with a history of diabetes-induced renal failure, urethral stricture, or neuromuscular bladder disorder due to their risk for developing BSIU. Future research should explore strategies to mitigate BSIU risk in these high-risk KTR and reduce the associated risk of long-term graft failure.

Screening asthmatics for atopic status using the ALergy EXplorer (ALEX2) macroarray.

BACKGROUND: Screening asthma patients for atopy facilitates management. Since 2010, the core biomarker for screening asthma subjects for atopic status has been the qualitative Phadiatop. multi-aeroallergen screen. A more quantitative macroarray, the Allergy Explorer (ALEX2), shows promise as an alternative. OBJECTIVE: The study's goal was to examine the pros and cons of the use of ALEX2 in the screening of asthma patients for atopic status. METHODS: We evaluated the atopic (IgE-sensitization) status in asthmatic Amish and Hutterite farm children using the ImmunoCAP and ALEX2 assays in Phadiatop equivocal and positive subjects. RESULTS: All 42 asthmatic children were analyzed by Phadiatop and total serum IgE. Of these, 22 had a negative Phadiatop (<0.1 kUa/L) and total IgE <100 kU/L which defined them as non-atopic and they were excluded from ALEX2 testing. Of six children with equivocal Phadiatops (0.1-0.2 kUa/L-Group 1) and three children with a negative Phadiatop but total IgE >100 kUa/L (group 3), 44% (n = 4) had detectable IgE antibody by ALEX2 to mite, tree pollen, and other allergens not detected by Phadiatop, but confirmed by allergen-specific ImmunoCAP testing. In 11 Phadiatop positive subjects (>0.2 kUa/L-group 2), all but one were positive by ALEX2. IgE antibody specific for mold and rabbit aeroallergens matched their agricultural and pet exposure history. Three children were positive for IgE antibody to allergens in the profilin, nsLTP, or PR-10 cross-reactive protein families. CONCLUSION: Judicious use of ALEX2's enhanced specificity data not provided by the Phadiatop can aid in the interpretation of sensitization patterns and planning management of atopic asthmatics, but sensitization relevance must be confirmed by the patient's clinical history.

A pilot feasibility and acceptability trial of an internet indicated prevention program for perfectionism to reduce eating disorder symptoms in adolescents.

PURPOSE: Perfectionism is a transdiagnostic risk factor for eating disorders. Treating perfectionism can reduce symptoms of eating disorders. No research has examined an indicated prevention trial using internet-based Cognitive-Behavioural Therapy for Perfectionism (ICBT-P) in adolescent girls at elevated risk for eating disorders. Our aim was to conduct a preliminary feasibility trial using a co-designed ICBT-P intervention. It was hypothesised that a higher proportion of participants in the ICBT-P condition would achieve reliable and clinically significant change on perfectionism, eating disorders, anxiety and depression, compared to waitlist control. METHODS: Twenty-one adolescent girls with elevated symptoms of eating disorders (M age = 16.14 years) were randomised to a 4-week online feasibility trial of a co-designed ICBT-P prevention program or waitlist control. Qualitative surveys were used to gain participant perspectives. RESULTS: The ICBT-P condition had a higher proportion of participants achieve reliable change and classified as recovered on perfectionism and symptoms of eating disorders and anxiety, compared to waitlist control. Qualitative findings indicated that 100% of participants found the program helpful. CONCLUSION: The results indicate ICBT-P is a feasible and acceptable program for adolescent girls with elevated eating disorder symptoms. Future research is required to examine outcomes in a randomised controlled trial. LEVEL OF EVIDENCE: Level III: Evidence obtained from well-designed cohort or case-control analytic studies. TRIAL REGISTRATION NUMBER: This trial was prospectively registered with Australian and New Zealand Clinical Trials Registry (ACTRN12620000951954P) on 23/09/2020.

Characterization of Escherichia coli and Other Enterobacterales Resistant to Extended-Spectrum Cephalosporins Isolated from Dairy Manure in Ontario, Canada.

Extended-spectrum cephalosporins (ESCs) resistance genes, such as blaCTX-M, blaCMY, and blaSHV, have been found regularly in bacteria from livestock. However, information on their distribution in dairy cattle in Canada and on the associated genome sequences of ESC-resistant Enterobacterales is sparse. In this study, the diversity and distribution of ESC-resistant Escherichia coli throughout manure treatments in six farms in Southern Ontario were assessed over a one-year period, and their ESC-resistance plasmids were characterized. The manure samples were enriched using selective media. The resulting isolates were screened via polymerase chain reaction for blaCTX-M, blaCMY, and blaSHV. No E. coli carrying blaSHV were detected. Escherichia coli (n = 248) carrying blaCTX-M or blaCMY underwent whole-genome sequencing using an Illumina MiSeq/NextSeq. These isolates were typed using multilocus sequence typing (MLST) and their resistance gene profiles. A subset of E. coli (n = 28) were sequenced using Oxford Nanopore Technologies. Plasmids were assembled using Unicycler and characterized via the resistance genes pattern, replicon type, plasmid MLST, phylogenetic analysis, and Mauve alignments. The recovery of ESC-resistant Enterobacterales (18 species, 8 genera) was drastically reduced in manure outputs. However, multiple treatment stages were needed to attain a significant reduction. 62 sequence types were identified, with ST10, ST46, ST58, ST155, ST190, ST398, ST685, and ST8761 being detected throughout the treatment pipeline. These STs overlapped with those found on multiple farms. The ESC-resistance determinants included CTX-M-1, -14, -15, -17, -24, -32, -55, and CMY-2. The plasmids carrying blaCTX-M were more diverse than were the plasmids carrying blaCMY. Known "epidemic plasmids" were detected for both blaCTX-M and blaCMY. IMPORTANCE The increase in antimicrobial resistance is of concern for human and animal health, especially when resistance is conferred to extended-spectrum cephalosporins, which are used to treat serious infections in both human and veterinary medicine. Bacteria carrying extended-spectrum cephalosporin resistance genes, including blaCTX-M and blaCMY, are frequently found in dairy manure. Manure treatment influences the loads and diversity of bacteria, including those carrying antimicrobial resistance genes, such as Enterobacterales and Escherichia coli. Any bacteria that survive the treatment process are subsequently applied to the environment. Enterobacterales carrying blaCTX-M or blaCMY can contaminate soil and crops consumed by humans and animals, thereby increasing the potential for antimicrobial resistance genes to integrate into the human gut microflora through horizontal gene transfer. This furthers the dissemination of resistance. Therefore, it is imperative to understand the effects manure treatments have on ESC-resistance in environmentally applied manure.

Longitudinal association between cardiovascular risk factors and depression in young people: a systematic review and meta-analysis of cohort studies.

BACKGROUND: Depression is a common and serious mental illness that begins early in life. An association between cardiovascular disease (CVD) and subsequent depression is clear in adults. We examined associations between individual CVD risk factors and depression in young people. METHODS: We searched MEDLINE, EMBASE, and PsycINFO databases from inception to 1 January 2020. We extracted data from cohort studies assessing the longitudinal association between CVD risk factors [body mass index (BMI), smoking, systolic blood pressure (SBP), total cholesterol, high-density lipoprotein] and depression, measured using a validated tool in individuals with mean age of 24 years or younger. Random effect meta-analysis was used to combine effect estimates from individual studies, including odds ratio (OR) for depression and standardised mean difference for depressive symptoms. RESULTS: Based on meta-analysis of seven studies, comprising 15 753 participants, high BMI was associated with subsequent depression [pooled OR 1.61; 95% confidence interval (CI) 1.21-2.14; I2 = 31%]. Based on meta-analysis of eight studies, comprising 30 539 participants, smoking was associated with subsequent depression (pooled OR 1.73; 95% CI 1.36-2.20; I2 = 74%). Low, but not high, SBP was associated with an increased risk of depression (pooled OR 3.32; 95% CI 1.68-6.55; I2 = 0%), although this was based on a small pooled high-risk sample of 893 participants. Generalisability may be limited as most studies were based in North America or Europe. CONCLUSIONS: Targeting childhood/adolescent smoking and obesity may be important for the prevention of both CVD and depression across the lifespan. Further research on other CVD risk factors including blood pressure and cholesterol in young people is required.

Consensus recommendations for the assessment and treatment of perinatal obsessive-compulsive disorder (OCD): A Delphi study.

The perinatal period is one of increased vulnerability to parents experiencing the onset of, or an increase of existing, obsessive-compulsive disorder (OCD) symptoms. Existing OCD and perinatal mental health best practice guidelines do not detail specific considerations relevant to OCD in the perinatal period ('Perinatal OCD'). Perinatal OCD risks being undiagnosed or misdiagnosed, and subsequently untreated or mistreated, with potential negative impacts for individuals and families experiencing this problem, highlighting the importance of specific guidance. This study employed a modified Delphi survey methodology to establish recommended best practice for the assessment and treatment of perinatal OCD. A literature review identified 103 initial best practice recommendations, and participants suggested 18 further recommendations. These recommendations were rated for importance over three survey rounds by two expert panels, comprising of 15 professionals with clinical or research expertise in perinatal OCD and 14 consumers with lived experience of perinatal OCD. One-hundred and two statements were endorsed for inclusion in the final set of recommendations for clinical best practice with perinatal OCD. These recommendations inform practice across eight themes; psychoeducation, screening, assessment, differential diagnosis, case care considerations, treatment, partners & families, and culture & diversity. This novel study is the first to collate and outline a set of clinical best practice recommendations, developed using the consensus perspectives of both individuals with lived experience and professionals with relevant expertise, for supporting individuals with perinatal OCD and their families. Differences between panel perspectives, and directions for future research are also discussed.

Bone morphogenetic protein 2- and estradiol-17ß-induced changes in ovarian transcriptome during primordial follicle formation†.

Estradiol-17ß has been shown to promote primordial follicle formation and to involve bone morphogenetic protein 2 (BMP2) as a downstream effector to promote primordial follicle in hamsters. However, the molecular mechanism whereby these factors regulate ovarian somatic cells to pre-granulosa cells transition leading to primordial follicle formation remains unclear. The objective of this study was to determine whether BMP2 and/or estradiol-17ß would regulate the expression of specific ovarian transcriptome during pre-granulosa cells transition and primordial follicle formation in the mouse ovary. BMP2 mRNA level increased during the period of primordial follicle formation with the concurrent presence of BMP2 protein in ovarian somatic cells. Estradiol-17ß but not BMP2 exposure led to increased expression of ovarian BMP2 messenger RNA (mRNA), and the effect of estradiol-17ß could not be suppressed by 4-[6-[4-(1-Piperazinyl)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]quinoline dihydrochloride (LDN) 193189. BMP2 or estradiol-17ß stimulated primordial follicle formation without inducing apoptosis. Ribonucleic acid-sequence analysis (RNA-seq) of ovaries exposed to exogenous BMP2 or estradiol-17ß revealed differential expression of several thousand genes. Most of the differentially expressed genes, which were common between BMP2 or estradiol-17ß treatment demonstrated concordant changes, suggesting that estradiol-17ß and BMP2 affected the same set of genes during primordial follicle formation. Further, we have identified that estradiol-17ß, in cooperation with BMP2, could affect the expression of three major transcription factors, GATA binding protein 2, GATA binding protein 4 and Early growth response 2, and one serine protease, hepsin, in pre-granulosa cells during primordial follicle formation. Taken together, results of this study suggest that estradiol-17ß and BMP2 may regulate ovarian gene expression that promote somatic cells to pre-granulosa cells transition and primordial follicle formation in the mouse ovary.

Characterisation of the consequences of maternal immune activation on distinct cell populations in the developing rat spinal cord.

Maternal immune activation (MIA) during gestation has been implicated in the development of neurological disorders such as schizophrenia and autism. Epidemiological studies have suggested that the effect of MIA may depend on the gestational timing of the immune challenge and the region of the central nervous system (CNS) in question. This study investigated the effects of MIA with 100 µg/kg lipopolysaccharide at either Embryonic days (E)12 or E16 on the oligodendrocytes, microglia and astrocytes of the offspring spinal cord. At E16, MIA decreased the number of olig2+ and Iba-1+ cells in multiple grey and white matter regions of the developing spinal cord 5 h after injection. These decreases were not observed at postnatal day 14. In contrast, MIA at E12 did not alter Olig2+ or Iba-1+ cell number in the developing spinal cord 5 h after injection, however, Olig2+ cell number was decreased in the ventral grey matter of the P14 spinal cord. No changes were observed in glial fibrillary acidic protein (GFAP) expression at P14 following MIA at either E12 or E16. These data suggest that E16 may be a window of immediate vulnerability to MIA during spinal cord development, however, the findings also suggest that the developmental process may be capable of compensation over time. Potential changes in P14 animals following the challenge at E12 are indicative of the complexity of the effects of MIA during the developmental process.

An analysis of factors that influence patient preference of third-line therapy for overactive bladder.

OBJECTIVE: Patients with overactive bladder (OAB) refractory to first- and second-line therapy may pursue third-line therapies, including intradetrusor onabotulinum toxin-A (BTX), peripheral tibial nerve stimulation (PTNS), and sacral neuromodulation (SNM). The factors that influence patient preference for each treatment modality have not yet been explored. This study sought to investigate the specific parameters that patients consider in choosing a third-line therapy for OAB. METHODS: Patients refractory to first- and second-line therapies for OAB were identified in our outpatient clinic and asked to watch an educational video providing information on the risks and benefits of each third-line treatment option. They were then given a questionnaire to rank their preference of therapy and select reasons for why they found each therapy favorable and unfavorable. Patients under age 18 years, non-English speakers, those with a developmental disability, and those with a diagnosis of neurogenic bladder were excluded. RESULTS: Of the 98 patients included in the study, 40 participants (40.8%) chose intradetrusor BTX injections, 34 (34.7%) chose PTNS, and 16 (16.3%) chose SNM as their first choice. Seven patients (7.1%) chose none of the offered therapies, and one patient (1.0%) chose all three therapies with equal preference. BTX was found most attractive for its long efficacy (47%); its least attractive feature was the potential need for self-catheterization due to urinary retention (54%). PTNS was found most attractive for being a nonsurgical option (32%) and having no reported significant complications (39%); its least attractive feature was need for frequent office visits (61%). SNM was found most attractive for its potential for long-term relief without frequent office visits (53%); its least attractive feature was need for an implanted device (33%). Patients opting for SNM had higher scores on Urinary Distress Inventory-6 and Incontinence Impact Questionnaire-7 questionnaires when compared to patients opting for BTX injections or PTNS (p < 0.05). 47.4% of patients eventually pursued a third-line therapy. Of those, there was a 67.6% concordance rate between the therapy patients ranked first and the therapy they eventually underwent. CONCLUSIONS: Patients with more severe OAB symptoms opt for more invasive and less time-consuming therapy with the potential for long-term relief, namely SNM. Despite thorough counseling, many patients do not progress to advanced OAB therapies. Understanding factors that influence patients' affinity toward a specific type of treatment can aid with individualized counseling on third-line OAB therapies.

Causes of Post-Colonoscopy Colorectal Cancers Based on World Endoscopy Organization System of Analysis.

BACKGROUND & AIMS: Postcolonoscopy colorectal cancer (PCCRC) is CRC diagnosed after a colonoscopy in which no cancer was found. A consensus article from the World Endoscopy Organization (WEO) proposed an approach for investigating and categorizing PCCRCs detected within 4 years of a colonoscopy. We aimed to identify cases of PCCRC and the factors that cause them, test the WEO system of categorization, quantify the proportion of avoidable PCCRCs, and propose a target rate for PCCRCs detected within 3 years of a colonoscopy that did not detect CRC. METHODS: We performed a retrospective analysis of 107 PCCRCs identified at a single medical center in England from January 1, 2010, through December 31, 2017 using coding and endoscopy data. For each case, we reviewed clinical, pathology, radiology, and endoscopy findings. Using the WEO recommendations, we performed a root-cause analysis of each case, categorizing lesions as follows: possible missed lesion, prior examination adequate; possible missed lesion, prior examination inadequate; detected lesion, not resected; or likely incomplete resection of previously identified lesion. We determined whether PCCRCs could be attributed to the colonoscopist for technical or decision-making reasons, and whether the PCCRC was avoidable or unavoidable, based on the WEO categorization and size of tumor. The endoscopy reporting system provided performance data for individual endoscopists. RESULTS: Of the PCCRCs identified, 43% were in high-risk patients (those with inflammatory bowel disease, previous CRC, previous multiple large polyps, or hereditary cancer syndromes) and 66% were located distal to the hepatic flexure. There was no correlation between postcolonoscopy colorectal tumor size and time to diagnosis after index colonoscopy. Bowel preparation was poor in 19% of index colonoscopies, and only 36% of complete colonoscopies had adequate photodocumentation of completion. Development of 73% of PCCRCs was determined to be affected by technical endoscopic factors, 17% of PCCRCs by administrative factors (follow-up procedures delayed/not booked by administrative staff), and 27% of PCCRCs by decision-making factors. Twenty-seven percent of PCCRCs were categorized as possible missed lesion, prior examination adequate; 58% as possible missed lesion, prior examination inadequate; 8% as detected lesion, not resected; and 7% as incomplete resection of previously observed lesion; 89% were deemed to be avoidable. CONCLUSIONS: In a retrospective analysis of PCCRCs, using the WEO system of categorization, we found 43% to occur in high-risk patients; this might be reduced with more vigilant surveillance. Measures are needed to reduce technical, decision-making, and administrative factors. We found that 89% of PCCRCs may be avoidable. If half of avoidable PCCRCs could be prevented, the target rate of 2% for the PCCRC-3y (cancer diagnosed between 6 and 36 months after index colonoscopy) benchmark would be achievable.

A retrospective longitudinal evaluation of new overactive bladder patients in an FPMRS urologist practice: Are patients following up and utilizing third-line therapies?

AIMS: Third-line therapies are efficacious in improving overactive bladder (OAB) symptoms; however, OAB patients have poor follow-up and rarely progress to these therapies. Clinical care pathways (CCP) may improve OAB follow-up rates and third-line therapy use. We sought to determine how new OAB patients follow up and utilize third-line therapies with the implementation of an OAB CCP in a fellowship Female Pelvic Medicine and Reconstructive Surgery (FPMRS) trained urologist's academic practice. METHODS: We identified new OAB patients using ICD-9 and 10 codes. They were placed into two groups: pre- and post-CCP use. Basic demographic data were collected. Patients were evaluated in a retrospective longitudinal fashion over 12 months to determine follow-up and third-line therapy utilization. RESULTS: A total of 769 new OAB patients (261 pre-CCP and 508 post-CCP) were identified. The mean number of follow-up visits increased significantly at 6 months (0.94 vs. 1.64 visits, p = .001) and 12 months (1.26 vs. 2.46 visits, p < .003). Follow-up rates increased significantly at 3 months (38.7% vs. 50.2%, p = .002). Mean time to third-line therapy decreased significantly (280 days vs. 160 days, p = .016). Third-line therapy utilization therapy rates increased at 6 months (7.7% vs. 13.4%, p = .018) and at 12 months (11.1% vs. 16.5%, p = .044). CONCLUSIONS: New OAB patients follow-up and progress to third-line therapies faster and more frequently with the use of a CCP in an FPMRS-trained urologist practice. However, many OAB patients still fail to follow up and overall utilization of third-line therapies remains low. Future studies are warranted to identify factors to why overall OAB compliance remains low.

A nationwide parent survey of antibiotic use in Australian children.

BACKGROUND: Antimicrobial resistance is increasing globally, largely due to high rates of antibiotic use and misuse. Factors that influence frequent antibiotic use in children are poorly understood. OBJECTIVES: This study describes rates of antibiotic use in Australian children and investigates parental factors including knowledge, attitudes and behaviours that influence antibiotic use. METHODS: An online questionnaire relating to antibiotic use was administered as part of the Royal Children's Hospital National Child Health Poll to a randomly recruited nationwide sample of parents or guardians of children aged 0-17 years in Australia. Data on antibiotic use in children and parental knowledge of appropriate indications for antibiotics and behaviours were collected. Standard binary logistic regression was used to assess associations between parent demographics and behaviour with antibiotic administration. RESULTS: The survey was completed by 2157 parents (64% completion rate), of which 1131 (52%) reported having given oral antibiotics to one or more of their children in the preceding 12 months. Of the 3971 children represented overall, 1719 (43%) had received at least one course of antibiotics. The average number of courses per child was 0.86 overall and 1.96 courses per child among those with reported antibiotic use. Notably, 194/1131 (17%) parents reported giving antibiotics to their child without a prescription. Poor parental knowledge of antibiotic indications was associated with antibiotic use. CONCLUSIONS: Reducing excessive use of antibiotics in children is necessary in the global strategy for preventing antimicrobial resistance. This study identified areas for public health interventions to educate parents and increase regulation of access to antibiotics.

Cost-Effectiveness of Nusinersen and Universal Newborn Screening for Spinal Muscular Atrophy.

OBJECTIVE: To evaluate the cost-effectiveness of nusinersen with and without universal newborn screening for infantile-onset spinal muscular atrophy (SMA). STUDY DESIGN: A Markov model using data from clinical trials with US epidemiologic and cost data was developed. The primary interventions studied were nusinersen treatment in a screening setting, nusinersen treatment in a nonscreening setting, and standard care. Analysis was conducted from a societal perspective. RESULTS: Compared with no screening and no treatment, the incremental cost-effectiveness ratio (ICER) for nusinersen with screening was $330 558 per event-free life year (LY) saved, whereas the ICER for nusinersen treatment without screening was $508 481 per event-free LY saved. For nusinersen with screening to be cost-effective at a willingness-to-pay (WTP) threshold of $50 000 per event-free LY saved, the price would need to be $23 361 per dose, less than one-fifth its current price of $125 000. Preliminary data from the NURTURE trial indicated an 85.7% improvement in expected LYs saved compared with our base results. In probabilistic sensitivity analysis, nusinersen and screening was a preferred strategy 93% of the time at a $500 000 WTP threshold. CONCLUSION: Universal newborn screening for SMA provides improved economic value for payers and patients when nusinersen is available.

Prognosticating for Adult Patients With Advanced Incurable Cancer: a Needed Oncologist Skill.

OPINION STATEMENT: Patients with advanced cancer and their families commonly seek information about prognosis to aid decision-making in medical (e.g. surrounding treatment), psychological (e.g. saying goodbye), and social (e.g. getting affairs in order) domains. Oncologists therefore have a responsibility to identify and address these requests by formulating and sensitively communicating information about prognosis. Current evidence suggests that clinician predictions are correlated with actual survival but tend to be overestimations. In an attempt to cultivate prognostic skills, it is recommended that clinicians practice formulating and recording subjective estimates of prognosis in advanced cancer patient's medical notes. When possible, a multi-professional prognostic estimate should be sought as these may be more accurate than individual predictions alone. Clinicians may consider auditing the accuracy of their predictions periodically and using feedback from this process to improve their prognostic skills.Clinicians may also consider using validated prognostic tools to complement their clinical judgements. However, there is currently only limited evidence about the comparative accuracy of different prognostic tools or the extent to which these measures are superior to clinical judgement. Oncologists and palliative care physicians should ensure that they receive adequate training in advanced communication skills, which builds upon their pre-existing skills, to sensitively deliver information on prognosis. In particular, clinicians should acknowledge their own prognostic uncertainty and should emphasise the supportive care that can continue to be provided after stopping cancer-directed therapies.

Managing uncertainty and references to time in prognostic conversations with family members at the end of life: A conversation analytic study.

BACKGROUND: When patients are likely to die in the coming hours or days, families often want prognostic information. Prognostic uncertainty and a lack of end-of-life communication training make these conversations challenging. AIM: The objective of this study is to understand how clinicians and the relatives/friends of patients at the very end of life manage uncertainty and reference time in prognostic conversations. DESIGN: Conversation analysis of audio-recorded conversations between clinicians and the relatives/friends of hospice inpatients. SETTING/PARTICIPANTS: Experienced palliative care clinicians and relatives/friends of imminently dying hospice inpatients. Twenty-three recorded conversations involved prognostic talk and were included in the analysis. RESULTS: Requests for prognostic information were initiated by families in the majority of conversations. Clinicians responded using categorical time references such as 'days', allowing the provision of prognostic estimates without giving a precise time. Explicit terms such as 'dying' were rare during prognostic discussions. Instead, references to time were understood as relating to prognosis. Relatives displayed their awareness of prognostic uncertainty when requesting prognostic information, providing clinicians with 'permission' to be uncertain. In response, clinicians often stated their uncertainty explicitly, but presented evidence for their prognostic estimates, based on changes to the patient's function previously discussed with the family. CONCLUSION: Prognostic uncertainty was managed collaboratively by clinicians and families. Clinicians were able to provide prognostic estimates while being honest about the related uncertainty, in part because relatives displayed their awareness of uncertainty within their requests. The conversation analytic method identified contributions of both clinicians and families, and identified strategies based on real interactions, which could inform communication training.

Health practitioners' recognition and management of postpartum obsessive-compulsive thoughts of infant harm.

The postpartum period has been associated with elevated rates of onset of obsessive-compulsive disorder (OCD) among women, with a prevalence of 2-9%. Postpartum OCD is often characterized by recurrent, unwanted, and highly distressing thoughts, images, or impulses of deliberate infant harm. This study investigated health practitioners' recognition of, and clinical management strategies for, postpartum obsessive-compulsive symptoms (OCS). Ninety-four perinatal health practitioners from a range of disciplines and professional backgrounds completed a survey comprised of a hypothetical case vignette and questions eliciting their responses to a clinical presentation of postpartum infant harming obsessions. Almost 70% of participants did not accurately identify OCS within the case. Furthermore, the majority of practitioners endorsed at least one contraindicated clinical management strategy likely to aggravate postpartum OCS. Accurate recognition of OCS was associated with the selection of fewer contraindicated strategies. Some aspects of practitioner training and experience were associated with correct OCS identification. These findings underscore the need for targeted, interdisciplinary education to improve the detection and management of women experiencing postpartum OCS.

One factor? Two factor? Bi-factor? A psychometric evaluation of the Frost Multidimensional Scale and the Clinical Perfectionism Questionnaire.

The construct of perfectionism has been argued to consist of two factors, perfectionistic concerns and perfectionistic strivings. Though perfectionistic concerns are consistently associated with adverse outcomes, the evidence for perfectionistic strivings is mixed. Item cross-loadings of the two-factor model of perfectionism raise questions about whether the two factors assess both common and distinct aspects of perfectionism. The present study aimed to clarify the structure of the Frost Multidimensional Perfectionism Scale and the Clinical Perfectionism Scale, by comparing single-factor, two-factor, and bifactor models in a community sample (N = 397). Findings provided greater support for the bifactor model, relative to the two-factor or one-factor models, for the Frost Multidimensional Perfectionism Scale and the Clinical Perfectionism Scale. In each bifactor model, the general factor was positively associated with symptoms of depression, anxiety, and stress, while the perfectionistic strivings group factor was negatively associated with depression. Results suggest the bifactor model best represents the structure of perfectionism and provide additional support for the use of a general factor score in clinical treatment and research examining perfectionism.

Approaches to Photoprotection and Normalization in Highly Adherent Families of Children With Xeroderma Pigmentosum in the United Kingdom.

In this study, we examine photoprotection for children with Xeroderma pigmentosum (XP), a rare genetic skin disease requiring rigorous photoprotection, to reduce risks of severe burning and skin cancers from exposure to ultraviolet radiation (UVR). We elicit the views and experiences of both children and their parents to inform the care and support provided. Qualitative semistructured interviews were undertaken with 12 child-parent dyads recruited from the National XP Specialist service in London. We employed a framework approach to analysis. This identified a high level of photoprotection based either on "protection" to facilitate normal activities or "avoidance" of outdoor activity with priority given to normality in the future. These approaches were shaped by perceptions of clinical risk, the emphasis given to a normal family life and families' circumstances and resources. The findings contribute to notions of normalization and coping with demanding care regimens and inform approaches to working with families.