Case 324: CHANTER Syndrome.

HISTORY: A 69-year-old right-handed man with a history of substance use disorder, hypertension, and diabetes presented to the emergency department in an unresponsive state. Upon examination, apart from tachycardia (heart rate, 108 beats per minute), vital signs were within normal ranges (blood pressure, 134/102 mm Hg; temperature, 97.9 ºF (36.6 ºC); respiratory rate, 16 per minute; oxygen saturation, 96%). The patient had a Glasgow coma scale score of 8. Otherwise, the physical examination revealed no abnormalities. Prior psychiatric and surgical histories were unremarkable. There was no history of recent travel, camping, hiking, or vaccination. No family history could be obtained. Laboratory work-up revealed an elevated creatine kinase level (49 006 U/L [818.4 µkat/L]; normal reference range, 10-205 U/L [0.17-3.42 µkat/L]). An electrocardiogram showed sinus tachycardia without evidence of cardiac ischemia. An echocardiogram was unremarkable. Alanine aminotransferase (126 U/L [2.10 µkat/L]; normal reference range, 0-40 U/L [0-0.67 µkat/L]) and aspartate aminotransferase (488 U/L [8.15 µkat/L]; normal reference range, 3-44 U/L [0.05-0.74 µkat/L]) levels were elevated. Polymerase chain reaction results were negative for HIV-1, HIV-2, syphilis treponemal, and COVID-19 antibodies. The remaining routine laboratory work-up findings were within normal limits. Urine drug screening was positive for cocaine, marijuana, fentanyl, and benzodiazepines. Naloxone was administered, but the patient remained unresponsive. Intubation was performed for airway protection. Noncontrast and contrast-enhanced CT of the head and CT angiography were performed in the emergency department to rule out an acute intracranial abnormality. Multisequence MRI of the brain with administration of intravenous contrast material was ordered for further assessment. CT of the abdomen and pelvis was unremarkable (images not shown).

Case 324.

HISTORY: A 69-year-old right-handed man with a history of substance use disorder, hypertension, and diabetes presented to the emergency department in an unresponsive state. Upon examination, apart from tachycardia (heart rate, 108 beats per minute), vital signs were within normal ranges (blood pressure, 134/102 mm Hg; temperature, 97.9°F [36.6°C]; respiratory rate, 16 breaths per minute; oxygen saturation, 96%). He had a Glasgow coma scale score of 8. Otherwise, the physical examination revealed no abnormalities. His prior psychiatric and surgical histories were unremarkable. There was no history of recent travel, camping, hiking, or vaccination. No family history could be obtained. Laboratory work-up revealed an elevated creatine kinase level (49 006 U/L [818.4 µkat/L]; normal reference range, 10-205 U/L [0.17-3.42 µkat/L]). An electrocardiogram showed sinus tachycardia without evidence of cardiac ischemia. An echocardiogram was unremarkable. Alanine aminotransferase (126 U/L [2.10 µkat/L]; normal reference range, 0-40 U/L [0-0.67 µkat/L]) and aspartate aminotransferase (488 U/L [8.15 µkat/L]; normal reference range, 3-44 U/L [0.05-0.74 µkat/L]) levels were elevated. Polymerase chain reaction results were negative for HIV-1, HIV-2, syphilis treponemal, and COVID-19 antibodies. The rest of the routine laboratory work-up findings were within normal limits. Urine drug screening was positive for cocaine, marijuana, fentanyl, and benzodiazepines. Naloxone was administered, but the patient remained unresponsive. Intubation was performed for airway protection. Noncontrast and contrast-enhanced CT of the head (Fig 1) and CT angiography were performed in the emergency department to rule out an acute intracranial abnormality. Multisequence MRI of the brain with administration of intravenous contrast material was ordered for further assessment (Figs 2-4). CT of the abdomen and pelvis was unremarkable (images not shown).

Antibiotic dispensing during the COVID-19 pandemic: analysis of Welsh primary care dispensing data.

BACKGROUND: The COVID-19 pandemic led to rapid changes in demand and delivery of primary care services that could have led to increases in antibiotic prescribing. OBJECTIVE: We investigated the impact of the COVID-19 pandemic on oral antibiotic dispensing rates in primary care in Wales using longitudinal analysis of monthly oral antibiotic dispensing data from 1 April 2018 to 30 April 2021. METHODS: We used All-Wales primary care dispensing data. We examined trends in oral antibiotic dispensing per 1,000 people for Wales and for individual Health Boards. We used interrupted time series analysis to estimate changes in trends pre- and post-April 2020 to assess the impact of the first and subsequent lockdowns. RESULTS: Between April 2020 and April 2021, antibiotic dispensing in Wales was lower compared with the same period in 2018 and 2019, with an average monthly decrease of 14.00 dispensed items per 1,000 registered patients (95% confidence interval 19.89-8.11). The overall prepandemic monthly antibiotic dispensing rate ranged from 48.5 to 67.4 antibiotic items per 1,000 registered patients. From the onset of the pandemic, it ranged from 40.3 to 49.07 antibiotic items per 1,000 registered patients. This reduction was primarily driven by narrow-spectrum antibiotics. Statistically significant reductions were also observed for antibiotics commonly dispensed for the treatment of respiratory tract infections. Dispensing of antibiotics primarily used for urinary and skin infections remained stable. CONCLUSIONS: Despite complexities of consulting during the COVID-19 pandemic in primary care we found no evidence of an increase in antibiotic dispensing during this time.

A considerable amount of work has been done in recent years to reduce unnecessary antibiotic prescribing. The COVID-19 pandemic has changed the way patients interact with their General Practitioners (GPs), with more consultations being undertaken remotely, either over the phone or online, with less face-to-face contact. It is not clear how these changes have affected antibiotic prescribing by GPs. We looked at the number of antibiotic items dispensed in Wales between April 2018 and April 2021 to assess the impact of the first lockdown. Fewer antibiotics were dispensed from April 2020 to April 2021, compared with the period before the COVID-19 pandemic (April 2018­March 2020). Dispensing of antibiotics used to treat chest, ear, and throat infections reduced following the start of the UK lockdown. There was no change in dispensing of antibiotics used to treat skin and urine infections. Reassuringly, dispensing of antibiotics that target several different types of bacteria (broad-spectrum antibiotics) did not increase during the COVID-19 pandemic.

Changing sexual behaviours amongst MSM during the COVID-19 restrictions in Wales: a mixed methods study.

BACKGROUND: The COVID-19 pandemic and its associated restrictions stopped people freely engaging in sexual behaviour. We explored sexual behaviour amongst men who have sex with men (MSM) using mixed methods during the multiple lockdowns in Wales. METHODS: An online survey was advertised on social media platforms (focusing on Welsh LGBT groups), from June 2020 to July 2020. MSM over 16 years were invited to take part if they were resident in Wales. Qualitative interviews were undertaken as part of a study examining knowledge and awareness of sexual health. Interviews were conducted between September 2020 and February 2021 via Zoom©. Interview data was analysed thematically and integrated with survey data. RESULTS: The survey received 70 responses, 60% (n = 42) reported not having sexual activity during lockdown. Restrictions altered the number of new sexual partners per week with over 80% (n = 56) not having any new sexual partners for the 12 weeks of the first lockdown. However, as the weeks progressed following the first lockdown there was an increase in the number of new sexual partners. Interview data indicated that the COVID-19 pandemic had a large impact on reducing sexual behaviour with other MSM in Wales. 'Lockdown fatigue' was viewed to result in different levels of adherence to the lockdown rules depending on the lockdown being discussed. Of those engaging in sex outside the rules, 'shame' was commonly reported. The restrictions were believed to have a positive impact on reducing the spread of sexually transmitted infections. CONCLUSIONS: The COVID-19 pandemic and associated restrictions had a significant impact on sexual behaviours among MSM in Wales, with the majority fully adhering to the lockdown rules. Although the population were largely compliant with the lockdown restrictions, lockdown fatigue may suggest that any future lockdowns might not have the same effect.

The relationship between HIV pre-exposure prophylaxis, sexually transmitted infections, and antimicrobial resistance: a qualitative interview study of men who have sex with men.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is a medication that prevents the acquisition of HIV. It has been targeted towards men who have sex with men (MSM). Since its introduction there have been concerns raised around changes in sexual behaviour such as increased condomless anal intercourse (CAI), leading to an elevation in sexually transmitted infections (STIs). With antimicrobial resistant strains of STIs rising, there are concerns that PrEP may be contributing to this growth. This study aims to understand how MSM conceptualise the relationship between PrEP, STIs and antimicrobial resistance (AMR). METHODS: Twenty semi-structured interviews were conducted online using Zoom. Participants include a mix of PrEP related experiences (never used, currently use, previously used). Reflexive thematic analysis was undertaken by the lead author with 10% of transcripts double coded. RESULTS: MSM in Wales have positive views and a good knowledge of PrEP and awareness of bacterial STIs. PrEP is perceived by many to lead to a reduction in condom use and increase in STIs but reported condom use behaviours presented to be stable in terms of PrEP initiation. PrEP use is influenced by increased concern for HIV and minimal concern for bacterial STIs. Awareness of AMR STIs was lacking. CONCLUSIONS: There is a belief that PrEP use will lead to an increase in STI rates through reduced condom use, despite reported behaviours often being stable in relation to PrEP initiation, PrEP stigma may be influencing this dichotomy. Concern and awareness for resistant STIs is low, with little association to PrEP.

Bottom trawl fishing footprints on the world's continental shelves.

Bottom trawlers land around 19 million tons of fish and invertebrates annually, almost one-quarter of wild marine landings. The extent of bottom trawling footprint (seabed area trawled at least once in a specified region and time period) is often contested but poorly described. We quantify footprints using high-resolution satellite vessel monitoring system (VMS) and logbook data on 24 continental shelves and slopes to 1,000-m depth over at least 2 years. Trawling footprint varied markedly among regions: from <10% of seabed area in Australian and New Zealand waters, the Aleutian Islands, East Bering Sea, South Chile, and Gulf of Alaska to >50% in some European seas. Overall, 14% of the 7.8 million-km2 study area was trawled, and 86% was not trawled. Trawling activity was aggregated; the most intensively trawled areas accounting for 90% of activity comprised 77% of footprint on average. Regional swept area ratio (SAR; ratio of total swept area trawled annually to total area of region, a metric of trawling intensity) and footprint area were related, providing an approach to estimate regional trawling footprints when high-resolution spatial data are unavailable. If SAR was ≤0.1, as in 8 of 24 regions, there was >95% probability that >90% of seabed was not trawled. If SAR was 7.9, equal to the highest SAR recorded, there was >95% probability that >70% of seabed was trawled. Footprints were smaller and SAR was ≤0.25 in regions where fishing rates consistently met international sustainability benchmarks for fish stocks, implying collateral environmental benefits from sustainable fishing.

Global analysis of depletion and recovery of seabed biota after bottom trawling disturbance.

Bottom trawling is the most widespread human activity affecting seabed habitats. Here, we collate all available data for experimental and comparative studies of trawling impacts on whole communities of seabed macroinvertebrates on sedimentary habitats and develop widely applicable methods to estimate depletion and recovery rates of biota after trawling. Depletion of biota and trawl penetration into the seabed are highly correlated. Otter trawls caused the least depletion, removing 6% of biota per pass and penetrating the seabed on average down to 2.4 cm, whereas hydraulic dredges caused the most depletion, removing 41% of biota and penetrating the seabed on average 16.1 cm. Median recovery times posttrawling (from 50 to 95% of unimpacted biomass) ranged between 1.9 and 6.4 y. By accounting for the effects of penetration depth, environmental variation, and uncertainty, the models explained much of the variability of depletion and recovery estimates from single studies. Coupled with large-scale, high-resolution maps of trawling frequency and habitat, our estimates of depletion and recovery rates enable the assessment of trawling impacts on unprecedented spatial scales.

Longer-term functional outcomes and everyday listening performance for young children through to young adults using bilateral implants.

OBJECTIVES: First, to document a broad range of functional outcomes of bilateral implantation for young children through young adults at a postoperative point at which stable outcomes could be expected. Second, to evaluate the relationship between functional outcomes and age at bilateral implantation and time between implants. DESIGN: A study-specific questionnaire was administered to parents in an interview 3.5 years or more after sequential (n = 50) or simultaneous (n = 7) implants were received by their child. Median age at bilateral implantation was 4.1 years (range 0.7 to 19.8) and time between implants was 2.7 years (range 0.0 to 16.7). RESULTS: On the basis of parent report, 72% of the sequentially implanted children and young adults found it easy/only "a bit difficult" to adapt to the second implant, and were "happily wearing both implants together most of the time" by 6 months or before; 26% had not adapted, with both implants not worn most of the time or worn as a parental requirement. Seventy-two percent of sequentially implanted children and young adults had a positive attitude toward the second implant, including 9 whose early postoperative attitude was negative or neutral. The majority of children and young adults preferred bilateral implants (70%) and used the two full time (72%), while around half demonstrated similar performance with each implant alone. The proportion of nonusers or very minimal users of the second implant was just 9%. Eighty-eight percent of parents reported superior performance with bilateral versus a unilateral implant (n = 40), or that only bilateral implants were worn (n = 10) so performance could not be compared. The most commonly identified areas of superiority were localization, less need for repetition, and increased responsiveness. In balancing risks and costs with benefits, most parents (86%) considered the second implant worthwhile. Regarding the relationship between outcomes and demographic factors, the group achieving similar performance with each implant alone was younger at bilateral implantation and had less time between implants, and the group bilaterally implanted before 3.5 years of age (who also had less than 2 years between implants) had a higher proportion of positive outcomes on all functional outcome measures. CONCLUSION: Overall, the results indicate primarily positive functional outcomes for children and young adults receiving bilateral implants at all ages, including when the delay between implants is long. The results are important for evidence-based preoperative counseling, which helps families to make informed decisions and develop appropriate expectations. The results are also important for the development of clinical management practices that support and encourage the minority of recipients who have difficulty adapting to bilateral implants or achieving full-time use.

Acute Renal Failure with Severe Loin Pain and Patchy Renal Ischemia after Anaerobic Exercise in Active Duty Marines.

Acute renal failure with severe loin pain and patchy renal ischemia after anaerobic exercise (ALPE) is a rare cause of exertional acute kidney injury. The proposed mechanism of injury in ALPE is renovascular spasm, in the setting of oxidative stress and muscular damage, which creates a characteristic wedge-shaped infarction pattern on delayed imaging. Patients present with nausea, vomiting, loin or abdominal pain, and fatigue within 1-2 days of anaerobic exercise, associated with an acute rise in serum creatinine, which generally plateaus within 3 days. This process is likely exacerbated by dehydration, analgesic usage, and lower baseline fitness levels. This disease process is distinct from rhabdomyolysis, in that creatine kinase levels are not significantly elevated, myoglobinuria is not seen, and aggressive fluid resuscitation is not beneficial. We present three cases of ALPE following participation in the Marine Combat Fitness Test (CFT), an anaerobic evolution. Medical workup demonstrated no additional etiology for acute renal failure. The average peak creatinine in these patients was 2.9 mg/dL, and all demonstrated return to normal renal function, without hemodialysis. One patient experienced recurrent ALPE, after short-interval CFT participation. Military medical providers should be aware of this diagnosis when evaluating service members with acute renal injury after exercise. The clinical course is benign, and affected service members are at increased risk of recurrence, with subsequent intense exercise. Service members should engage in a graduated exercise program, before intense exercise activities, and should be monitored closely for recurrent renal injury.

Curriculum mapping to audit and grow longitudinal graduate medical education leadership training.

BACKGROUND: Residents need and want practical leadership training, yet leadership curricula are lacking in graduate medical education (GME). We describe our process of curriculum mapping, a method for auditing a curriculum, and its role in iterative leadership curriculum development. AIMS: To show how to create a curriculum map for auditing a curriculum using examples from our leadership curriculum and to demonstrate its value through case examples of leadership education integration into existing resident experiences. METHODS: We selected our recent systematic review on current leadership curricula to prioritise leadership content given it was the basis for our initial curriculum. We identified existing resident experiences where training can occur. We use the selected content and training environments, layered with a modified Miller's pyramid, to construct a curriculum map. RESULTS: Our curriculum map provides an example of curriculum auditing that reveals opportunities for leadership training that could be integrated into current residency experiences. We provide case examples of application. DISCUSSION: Effective leadership training should address critical topics and capitalise on experiential learning opportunities that exist within residency training programmes. The training must be seamlessly integrated into the demanding obligations of GME trainees, a process that can be achieved using curriculum mapping. Curriculum mapping can provide insight into a residency programme's leadership curriculum and create a direction for future leadership curriculum development.

The Association of Resilience with Psychosocial Outcomes in Teenagers and Young Adults with Cancer.

Purpose: There is limited research on the psychological impact of cancer for teenagers and young adults (TYAs) and the role of protective factors such as resilience. This study investigated associations between resilience and psychosocial outcomes in this group. Methods: Data were collected from TYAs (aged 16-24) who attended the TYA cancer clinic at Guy's Hospital between 2013 and 2021. Participants (N = 63) completed psychosocial questionnaires within 4 weeks of their treatment start date (T1) and again between 9 and 15 months later (T2). We used separate multivariable linear regression models to analyze associations of resilience (Brief Resilience Questionnaire) with outcomes measured at T2, including symptoms of depression (Patient Health Questionnaire [PHQ]-9), anxiety (Generalized Anxiety Disorder [GAD]-7), and subjective quality of life. Models were adjusted for age, gender, ethnicity, and T1 outcome assessments. Results: Higher resilience at T1 was associated with increased anxiety (ß = 1.68; bootstrapped confidence interval [95% CI -0.28 to 3.19]), depression (ß = 1.24; [-0.85 to 2.90]), and quality of life (5.76; [-0.88 to 15.60]). In contrast, an increase in resilience over time was associated with decreases in the same period in anxiety (ß = -3.16; [-5.22 to -1.47]) and depression (ß = -2.36, [-4.41 to -0.58]), and an increase in quality of life (ß = 9.82, [-0.24 to 21.13]). Conclusion: Increases in resilience during cancer treatment were associated with reduced symptoms of depression and anxiety in TYAs. We discuss factors likely to influence these outcomes, the implications for psychosocial interventions in this population, and identify further research to explore the impact of other factors such as diagnosis and treatment type.

A Systematic Review of the Psychosocial Measures Used in Teenage and Young Adult Cancer.

Background: Teenagers and young adults (TYAs; ages 16-24 in the United Kingdom) with cancer have specific needs and experience worse physiological and psychological outcomes compared with pediatric and adult cancer. In the United Kingdom, psychosocial screening is a mandatory part of TYA care. However, there is a lack of age-appropriate and acceptable psychosocial measures for this population. This review aimed to (1) identify the psychosocial measures utilized and available for TYA cancer and (2) describe their psychometric properties. Methods: We searched five databases for studies meeting the eligibility criteria. We extracted data relevant to the review and assessed study quality using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) guidelines and the Hughes Quality Assessment Tool developed by the research team. Results: We identified 40 studies that included 105 psychosocial measures. The main constructs measured were distress, depression, and anxiety. The TYA age range varied widely. Reporting of psychosocial measures and their psychometric properties was poor, and most measures were not validated or developed for TYA cancer populations. Discussion: There is an urgent need for psychosocial measures that are designed for and validated in TYA cancer populations. Appropriate measures would enable clinicians to reliably identify and effectively support the psychosocial challenges faced by TYAs. The use of validated psychosocial measures enables earlier detection of difficulties, fosters patient-centered care, and is cost-effective since resources can be allocated to those most in need.

Assessing children who are acutely ill in general practice using the National PEWS and LqSOFA clinical scores: a retrospective cohort study.

BACKGROUND: Clinical tools are needed in general practice to help identify children who are seriously ill. The Liverpool quick Sequential Organ Failure Assessment (LqSOFA) was validated in an emergency department and performed well. The National Paediatric Early Warning System (PEWS) has been introduced in hospitals throughout England with hopes for implementation in general practice. AIM: To validate the LqSOFA and National PEWS in general practice. DESIGN AND SETTING: Secondary analysis of 6703 children aged <5 years presenting to 225 general practices in England and Wales with acute illnesses, linked to hospital data. METHOD: Variables from the LqSOFA and National PEWS were mapped onto study data to calculate score totals. A primary outcome of admission within 2 days of GP consultation was used to calculate sensitivity, specificity, negative predictive values (NPVs), positive predictive values (PPVs), and area under the receiver operating characteristic curve (AUC). RESULTS: A total of 104/6703 children were admitted to hospital within 2 days (pre-test probability 1.6%) of GP consultation. The sensitivity of the LqSOFA was 30.6% (95% confidence interval [CI] = 21.8% to 41.0%), with a specificity of 84.7% (95% CI = 83.7% to 85.6%), PPV of 3.0% (95% CI = 2.1% to 4.4%), NPV of 98.7% (95% CI = 98.4% to 99.0%), and AUC of 0.58 (95% CI = 0.53 to 0.63). The sensitivity of the National PEWS was 81.0% (95% CI = 71.0% to 88.1%), with a specificity of 32.5% (95% CI = 31.2% to 33.8%), PPV of 1.9% (95% CI = 1.5% to 2.5%), NPV of 99.1% (95% CI = 98.4% to 99.4%), and AUC of 0.66 (95% CI = 0.59 to 0.72). CONCLUSION: Although the NPVs appear useful, owing to low pre-test probabilities rather than discriminative ability, neither tool accurately identified admissions to hospital. Unconsidered use by GPs could result in unsustainable referrals.

Long-term consequences of urinary tract infection in childhood: an electronic population-based cohort study in Welsh primary and secondary care.

BACKGROUND: Childhood urinary tract infection (UTI) can cause renal scarring, and possibly hypertension, chronic kidney disease (CKD), and end-stage renal failure (ESRF). Previous studies have focused on selected populations, with severe illness or underlying risk factors. The risk for most children with UTI is unclear. AIM: To examine the association between childhood UTI and outcomes in an unselected population of children. DESIGN AND SETTING: A retrospective population-based cohort study using linked GP, hospital, and microbiology records in Wales, UK. METHOD: Participants were all children born in 2005-2009, with follow-up until 31 December 2017. The exposure was microbiologically confirmed UTI before the age of 5 years. The key outcome measures were renal scarring, hypertension, CKD, and ESRF. RESULTS: In total, 159 201 children were included; 77 524 (48.7%) were female and 7% (n = 11 099) had UTI before the age of 5 years. A total of 0.16% (n = 245) were diagnosed with renal scarring by the age of 7 years. Odds of renal scarring were higher in children by age 7 years with UTI (1.24%; adjusted odds ratio 4.60 [95% confidence interval [CI] = 3.33 to 6.35]). Mean follow-up was 9.53 years. Adjusted hazard ratios were: 1.44 (95% CI = 0.84 to 2.46) for hypertension; 1.67 (95% CI = 0.85 to 3.31) for CKD; and 1.16 (95% CI = 0.56 to 2.37) for ESRF. CONCLUSION: The prevalence of renal scarring in an unselected population of children with UTI is low. Without underlying risk factors, UTI is not associated with CKD, hypertension, or ESRF by the age of 10 years. Further research with systematic scanning of children's kidneys, including those with less severe UTI and without UTI, is needed to increase the certainty of these results, as most children are not scanned. Longer follow-up is needed to establish if UTI, without additional risk factors, is associated with hypertension, CKD, or ESRF later in life.

Human parechovirus meningoencephalitis.

Human parechovirus-3 (HPeV-3) infection is one of the differential diagnoses of neonatal meningoencephalitis. A 13-day-old full-term female neonate presented with a seizure. Brain MRI showed classic imaging findings of the meningoencephalitis which was confirmed on cerebrospinal fluid analysis. Contribution: The HPeV-3 is an emerging pathogen for neonatal meningoencephalitis. The case in this study is unique with classic imaging findings, which are not routinely encountered in day-to-day practice. This case raises reader awareness.

Perspectives of Statistician, Microbiologist, and Clinician Stakeholders on the Use of Microbiological Outcomes in Randomised Trials of Antimicrobial Stewardship Interventions.

Microbiological data are used as indicators of infection, for diagnosis, and the identification of antimicrobial resistance in trials of antimicrobial stewardship interventions. However, several problems have been identified in a recently conducted systematic review (e.g., inconsistency in reporting and oversimplified outcomes), which motivates the need to understand and improve the use of these data including analysis and reporting. We engaged key stakeholders including statisticians, clinicians from both primary and secondary care, and microbiologists. Discussions included issues identified in the systematic review and questions about the value of using microbiological data in clinical trials, perspectives on current microbiological outcomes reported in trials, and alternative statistical approaches to analyse these data. Various factors (such as unclear sample collection process, dichotomising or categorising complex microbiological data, and unclear methods of handling missing data) were identified that contributed to the low quality of the microbiological outcomes and the analysis of these outcomes in trials. Whilst not all of these factors would be easy to overcome, there is room for improvement and a need to encourage researchers to understand the impact of misusing these data. This paper discusses the experience and challenges of using microbiological outcomes in clinical trials.

What is the Diagnostic Accuracy of Novel Urine Biomarkers for Urinary Tract Infection?

Background: Urinary tract infection (UTI) affects half of women at least once in their lifetime. Current diagnosis involves urinary dipstick and urine culture, yet both methods have modest diagnostic accuracy, and cannot support decision-making in patient populations with high prevalence of asymptomatic bacteriuria, such as older adults. Detecting biomarkers of host response in the urine of hosts has the potential to improve diagnosis. Objectives: To synthesise the evidence of the diagnostic accuracy of novel biomarkers for UTI, and of their ability to differentiate UTI from asymptomatic bacteriuria. Design: A systematic review. Data Sources and Methods: We searched MEDLINE, EMBASE, CINAHL and Web of Science for studies of novel biomarkers for the diagnosis of UTI. We excluded studies assessing biomarkers included in urine dipsticks as these have been well described previously. We included studies of adult patients (≥16 years) with a suspected or confirmed urinary tract infection using microscopy and culture as the reference standard. We excluded studies using clinical signs and symptoms, or urine dipstick only as a reference standard. Quality appraisal was performed using QUADAS-2. We summarised our data using point estimates and data accuracy statistics. Results: We included 37 studies on 4009 adults measuring 66 biomarkers. Study quality was limited by case-control design and study size; only 4 included studies had a prospective cohort design. IL-6 and IL-8 were the most studied biomarkers. We found plausible evidence to suggest that IL-8, IL-6, GRO-a, sTNF-1, sTNF-2 and MCR may benefit from more rigorous evaluation of their potential diagnostic value for UTI. Conclusions: There is insufficient evidence to recommend the use of any novel biomarker for UTI diagnosis at present. Further evaluation of the more promising candidates, is needed before they can be recommended for clinical use.

Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer.

PURPOSE: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis. EXPERIMENTAL DESIGN: Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection. CONCLUSIONS: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.

Accuracy of the NICE traffic light system in children presenting to general practice: a retrospective cohort study.

BACKGROUND: The National Institute for Health and Care Excellence (NICE) traffic light system was created to facilitate the assessment of unwell children in primary care. To the authors' knowledge, no studies have validated this tool in UK general practice. AIM: To evaluate the accuracy of this system for detecting serious illness in children presenting to general practice. DESIGN AND SETTING: A retrospective diagnostic accuracy study was undertaken, using a cohort of acutely unwell children aged <5 years presenting to general practice in England and Wales. METHOD: The traffic light categories of 6703 children were linked with hospital data to identify admissions and diagnoses. The sensitivity and specificity of these categories were calculated against the reference standard: a hospital-diagnosed serious illness within 7 days of GP consultation, measured using International Classification of Diseases, 10th Revision codes. RESULTS: In total, 2116 (31.6%) children were categorised as 'red'; 4204 (62.7%) as 'amber'; and 383 (5.7%) as 'green'. There were 139 (2.1%) children who were admitted to hospital within 7 days of consultation, of whom 17 (12.2%; 0.3% overall) had a serious illness. The sensitivity of the red category (versus amber and green) was 58.8% (95% confidence interval [CI] = 32.9 to 81.6) and the specificity 68.5% (95% CI = 67.4 to 69.6). The sensitivity and specificity of red and amber combined (versus green) was 100% (95% CI = 80.5 to 100) and 5.7% (95% CI = 5.2 to 6.3), respectively. CONCLUSION: The NICE traffic light system did not accurately detect children admitted with a serious illness, nor those not seriously ill who could have been managed at home. This system is not suitable for use as a clinical tool in general practice. Further research is required to update or replace the system.