Impact of antiretroviral therapy during primary HIV infection on T-cell immunity after treatment interruption.

This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.

Differences in neuroinflammation in people who started antiretroviral treatment during primary versus chronic HIV infection: an 18kDa Translocator protein (TSPO) positron emission tomography (PET) study.

Persistent inflammation is described in people with HIV (PWH) on antiretroviral treatment (ART). Early ART initiation is associated with reduced inflammation. We aimed to evaluate neuroinflammation, using translocator protein (TSPO) [11C]PBR28 PET neuroimaging in PWH who initiated ART during acute HIV (aPWH) versus chronic HIV infection (cPWH) versus a control population. This was a cross-sectional, observational study. All participants underwent [11C]PBR28 PET-CT neuroimaging. Using a two-tissue compartment model, total volume of distribution (VT) and distribution volume ratios (DVR) using cortical grey matter as a pseudo-reference region at 20 regions of interest (ROIs) were calculated. Differences in VT and DVR were compared between groups using the Kruskall-Wallis test. Seventeen neuro-asymptomatic male PWH on ART (9 aPWH, 8 cPWH) and 8 male control participants (CPs) were included. Median (interquartile range, IQR) age was 40 (30, 46), 44 (41, 47) and 21 (20, 25) years in aPWH, cPWH and CPs, respectively. Median (IQR) CD4 (cells/µL) and CD4:CD8 were 687 (652, 1014) and 1.37 (1.24, 1.42), and 700 (500, 720) and 0.67 (0.64, 0.82) in aPWH and cPWH, respectively. Overall, no significant difference in VT and DVR were observed between the three groups at any ROIs. cPWH demonstrated a trend towards higher mean VT compared with aPWH and CPs at most ROIs. No significant differences in neuroinflammation, using [11C]PBR28 binding as a proxy, were identified between cPWH, aPWH and CPs. A trend towards lower absolute [11C]PBR28 binding was seen amongst aPWH and CPs, suggesting early ART may mitigate neuroinflammation.

Caesarean section and anal incontinence in women after obstetric anal sphincter injury: A systematic review and meta-analysis.

BACKGROUND: Approximately 50% women who give birth after obstetric anal sphincter injury (OASI) develop anal incontinence (AI) over their lifetime. OBJECTIVE: To evaluate current evidence for a protective benefit of planned caesarean section (CS) to prevent AI after OASI. SEARCH STRATEGY: MEDLINE/PubMed, Embase 1974-2024, CINAHL and Cochrane to 7 February 2024 (PROSPERO CRD42022372442). SELECTION CRITERIA: All studies reporting outcomes after OASI and a subsequent birth, by any mode. DATA COLLECTION AND ANALYSIS: Eighty-six of 2646 screened studies met inclusion criteria, with nine studies suitable to meta-analyse the primary outcome of 'adjusted AI' after OASI and subsequent birth. Subgroups: short-term AI, long-term AI, AI in asymptomatic women. SECONDARY OUTCOMES: total AI, quality of life, satisfaction/regret, solid/liquid/flatal incontinence, faecal urgency, AI in women with and without subsequent birth, change in AI pre- to post- subsequent birth. MAIN RESULTS: There was no evidence of a difference in adjusted AI after subsequent vaginal birth compared with CS after OASI across all time periods (OR = 0.92, 95% CI 0.72-1.20; 9 studies, 2104 participants, I2 = 0% p = 0.58), for subgroup analyses or secondary outcomes. There was no evidence of a difference in AI in women with or without subsequent birth (OR = 1.00 95% CI 0.65-1.54; 10 studies, 970 participants, I2 = 35% p = 0.99), or pre- to post- subsequent birth (OR = 0.79 95% CI 0.51-1.25; 13 studies, 5496 participants, I2 = 73% p = 0.31). CONCLUSIONS: Due to low evidence quality, we are unable to determine whether planned caesarean is protective against AI after OASI. Higher quality evidence is required to guide personalised decision-making for asymptomatic women and to determine the effect of subsequent birth mode on long-term AI outcomes.

Utility of Repetitive Transcranial Magnetic Stimulation for Chronic Daily Headache Prophylaxis: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Management of chronic daily headaches (CDH) remains challenging due to the limited efficacy of standard prophylactic pharmacological measures. Several studies have reported that repetitive transcranial magnetic stimulation (rTMS) can effectively treat chronic headaches. The objective was to determine the utility of rTMS for immediate post-treatment and sustained CDH prophylaxis. RECENT FINDINGS: All procedures were conducted per PRISMA guidelines. PubMed, Scopus, Web of Science, and ProQuest databases were searched for controlled clinical trials that have tested the efficacy of rTMS on populations with CDH. DerSimonian-Laird random-effects meta-analyses were performed using the 'meta' package in R to examine the post- vs. pre-rTMS changes in standardized headache intensity and frequency compared to sham-control conditions. Thirteen trials were included with a combined study population of N = 538 patients with CDH (rTMS, N = 284; Sham, N = 254). Patients exposed to rTMS had significantly reduced standardized CDH intensity and frequency in the immediate post-treatment period (Hedges' g = -1.16 [-1.89, -0.43], p = 0.002 and Δ = -5.07 [-10.05, -0.11], p = 0.045 respectively). However, these effects were sustained marginally in the follow-up period (Hedges' g = -0.43 [-0.76, -0.09], p = 0.012 and Δ = -3.33 [-5.52, -1.14], p = 0.003). Significant between-study heterogeneity was observed, at least partially driven by variations in rTMS protocols. Despite the observed clinically meaningful and statistically significant benefits in the immediate post-treatment period, the prophylactic effects of rTMS on CDH do not seem to sustain with discontinuation. Thus, the cost-effectiveness of the routine use of rTMS for CDH prophylaxis remains questionable. REGISTRATION: Protocol preregistered in PROSPERO International Prospective Register of Systematic Reviews (CRD42021250100).

The Who, What, When, and Where of Inpatient Direct Oral Penicillin Challenge-Implications for Health Services Implementation.

Inpatient direct oral challenge programs are increasingly deployed as part of antimicrobial stewardship initiatives to reduce the burden and impacts of penicillin allergy labels on antibiotic prescribing. Using data from a prospective, multicenter cohort inpatient penicillin allergy program, we identify the key targets for delabeling to aid health service implementation.

Transcriptional profiling of Pseudomonas aeruginosa mature single- and dual-species biofilms in response to meropenem.

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen frequently isolated from chronic infections of the cystic fibrosis lung and burn wounds, and is a major cause of antimicrobial-resistant nosocomial infections. P. aeruginosa is frequently co-isolated with the opportunistic fungal pathogen Candida albicans, with the presence of C. albicans in dual-species biofilms promoting tolerance to meropenem. Here, transcription profiling of mature P. aeruginosa single- or dual-species biofilms was carried out to understand the molecular mechanism(s) by which C. albicans enhances meropenem tolerance. C. albicans appeared to have a mild impact on the transcriptome of P. aeruginosa mature biofilms, with most differentially regulated genes being involved in interkingdom interactions (i.e. quorum sensing and phenazine biosynthesis). The addition of meropenem to mature single- or dual-species biofilms resulted in a significant bacterial transcriptional response, including the induction of the beta-lactamase, ampC, genes involved in biofilm formation. P. aeruginosa elicited a similar transcriptional response to meropenem in the presence of C. albicans, but C. albicans promoted the expression of additional efflux pumps, which could play roles in increasing the tolerance of P. aeruginosa to meropenem.

Pseudomonas aeruginosa increases the susceptibility of Candida albicans to amphotericin B in dual-species biofilms.

BACKGROUND: Biofilms are the leading cause of nosocomial infections and are hard to eradicate due to their inherent antimicrobial resistance. Candida albicans is the leading cause of nosocomial fungal infections and is frequently co-isolated with the bacterium Pseudomonas aeruginosa from biofilms in the cystic fibrosis lung and severe burn wounds. The presence of C. albicans in multispecies biofilms is associated with enhanced antibacterial resistance, which is largely mediated through fungal extracellular carbohydrates sequestering the antibiotics. However, significantly less is known regarding the impact of polymicrobial biofilms on antifungal resistance. RESULTS: Here we show that, in dual-species biofilms, P. aeruginosa enhances the susceptibility of C. albicans to amphotericin B, an effect that was biofilm specific. Transcriptional analysis combined with gene ontology enrichment analysis identified several C. albicans processes associated with oxidative stress to be differentially regulated in dual-species biofilms, suggesting that P. aeruginosa exerts oxidative stress on C. albicans, likely through the secretion of phenazines. However, the mitochondrial superoxide dismutase SOD2 was significantly down-regulated in the presence of P. aeruginosa. Monospecies biofilms of the sod2Δ mutant were more susceptible to amphotericin B, and the susceptibility of these biofilms was further enhanced by exogenous phenazines. CONCLUSIONS: We propose that in dual-species biofilms, P. aeruginosa simultaneously induces mitochondrial oxidative stress, while down-regulating key detoxification enzymes, which prevents C. albicans mounting an appropriate oxidative stress response to amphotericin B, leading to fungal cell death. This work highlights the importance of understanding the impact of polymicrobial interactions on antimicrobial susceptibility.

Counseling women of reproductive age about emergency preparedness - Provider attitudes and practices.

We report healthcare provider attitudes and practices on emergency preparedness counseling for women of reproductive age (WRA), including pregnant, postpartum, and lactating women (PPLW), for disasters and weather emergencies. DocStyles is a web-based panel survey of primary healthcare providers in the United States. During March 17-May 17, 2021, obstetricians-gynecologists, family practitioners, internists, nurse practitioners, and physician assistants were asked about the importance of emergency preparedness counseling, level of confidence, frequency, barriers to providing counseling, and preferred resources to support counseling among WRA and PPLW. We calculated frequencies of provider attitudes and practices, and prevalence ratios with 95% CIs for questions with binary responses. Among 1503 respondents (family practitioners (33%), internists (34%), obstetrician-gynecologists (17%), nurse practitioners (8%), and physician assistants (8%)), 77% thought emergency preparedness was important, and 88% thought counseling was necessary for patient health and safety. However, 45% of respondents did not feel confident providing emergency preparedness counseling, and most (70%) had never talked to PPLW about this topic. Respondents cited not having time during clinical visits (48%) and lack of knowledge (34%) as barriers to providing counseling. Most respondents (79%) stated they would use emergency preparedness educational materials for WRA, and 60% said they were willing to take an emergency preparedness training. Healthcare providers have opportunities to provide emergency preparedness counseling; however, many have not, noting lack of time and knowledge as barriers. Emergency preparedness resources combined with training may improve healthcare provider confidence and increase delivery of emergency preparedness counseling.

A qualitative study to explore the symptoms and impacts of Crohn's disease and to develop the Crohn's Disease Diary.

PURPOSE: To explore symptoms and disease impacts of Crohn's disease and to develop a new patient-reported outcomes (PRO) measure according to industry best practices. METHODS: A conceptual model of relevant symptoms experienced by patients with Crohn's disease was developed following a literature review. Three rounds of combined qualitative semi-structured concept elicitation and cognitive debriefing interviews with 36 patients (≥ 16 years) with Crohn's disease and 4 clinicians were conducted to further explore the most commonly reported and most bothersome symptoms to patients. Interview results were used to update the conceptual model as well as items and response options included in The Crohn's Disease Diary, a new PRO measure. RESULTS: All patients (N = 36) reported abdominal pain, loose or liquid bowel movements, and high or increased frequency of bowel movements, with most reporting these symptoms spontaneously (100%, 92%, and 75%, respectively). All patients reported bowel movement urgency, but 61% reported this symptom only when probed. Most also reported that symptoms impacted activities of daily living, work/school, and emotional, social, and physical functioning (overall, 78%-100%; spontaneously, 79% - 92%). Data regarding core symptoms of Crohn's disease from clinician concept elicitation interviews supported patient data. The 17-item Crohn's Disease Diary assesses core symptoms and impacts of Crohn's disease over 24 h, and extraintestinal manifestations over 7 days. The content validity of the diary was confirmed during cognitive debriefing interviews. CONCLUSION: The Crohn's Disease Diary is a new PRO measure for the assessment of Crohn's disease symptoms and impacts, developed according to industry best practices.

Evidence for Selection in the Abundant Accessory Gene Content of a Prokaryote Pangenome.

A pangenome is the complete set of genes (core and accessory) present in a phylogenetic clade. We hypothesize that a pangenome's accessory gene content is structured and maintained by selection. To test this hypothesis, we interrogated the genomes of 40 Pseudomonas species for statistically significant coincident (i.e., co-occurring/avoiding) gene patterns. We found that 86.7% of common accessory genes are involved in ≥1 coincident relationship. Further, genes that co-occur and/or avoid each other-but are not vertically inherited-are more likely to share functional categories, are more likely to be simultaneously transcribed, and are more likely to produce interacting proteins, than would be expected by chance. These results are not due to coincident genes being adjacent to one another on the chromosome. Together, these findings suggest that the accessory genome is structured into sets of genes that function together within a given strain. Given the similarity of the Pseudomonas pangenome with open pangenomes of other prokaryotic species, we speculate that these results are generalizable.

Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data.

Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

Nutrition and indoor cycling: a cross-sectional analysis of carbohydrate intake for online racing and training.

Cycling is a sport characterised by high training load, and adequate nutrition is essential for training and race performance. With the increased popularity of indoor trainers, cyclists have a unique opportunity to practice and implement key nutritional strategies. This study aimed to assess carbohydrate (CHO) intake of cyclists training or racing in this unique scenario for optimising exercise nutrition. A mixed-methods approach consisting of a multiple-pass self-report food recall and questionnaire was used to determine total CHO intake pre, during and post-training or racing using a stationary trainer and compared with current guidelines for endurance exercise. Sub-analyses were also made for higher ability cyclists (>4 W/kg functional threshold power), races v. non-races and 'key' training sessions. Mean CHO intake pre and post-ride was 0·7 (sd 0·6) and 1·0 (sd 0·8) g kg/BM and 39·3 (sd 27·5) g/h during training. CHO intake was not different for races (pre/during/post, P = 0·31, 0·23, 0·18, respectively), 'key sessions' (P = 0·26, 0·89, 0·98) or higher ability cyclists (P = 0·26, 0·76, 0·45). The total proportion of cyclists who failed to meet CHO recommendations was higher than those who met guidelines (pre = 79 %, during = 86 %, post = 89 %). Cyclists training or racing indoors do not meet current CHO recommendations for cycling performance. Due to the short and frequently high-intensity nature of some sessions, opportunity for during exercise feeding may be limited or unnecessary.

Genetic Diversity and Aggressiveness of Fusarium virguliforme Isolates Across the Midwestern United States.

Sudden death syndrome (SDS) of soybean is a damaging disease caused by the fungus Fusarium virguliforme. Since this pathogen was first reported in the southern U.S. state of Arkansas in 1971, it has spread throughout the midwestern United States. The SDS pathogen primarily colonizes roots but also produces toxins that translocate to and damage leaves. Previous studies have detected little to no genetic differentiation among isolates, suggesting F. virguliforme in North America has limited genetic diversity and a clonal population structure. Yet, isolates vary in virulence to roots and leaves. We characterized a set of F. virguliforme isolates from the midwestern United States, representing a south to north latitudinal gradient from Arkansas to Minnesota. Ten previously tested microsatellite loci were used to genotype isolates, and plant assays were conducted to assess virulence. Three distinct population clusters were differentiated across isolates. Although isolates ranged in virulence classes from low to very high, little correlation was found between virulence phenotype and cluster membership. Similarly, population structure and geographic location were not highly correlated. However, the earliest diverging cluster had the lowest genetic diversity and was detected only in southern states, whereas the two other clusters were distributed across the Midwest and were predominant in Minnesota. One of the midwestern clusters had the greatest genetic diversity and was found along the northern edge of the known distribution. The results support three genetically distinct population clusters of F. virguliforme in the United States, with two clusters contributing most to spread of this fungus across the Midwest.

Methodological Considerations for Investigating Iron Status and Regulation in Exercise and Sport Science Studies.

Iron deficiency is a common health issue in active and athlete populations. Accordingly, research into iron status, regulation, absorption, and iron deficiency treatment strategies is increasing at a rapid rate. However, despite the increase in the quantity of research, various methodological issues need to be addressed as we progress our knowledge in this area. The purpose of this review is to highlight specific considerations for conducting iron-related research in active and athlete populations. First, we discuss the methodological importance of assessment and interpretation of iron status, with reference to blood collection protocols, participant screening procedures, and biomarker selection. Next, we consider numerous variables that should be accounted for in the design of iron-related research studies, such as the iron regulatory hormone hepcidin and its interaction with exercise, in addition to an examination of female physiology and its impact on iron metabolism. Subsequently, we explore dietary iron and nutrient interactions that impact iron regulation and absorption, with recommendations made for optimal methodological control. Consideration is then given to key features of long-term study designs, such as the monitoring of training load, oral iron supplementation, dietary analysis, and general lifestyle factors. Finally, we conclude our recommendations with an exploration of stable iron isotope tracers as a methodology to measure iron absorption. Ultimately, it is our intention that this review can be used as a guide to improve study design, biomarker analysis, and reporting of findings, to maximize the quality of future research outputs in iron-related research focused on active and athlete populations.

Adaptation to a low carbohydrate high fat diet is rapid but impairs endurance exercise metabolism and performance despite enhanced glycogen availability.

KEY POINTS: Brief (5-6 days) adaptation to a low carbohydrate high fat diet in elite athletes increased exercise fat oxidation to rates previously observed with medium (3-4 weeks) or chronic (>12 months) adherence to this diet, with metabolic changes being washed out in a similar time frame. Increased fat utilisation during exercise was associated with a 5-8% increase in oxygen cost at speeds related to Olympic Programme races. Acute restoration of endogenous carbohydrate (CHO) availability (24 h high CHO diet, pre-race CHO) only partially restored substrate utilisation during a race warm-up. Fat oxidation continued to be elevated above baseline values although it was lower than achieved by 5-6 days' keto adaptation; CHO oxidation only reached 61% and 78% of values previously seen at exercise intensities related to race events. Acute restoration of CHO availability failed to overturn the impairment of high-intensity endurance performance previously associated with low carbohydrate high fat adaptation, potentially due to the blunted capacity for CHO oxidation. ABSTRACT: We investigated substrate utilisation during exercise after brief (5-6 days) adaptation to a ketogenic low-carbohydrate (CHO), high-fat (LCHF) diet and similar washout period. Thirteen world-class male race walkers completed economy testing, 25 km training and a 10,000 m race (Baseline), with high CHO availability (HCHO), repeating this (Adaptation) after 5-6 days' LCHF (n = 7; CHO: <50 g day-1 , protein: 2.2 g kg-1 day-1 ; 80% fat) or HCHO (n = 6; CHO: 9.7 g kg-1 day-1 ; protein: 2.2 g kg-1 day-1 ) diet. An Adaptation race was undertaken after 24 h HCHO and pre-race CHO (2 g kg-1 ) diet, identical to the Baseline race. Substantial (>200%) increases in exercise fat oxidation occurred in the LCHF Adaptation economy and 25 km tests, reaching mean rates of ∼1.43 g min-1 . However, relative V̇O2 (ml min-1  kg-1 ) was higher (P < 0.0001), by ∼8% and 5% at speeds related to 50 km and 20 km events. During Adaptation race warm-up in the LCHF group, rates of fat and CHO oxidation at these speeds were decreased and increased, respectively (P < 0.001), compared with the previous day, but were not restored to Baseline values. Performance changes differed between groups (P = 0.009), with all HCHO athletes improving in the Adaptation race (5.7 (5.6)%), while 6/7 LCHF athletes were slower (2.2 (3.4)%). Substrate utilisation returned to Baseline values after 5-6 days of HCHO diet. In summary, robust changes in exercise substrate use occurred in 5-6 days of extreme changes in CHO intake. However, adaptation to a LCHF diet plus acute restoration of endogenous CHO availability failed to restore high-intensity endurance performance, with CHO oxidation rates remaining blunted.

The Penicillin Allergy Delabeling Program: A Multicenter Whole-of-Hospital Health Services Intervention and Comparative Effectiveness Study.

BACKGROUND: Penicillin allergies are associated with inferior patient and antimicrobial stewardship outcomes. We implemented a whole-of-hospital program to assess the efficacy of inpatient delabeling for low-risk penicillin allergies in hospitalized inpatients. METHODS: Patients ≥ 18 years of age with a low-risk penicillin allergy were offered a single-dose oral penicillin challenge or direct label removal based on history (direct delabeling). The primary endpoint was the proportion of patients delabeled. Key secondary endpoints were antibiotic utilization pre- (index admission) and post-delabeling (index admission and 90 days). RESULTS: Between 21 January 2019 and 31 August 2019, we assessed 1791 patients reporting 2315 antibiotic allergies, 1225 with a penicillin allergy. Three hundred fifty-five patients were delabeled: 161 by direct delabeling and 194 via oral penicillin challenge. Ninety-seven percent (194/200) of patients were negative upon oral penicillin challenge. In the delabeled patients, we observed an increase in narrow-spectrum penicillin usage (adjusted odds ratio [OR], 10.51 [95% confidence interval {CI}, 5.39-20.48]), improved appropriate antibiotic prescribing (adjusted OR, 2.13 [95% CI, 1.45-3.13]), and a reduction in restricted antibiotic usage (adjusted OR, 0.38 [95% CI, .27-.54]). In the propensity score analysis, there was an increase in narrow-spectrum penicillins (OR, 10.89 [95% CI, 5.09-23.31]) and ß-lactam/ß-lactamase inhibitors (OR, 6.68 [95% CI, 3.94-11.35]) and a reduction in restricted antibiotic use (OR, 0.52 [95% CI, .36-.74]) and inappropriate prescriptions (relative risk ratio, 0.43 [95% CI, .26-.72]) in the delabeled group compared with the group who retained their allergy label. CONCLUSIONS: This health services program using a combination of direct delabeling and oral penicillin challenge resulted in significant impacts on the use of preferred antibiotics and appropriate prescribing.

The role of potentiating mutations in the evolution of pandemic Escherichia coli clones.

The Escherichia coli species exhibits a vast array of variable lifestyles, including environmental, commensal, and pathogenic organisms. Many of these E. coli contribute significantly to the global threat of antimicrobial resistance (AMR). Multidrug-resistant (MDR) clones of E. coli have arisen multiple times over varying timescales. The repeated emergence of successful pandemic clones, including the notorious ST131 lineage, highlights a desperate need to further study the evolutionary processes underlying their emergence and success. Here, we review the evolutionary emergence of E. coli ST131 pandemic clones and draw parallels between their evolutionary trajectories and those of other lineages. From colonization and expansion to the acquisition of multidrug resistance plasmids, potentiating mutations are present at each stage, leading to a proposed sequence of events that may result in the formation of an antimicrobial-resistant pandemic clone.

Development of a Clinical Global Impression of Change (CGI-C) and a Caregiver Global Impression of Change (CaGI-C) measure for ambulant individuals with Duchenne muscular dystrophy.

BACKGROUND: In clinical trials for rare diseases, such as Duchenne muscular dystrophy, clinical outcome assessments (COA) used to assess treatment benefit are often generic and may not be sensitive enough to detect change in specific patient populations. Thus, there is a need for disease specific COAs that track meaningful change among individuals. When developing such measures, input from clinicians, caregivers and patients is critical for assessing clinically relevant concepts and ensuring validity of the measure. METHOD: The aim of this study was to develop two Duchenne-specific global impression items for use in clinical trials. The development of the Duchenne Clinical Global Impression of Change (CGI-C) and Caregiver Global Impression of Change (CaGI-C) was informed by findings from concept elicitation (CE) interviews with clinicians, caregivers and individuals with Duchenne. Through cognitive debriefing (CD) interviews, clinicians and caregivers evaluated draft CGI-C and CaGI-C items to ensure relevance and understanding of the items and instructions. Suggestions made during the CD interviews were incorporated into the finalized CGI-C and CaGI-C measures. RESULTS: The symptoms most frequently reported by clinicians, caregivers and individuals with Duchenne were muscle weakness, fatigue, cardiac difficulties and pain. Regarding physical functioning, all three populations noted that small changes in functional ability were meaningful, particularly when independence was impacted. Caregivers and clinicians reported that changes in speed, endurance and quality of movement were important, as was improvement in the ability of individuals to keep up with their peers. A change in the ability to complete everyday activities was also significant to families. These results were used to create two global impression of change items and instruction documents for use by clinicians (CGI-C) and caregivers (CaGI-C). Overall, both items were well understood by participants. The descriptions and examples developed from the CE interviews were reported to be relevant and appropriate for illustrating different levels of meaningful change in patients with Duchenne. Modifications were made based on caregiver and clinician CD feedback . CONCLUSIONS: As part of a holistic measurement strategy, such COA can be incorporated into the clinical trial setting to assess global changes in relevant symptoms and functional impacts associated with Duchenne.

Real-world effectiveness and safety of ustekinumab for the treatment of Crohn's disease: the Scottish ustekinumab cohort.

BACKGROUND AND AIM: Ustekinumab is a monoclonal antibody that targets interleukin-12/23. In Scotland, it was approved for the treatment of moderate to severe Crohn's disease in 2017. The objective of this study was to establish the real-world effectiveness and safety of ustekinumab in the treatment of Crohn's disease. METHODS: We conducted a retrospective study of patients receiving ustekinumab across eight Scottish National Health Service health boards between 2017 and 2019. Inclusion criteria included a diagnosis of Crohn's disease with symptoms attributed to active disease plus objective signs of inflammation at baseline (C-reactive protein ≥ 5 mg/L or fecal calprotectin ≥ 250 µg/g or inflammation on endoscopy/magnetic resonance imaging) and completion of induction plus at least one clinical follow-up at 8 weeks. Kaplan-Meier survival analysis was used to establish 12-month cumulative rates of clinical remission, mucosal healing, deep remission, and perianal fistula response. Rates of serious adverse events were described quantitatively. RESULTS: Our cohort consisted of 216 patients (female sex, 37.9%; median age, 39.0 years, interquartile range [IQR] 28.8-51.8 years; disease duration, 9.9 years, IQR 6.0-16.5 years; prior biologic, 98.6%) with a median follow-up of 35.0 weeks (IQR 17.4-52.0 weeks). Twelve-month cumulative rates of clinical remission, mucosal healing, and deep remission (clinical remission plus mucosal healing) were 32.0%, 32.7%, and 19.3%, respectively. In patients with active perianal disease (n = 37), the 12-month cumulative perianal response rate was 53.1%. The serious adverse event rate was 13.6 per 100 patient-years of follow-up. CONCLUSION: Ustekinumab is a safe and effective treatment for the treatment of complex Crohn's disease.

Candida albicans enhances meropenem tolerance of Pseudomonas aeruginosa in a dual-species biofilm.

BACKGROUND: Pseudomonas aeruginosa is an opportunistic bacterium that infects the airways of cystic fibrosis patients, surfaces of surgical and burn wounds, and indwelling medical devices. Patients are prone to secondary fungal infections, with Candida albicans being commonly co-isolated with P. aeruginosa. Both P. aeruginosa and C. albicans are able to form extensive biofilms on the surfaces of mucosa and medical devices. OBJECTIVES: To determine whether the presence of C. albicans enhances antibiotic tolerance of P. aeruginosa in a dual-species biofilm. METHODS: Single- and dual-species biofilms were established in microtitre plates and the survival of each species was measured following treatment with clinically relevant antibiotics. Scanning electron microscopy and confocal microscopy were used to visualize biofilm structure. RESULTS: C. albicans enhances P. aeruginosa biofilm tolerance to meropenem at the clinically relevant concentration of 5 mg/L. This effect is specific to biofilm cultures and is dependent upon C. albicans extracellular matrix polysaccharides, mannan and glucan, with C. albicans cells deficient in glycosylation structures not enhancing P. aeruginosa tolerance to meropenem. CONCLUSIONS: We propose that fungal mannan and glucan secreted into the extracellular matrix of P. aeruginosa/C. albicans dual-species biofilms play a central role in enhancing P. aeruginosa tolerance to meropenem, which has direct implications for the treatment of coinfected patients.