The evolution of non-small cell lung cancer metastases in TRACERx.

Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metastases diverged early, before the last clonal sweep in the primary tumour, and early divergence was enriched for patients who were smokers at the time of initial diagnosis. Simulations suggested that early metastatic divergence more frequently occurred at smaller tumour diameters (less than 8 mm). Single-region primary tumour sampling resulted in 83% of late divergence cases being misclassified as early, highlighting the importance of extensive primary tumour sampling. Polyclonal dissemination, which was associated with extrathoracic disease recurrence, was found in 32% of cases. Primary lymph node disease contributed to metastatic relapse in less than 20% of cases, representing a hallmark of metastatic potential rather than a route to subsequent recurrences/disease progression. Metastasis-seeding subclones exhibited subclonal expansions within primary tumours, probably reflecting positive selection. Our findings highlight the importance of selection in metastatic clone evolution within untreated primary tumours, the distinction between monoclonal versus polyclonal seeding in dictating site of recurrence, the limitations of current radiological screening approaches for early diverging tumours and the need to develop strategies to target metastasis-seeding subclones before relapse.

Small lightning flashes from shallow electrical storms on Jupiter.

Lightning flashes have been observed by a number of missions that visited or flew by Jupiter over the past several decades. Imagery led to a flash rate estimate of about 4 × 10-3 flashes per square kilometre per year (refs. 1,2). The spatial extent of Voyager flashes was estimated to be about 30 kilometres (half-width at half-maximum intensity, HWHM), but the camera was unlikely to have detected the dim outer edges of the flashes, given its weak response to the brightest spectral line of Jovian lightning emission, the 656.3-nanometre Hα line of atomic hydrogen1,3-6. The spatial resolution of some cameras allowed investigators to confirm 22 flashes with HWHM greater than 42 kilometres, and to estimate one with an HWHM of 37 to 45 kilometres (refs. 1,7-9). These flashes, with optical energies comparable to terrestrial 'superbolts'-of (0.02-1.6) × 1010 joules-have been interpreted as tracers of moist convection originating near the 5-bar level of Jupiter's atmosphere (assuming photon scattering from points beneath the clouds)1-3,7,8,10-12. Previous observations of lightning have been limited by camera sensitivity, distance from Jupiter and long exposures (about 680 milliseconds to 85 seconds), meaning that some measurements were probably superimposed flashes reported as one1,2,7,9,10,13. Here we report optical observations of lightning flashes by the Juno spacecraft with energies of approximately 105-108 joules, flash durations as short as 5.4 milliseconds and inter-flash separations of tens of milliseconds, with typical terrestrial energies. The flash rate is about 6.1 × 10-2 flashes per square kilometre per year, more than an order of magnitude greater than hitherto seen. Several flashes are of such small spatial extent that they must originate above the 2-bar level, where there is no liquid water14,15. This implies that multiple mechanisms for generating lightning on Jupiter need to be considered for a full understanding of the planet's atmospheric convection and composition.

Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/ß-catenin, mitogen-activated protein kinase, and TGF-ß receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Progress Toward Rubella and Congenital Rubella Syndrome Elimination - Worldwide, 2012-2022.

Rubella virus is a leading cause of vaccine-preventable birth defects. Infection during pregnancy can result in miscarriage, fetal death, stillbirth, or a constellation of birth defects, including cataracts, deafness, heart defects, and developmental delay, known as congenital rubella syndrome (CRS). A single dose of rubella-containing vaccine can provide lifelong protection against rubella. The Global Vaccine Action Plan 2011-2020 included a target to achieve elimination of rubella in at least five of the six World Health Organization (WHO) regions by 2020, and rubella elimination is a critical goal of the Immunization Agenda 2030. This report updates a previous report and describes progress toward rubella and CRS elimination during 2012-2022. During 2012-2022, among 194 WHO countries, the number that included rubella-containing vaccine (RCV) in their immunization schedules increased from 132 (68%) to 175 (90%) and the percentage of the world's infants vaccinated against rubella increased from 40% to 68%. Reported rubella cases declined 81%, from 93,816 in 2012 to 17,407 in 2022. Verification of rubella elimination was achieved in 98 (51%) of 194 countries by 2022, an increase from 84 (43%) countries in 2019. Despite significant progress in the introduction of RCV into routine immunization programs worldwide, approximately 25 million infants annually still do not have access to RCV. Nevertheless, even in complex settings, the increasing number of countries that have achieved and sustained rubella elimination demonstrates progress toward global rubella elimination.

COVID-19 Vaccination Coverage - World Health Organization African Region, 2021-2023.

With the availability of authorized COVID-19 vaccines in early 2021, vaccination became an effective tool to reduce COVID-19-associated morbidity and mortality. Initially, the World Health Organization (WHO) set an ambitious target to vaccinate 70% of the global population by mid-2022. However, in July 2022, WHO recommended that all countries, including those in the African Region, prioritize COVID-19 vaccination of high-risk groups, including older adults and health care workers, to have the greatest impact on morbidity and mortality. As of December 31, 2023, approximately 860 million doses of COVID-19 vaccine had been delivered to countries in the African Region, and 646 million doses had been administered. Cumulatively, 38% of the African Region's population had received ≥1 dose, 32% had completed a primary series, and 21% had received ≥1 booster dose. Cumulative total population coverage with ≥1 dose ranged by country from 0.3% to 89%. Coverage with the primary series among older age groups was 52% (range among countries = 15%-96%); primary series coverage among health care workers was 48% (range = 13%-99%). Although the COVID-19 public health emergency of international concern was declared over in May 2023, current WHO recommendations reinforce the need to vaccinate priority populations at highest risk for severe COVID-19 disease and death and build more sustainable programs by integrating COVID-19 vaccination into primary health care, strengthening immunization across the life course, and improving pandemic preparedness.

Lipidomic Profiling of Colorectal Lesions for Real-Time Tissue Recognition and Risk-Stratification Using Rapid Evaporative Ionization Mass Spectrometry.

OBJECTIVE: Rapid evaporative ionization mass spectrometry (REIMS) is a metabolomic technique analyzing tissue metabolites, which can be applied intraoperatively in real-time. The objective of this study was to profile the lipid composition of colorectal tissues using REIMS, assessing its accuracy for real-time tissue recognition and risk-stratification. SUMMARY BACKGROUND DATA: Metabolic dysregulation is a hallmark feature of carcinogenesis; however, it remains unknown if this can be leveraged for real-time clinical applications in colorectal disease. METHODS: Patients undergoing colorectal resection were included, with carcinoma, adenoma and paired-normal mucosa sampled. Ex vivo analysis with REIMS was conducted using monopolar diathermy, with the aerosol aspirated into a Xevo G2S QToF mass spectrometer. Negatively charged ions over 600 to 1000 m/z were used for univariate and multivariate functions including linear discriminant analysis. RESULTS: A total of 161 patients were included, generating 1013 spectra. Unique lipidomic profiles exist for each tissue type, with REIMS differentiating samples of carcinoma, adenoma, and normal mucosa with 93.1% accuracy and 96.1% negative predictive value for carcinoma. Neoplasia (carcinoma or adenoma) could be predicted with 96.0% accuracy and 91.8% negative predictive value. Adenomas can be risk-stratified by grade of dysplasia with 93.5% accuracy, but not histological subtype. The structure of 61 lipid metabolites was identified, revealing that during colorectal carcinogenesis there is progressive increase in relative abundance of phosphatidylglycerols, sphingomyelins, and mono-unsaturated fatty acid-containing phospholipids. CONCLUSIONS: The colorectal lipidome can be sampled by REIMS and leveraged for accurate real-time tissue recognition, in addition to riskstratification of colorectal adenomas. Unique lipidomic features associated with carcinogenesis are described.

Long-term functional results of transvaginal anal sphincter repair for faecal incontinence; a retrospective case series.

INTRODUCTION AND HYPOTHESIS: We report our experience with a transvaginal approach with overlapping anal sphincter repair. The aim of this cohort study was to evaluate long-term functional outcomes. Women who had undergone transvaginal anal sphincteroplasty for anal incontinence from July 2005 to July 2020 and attended a multidisciplinary team of urogynaecologists and colorectal surgeons at the Mercy Hospital Perineal clinic were included. METHODS: One hundred seven women were included in the study with a median follow-up of 57.5 months. We analysed outcomes by comparing patient's St Mark's score difference before and after surgery. Meaningful clinical difference (MID) was set at 5 points; complications and patient demographics were recorded along with a question about whether they would recommend this treatment to a friend. RESULTS: An improvement was seen in 69.3% of women with a marked improvement in 46.5%. Furthermore, 70% said they would recommend the procedure to a friend, if they were in a similar situation. Wound infection or partial perineal breakdown was reported in 45% of women but did not have a significant impact on outcomes. CONCLUSION: Transvaginal anal sphincter repair is associated with significant improvements in patients' St. Mark's score. Our data show that the long-term success rate of transvaginal/perineal AS repair may be better than previously reported in the literature with 70% of women satisfied at 57 months. Another benefit of the transvaginal route is the possibility of performing a pelvic floor and perineal repair at the time of surgery.

Conditional survival in patients with stage IB-IIIA melanoma undergoing sentinel node biopsy in Queensland: A longitudinal study.

BACKGROUND: Tumour characteristics such as thickness and ulceration, along with sentinel lymph node (SLN) status, have been essential in predicting survival in patients with locally invasive melanomas at the time of diagnosis. It is unclear if these prognostic factors are relevant 1, 2 or 5 years after diagnosis. OBJECTIVES: The key aim of this project was to analyse conditional survival in a cohort of Queensland patients with stage IB to IIIA melanomas (American Joint Committee on Cancer's staging system, 8th version) and to test the relevance of clinicopathological prognostic factors for melanoma outcome after varying intervals of survival time. METHODS: Patients with primary invasive cutaneous melanoma who were referred to a tertiary melanoma clinic and underwent SLN biopsy between 1994 and 2011 were ascertained. The effect of patient and tumour characteristics on melanoma survival were calculated using multivariate Cox proportional hazard models at diagnosis and at variable times after diagnosis. RESULTS: The final analysis included 651 patients (average age 49 years, 55.5% male) with stage IB to IIIA melanoma. At diagnosis, and after 1 and 2 years survived, SLN positivity, thickness and ulceration were predictive of 10-year survival since diagnosis. However, once patients survived 5 years, only SLN status was predictive. Overall conditional melanoma survival improved with increasing time survived. Five years after diagnosis, 10-year conditional melanoma survival (MSS) was 91% (95% CI 86%-95%) compared with 85% (82%-88%) predicted at diagnosis. The improvement in MSS was observed mainly for Stage II melanoma patients and not for those with a positive SLN biopsy. CONCLUSIONS: This study confirms the improvement of prognosis according to time survived since diagnosis suggesting that after 5 years survival the classic prognostic indicators may not have the same influence.

CO2 surgical laser for treatment of stress urinary incontinence in women: a randomized controlled trial.

BACKGROUND: Stress urinary incontinence is a common condition that can be treated conservatively and/or surgically. Given the risks of surgery, developing effective nonsurgical treatment options would be beneficial. Some studies have suggested that laser therapy may improve or cure stress urinary incontinence. However, there is a lack of sham-controlled randomized controlled trials to judge treatment efficacy. OBJECTIVE: This study aimed to compare the effects of CO2 vaginal laser vs sham therapy for treating stress urinary incontinence. STUDY DESIGN: This was a multicenter, participant-blinded, sham-controlled, parallel group (1:1) superiority randomized controlled trial performed in outpatient clinics in 2 hospitals. We included women aged 18 to 80 years with objective and subjective stress urinary incontinence. Participants had undertaken or declined supervised pelvic floor muscle training. Intervention was performed using a CO2 fractionated vaginal laser. Participants underwent 3 treatments, 4 weeks apart, with increasing energy and density settings. Sham treatment was performed using an identical technique with a deactivated pedal. The primary outcome was the subjective stress urinary incontinence rate (proportion with leak with cough, sneeze, or laughter) at 3 months after completion of treatment. Secondary outcomes included objective stress urinary incontinence, change in the disease-specific patient-reported outcomes, health-related quality of life, and adverse effects. Categorical outcomes were compared using the chi square test and continuous outcomes using analysis of covariance, adjusting for the baseline score. RESULTS: There were 52 participants who received laser and 49 who received sham treatment. One participant in each group withdrew from the study before the endpoint, and 2 participants in the laser group did not participate in the follow-up visits. Participant mean age was 53 (34-79) years. Mean body mass index was 26.1 (18.1-49.6); 90% were vaginally parous. At 3 months, there was no difference between the sham and active treatment arm in subjective stress urinary incontinence (46 [96%] vs 48 [98%]; relative risk, 0.98 [95% confidence interval, 0.91-1.05]; P=.55) or in objective stress urinary incontinence (37 [80%] vs 33 [80%]; relative risk, 0.99 [95% confidence interval, 0.81-1.23]; P=.995). Patient-reported outcomes and health-related quality of life were also comparable between the groups. Vaginal bleeding occurred in 3 participants after laser and 1 participant after sham treatment. Pain during treatment did not differ between laser and sham treatment. CONCLUSION: We were unable to show an improvement in stress urinary incontinence after CO2 vaginal laser therapy compared with sham treatment.

Progress Toward Measles Elimination - South-East Asia Region, 2003-2020.

In 2013, member states of the World Health Organization (WHO) South-East Asia Region* (SEAR) adopted the goal of measles elimination and rubella and congenital rubella syndrome control† by 2020 (1). In 2014, to provide impetus toward achieving this goal, the Regional Director declared measles elimination and rubella control one of the Regional Flagship Priorities. In 2019, SEAR member states declared a revised goal of eliminating both measles and rubella§ by 2023 (2). The recommended strategies to achieve elimination include 1) achieving and maintaining ≥95% coverage with 2 doses of measles- and rubella-containing vaccine in every district through routine or supplementary immunization activities¶ (SIAs); 2) developing and sustaining a sensitive and timely case-based surveillance system that meets recommended performance indicators**; 3) developing and maintaining an accredited laboratory network; 4) achieving timely identification, investigation, and response to measles outbreaks; and 5) collaborating with other public health initiatives to achieve the preceding four strategies. This report updates a previous report and describes progress toward measles elimination in SEAR during 2003-2020 (3). In 2002, coverage with the first dose of a measles-containing vaccine in routine immunization (MCV1) was 70%, and only three countries in SEAR had added a second routine dose of measles-containing vaccine in routine immunization (MCV2). During 2003-2020, all countries introduced MCV2, and estimated coverage with MCV1 increased 35%, from 65% to 88%, and coverage with MCV2 increased 1,233% from 6% to 80%. Approximately 938 million persons were vaccinated in SIAs. Annual reported measles incidence declined by 92%, from 57.0 to 4.8 cases per 1 million population, and estimated deaths decreased by 97%; an estimated 9.3 million deaths were averted by measles vaccination. By 2020, five countries were verified as having achieved measles elimination. To achieve measles elimination in the region by 2023, additional efforts are urgently needed to strengthen routine immunization services and improve measles-containing vaccine (MCV) coverage, conduct periodic high-quality SIAs, and strengthen measles case-based surveillance and laboratory capacity.

Effects of bowel preparation on intestinal bacterial associated urine and faecal metabolites and the associated faecal microbiome.

BACKGROUND: Urinary and faecal metabolic profiling have been extensively studied in gastrointestinal diseases as potential diagnostic markers, and to enhance our understanding of the intestinal microbiome in the pathogenesis these conditions. The impact of bowel cleansing on the microbiome has been investigated in several studies, but limited to just one study on the faecal metabolome. AIM: To compare the effects of bowel cleansing on the composition of the faecal microbiome, and the urine and faecal metabolome. METHODS: Urine and faecal samples were obtained from eleven patients undergoing colonoscopy at baseline, and then at day 3 and week 6 after colonoscopy. 16S rRNA gene sequencing was used to analyse changes in the microbiome, and metabonomic analysis was performed using proton nuclear magnetic resonance (1H NMR) spectroscopy. RESULTS: Microbiomic analysis demonstrated a reduction in alpha diversity (Shannon index) between samples taken at baseline and three days following bowel cleansing (p = 0.002), and there was no significant difference between samples at baseline and six weeks post colonoscopy. Targeted and non-targeted analysis of urinary and faecal bacterial associated metabolites showed no significant impact following bowel cleansing. CONCLUSIONS: Bowel cleansing causes a temporary disturbance in bacterial alpha diversity measured in faeces, but no significant changes in the faecal and urine metabolic profiles, suggesting that overall the faecal microbiome and its associated metabolome is resistant to the effects of an induced osmotic diarrhoea.

Is vaginal laxity an early symptom of pelvic organ prolapse?

INTRODUCTION AND HYPOTHESIS: We aimed to determine whether vaginal laxity (VL) may be an early symptom of pelvic organ prolapse (POP). METHODS: This was a retrospective observational study including patients referred to a urogynecological clinic owing to symptoms of pelvic floor dysfunction. The interview included inquiry about VL and POP symptoms. Clinical examination and translabial ultrasound (TLUS) were performed to assess for POP and levator hiatal ballooning. Analysis of ultrasound datasets was performed with the reviewer blinded against all other data. Linear regression models were used to evaluate associations between age categories and symptoms. RESULTS: The analysis included 531 patients. Mean age was 59.7 years (range 17.6-92.0), mean body mass index (BMI) was 29.5 kg/m2 (14.7-53.5) and 458 (86%) were vaginally parous. Overall, POP symptoms were reported by 258 patients (49%) and VL by 118 (22%). Significant clinical POP was diagnosed in 384 patients (72%). Levator hiatal ballooning on TLUS was noticed in 56%. VL and POP symptoms showed a divergent association with age (p = 0.02). This trend remained significant after controlling for clinically significant POP (p = 0.01) and levator hiatal ballooning (p = 0.002). Of 384 women with significant objective POP, 231 (60%) reported symptoms of POP. Of 153 women with asymptomatic POP, 7 (5%) reported symptoms of VL. CONCLUSIONS: With increasing age the prevalence of VL decreases, whereas symptoms of POP increase. However, only very few women with objective POP perceive VL as their only symptom, independent of age at presentation. Therefore, vaginal laxity does not seem to be an early symptom of prolapse.

Outcomes following sacrocolpopexy using ultralight and lightweight mesh.

INTRODUCTION AND HYPOTHESIS: This study reports the long-term anatomic and subjective outcomes following sacrocolpopexy based on mesh weight and provides device-specific data. METHODS: This cohort study compared ultra-lightweight (≤ 20 g/m2) with lightweight mesh (≥ 25 g/m2). The primary outcome was composite failure defined as at least one of ≥ stage 2 apical prolapse, anterior or posterior vaginal wall beyond hymen, complaint of bulge or retreatment. Effect measure estimates were calculated as the incidence rate ratio of composite failure comparing the use of ultra-light with lightweight mesh. Crude and adjusted incidence rate ratios (IRRs) were obtained using uni- and multivariable Poisson regression models. RESULTS: Of 358 women who met inclusion criteria, 220 (61%) agreed to attend for review; 95 (43%) had ultra-lightweight mesh and 125 (57%) had lightweight mesh including UpsylonTM. Median follow-up for ultra-light and lightweight mesh was 36 (IQR 22-42) and 63 (IQR 48-87) months, respectively (p < 0.001). Accounting for differences in follow-up time, there was no significant difference in composite failure between ultra-light and lightweight mesh groups (IRR 1.47, 95% CI 0.83-2.52, p = 0.15). This persisted after adjustment for age, body mass index, parity, smoking and presence of advanced prolapse prior to surgery (IRR 1.52, 95% CI 0.94-2.47, p = 0.087). Mesh exposure for both groups was mostly asymptomatic, and the rate was 7% for the ultra-light group and 8% in the lightweight group. Overall, repeat surgery for recurrent apical prolapse and mesh exposure occurred in 4% and 2%, respectively. CONCLUSIONS: Ultra-lightweight mesh appears to have similar incidence rate of failure compared to lightweight mesh. UpsylonTM mesh has a similar low rate of recurrent apical prolapse and mesh exposure.

Effect of serial awake prone positioning on oxygenation in patients admitted to intensive care with COVID-19.

INTRODUCTION: Awake prone positioning (APP) might benefit patients with COVID-19 by improving oxygenation, but it is unknown whether this improvement can be sustained with serial proning episodes. METHODS: We conducted a retrospective review of adults with COVID-19 admitted to one intensive care unit, in those who underwent APP and controls. Patients in both groups had type 1 respiratory failure requiring oxygen (but not initially intubated), confirmed SARS-CoV-2 PCR by nasopharyngeal swab and findings of multifocal ground-glass opacities on imaging. For the APP group, serial SpO2/FiO2 measurements were recorded after each proning episode. RESULTS: Of 77 patients admitted, 50 (65%) were excluded because they had already been intubated. Another 7 (9%) had undergone APP prior to admission. Of the remaining 20, 10 underwent APP and 10 were controls. Patients in both groups had similar demographics, subsequent intubation and survival. Of those who underwent APP, SpO2/FiO2 was most likely to increase after the first episode (before median: 152, IQR 135-185; after: median 192, IQR 156-234, p=0.04). Half of participants (5) in the APP group were unable to tolerate more than two APP episodes. CONCLUSIONS: Most patients with COVID-19 admitted to the intensive care are not suitable for APP. Of those who are, many cannot tolerate more than two episodes. Improvements in SpO2/FiO2 secondary to APP are transient and most likely in the first episode. Our findings may explain why other studies have failed to show improvements in mortality from APP despite improvements in oxygenation.

Strategies to prevent and manage running-related knee injuries: a systematic review of randomised controlled trials.

OBJECTIVE: To evaluate the effectiveness of interventions to prevent and manage knee injuries in runners. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, EMBASE, CINAHL, Web of Science and SPORTDiscus up to May 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised controlled trials (RCTs) with a primary aim of evaluating the effectiveness of intervention(s) to prevent or manage running-related knee injury. RESULTS: Thirty RCTs (18 prevention, 12 management) analysed multiple interventions in novice and recreational running populations. Low-certainty evidence (one trial, 320 participants) indicated that running technique retraining (to land softer) reduced the risk of knee injury compared with control treadmill running (risk ratio (RR) 0.32, 95% CI 0.16 to 0.63). Very low-certainty to low-certainty evidence from 17 other prevention trials (participant range: 24 -3287) indicated that various footwear options, multicomponent exercise therapy, graduated running programmes and online and in person injury prevention education programmes did not influence knee injury risk (RR range: 0.55-1.06). In runners with patellofemoral pain, very low-certainty to low-certainty evidence indicated that running technique retraining strategies, medial-wedged foot orthoses, multicomponent exercise therapy and osteopathic manipulation can reduce knee pain in the short-term (standardised mean difference range: -4.96 to -0.90). CONCLUSION: There is low-certainty evidence that running technique retraining to land softer may reduce knee injury risk by two-thirds. Very low-certainty to low-certainty evidence suggests that running-related patellofemoral pain may be effectively managed through a variety of active (eg, running technique retraining, multicomponent exercise therapy) and passive interventions (eg, foot orthoses, osteopathic manipulation). PROSPERO REGISTRATION NUMBER: CRD42020150630.

Development of a Measles and Rubella Multiplex Bead Serological Assay for Assessing Population Immunity.

Serosurveys are important tools for estimating population immunity and providing immunization activity guidance. The measles and rubella multiplex bead assay (MBA) offers multiple advantages over standard serological assays and was validated by comparison with the enzyme-linked immunosorbent assay (ELISA) and the measles plaque reduction neutralization (PRN) assay. Results from a laboratory-produced purified measles virus whole-virus antigen MBA (MeV WVAL) correlated better with ELISA and PRN than results from the baculovirus-expressed measles nucleoprotein (N) MBA. Therefore, a commercially produced whole-virus antigen (MeV WVAC) was evaluated. Serum IgG antibody concentrations correlated significantly with a strong linear relationship between the MeV WVAC and MeV WVAL MBAs (R = 0.962 and R2 = 0.926). IgG concentrations from the MeV WVAC MBA showed strong correlation with PRN titers (R = 0.846), with a linear relationship comparable to values obtained with the MeV WVAL MBA and PRN assay (R2 = 0.716 and R2 = 0.768, respectively). Receiver operating characteristic (ROC) curve analysis of the MeV WVAC using PRN titer as the comparator resulted in a seroprotection cutoff of 153 mIU/ml, similar to the established correlate of protection of 120 mIU/ml, with a sensitivity of 98% and a specificity of 83%. IgG concentrations correlated strongly between the rubella WVA MBA and ELISA (R = 0.959 and R2 = 0.919). ROC analysis of the rubella MBA using ELISA as the comparator yielded a cutoff of 9.36 IU/ml, similar to the accepted cutoff of 10 IU/ml for seroprotection, with a sensitivity of 99% and a specificity of 100%. These results support use of the MBA for multiantigen serosurveys assessing measles and rubella population immunity.

Dietary Blueberry and Soluble Fiber Supplementation Reduces Risk of Gestational Diabetes in Women with Obesity in a Randomized Controlled Trial.

BACKGROUND: Gestational diabetes mellitus (GDM) is a growing public health concern and maternal obesity and poor dietary intakes could be implicated. Dietary polyphenols and fiber mitigate the risk of diabetes and its complications, but little is known about their efficacy in preventing GDM. OBJECTIVES: We examined the effects of whole blueberry and soluble fiber supplementation on primary outcomes of cardiometabolic profiles in women at high risk of developing GDM. METHODS: Women (n = 34; mean ± SD age: 27 ± 5 y; BMI: 35.5 ± 4.0 kg/m2; previous history of GDM ∼56%; Hispanic ∼79%) were recruited in early pregnancy (<20 weeks of gestation) and randomly assigned to 1 of the following 2 groups for 18 wk: intervention (280 g whole blueberries and 12 g soluble fiber per day) and standard prenatal care (control). Both groups received nutrition education and maintained 24-h food recalls throughout the study. Data on anthropometrics, blood pressure, and blood samples for biochemical analyses were collected at baseline (<20 weeks), midpoint (24-28 weeks), and end (32-36 weeks) of gestation. Diagnosis of GDM was based on a 2-step glucose challenge test (GCT). Data were analyzed using a mixed-model ANOVA. RESULTS: Maternal weight gain was significantly lower in the dietary intervention than in the control group at the end of the trial (mean ± SD: 6.8 ± 3.2 kg compared with 12.0 ± 4.1 kg, P = 0.001). C-reactive protein was also lower in the intervention than in the control group (baseline: 6.1 ± 4.0 compared with 6.8 ± 7.2 mg/L; midpoint: 6.1 ± 3.7 compared with 7.5 ± 7.3 mg/L; end: 5.5 ± 2.2 compared with 9.5 ± 6.6 mg/L, respectively, P = 0.002). Blood glucose based on GCT was lower in the intervention than in the control (100 ± 33 mg/dL compared with 131 ± 40 mg/dL, P < 0.05). Conventional lipids (total, LDL, and HDL cholesterol and triglycerides) did not differ between groups over time. No differences were noted in infant birth weight. CONCLUSIONS: Whole blueberry and soluble fiber supplementation may prevent excess gestational weight gain and improve glycemic control and inflammation in women with obesity.This trial was registered at clinicaltrials.gov as NCT03467503.

Progress Toward Regional Measles Elimination - Worldwide, 2000-2020.

In 2012, the World Health Assembly endorsed the Global Vaccine Action Plan,* with the objective of eliminating measles† in five of the six World Health Organization (WHO) regions by 2020 (1). The Immunization Agenda 2021-2030 (IA2030)§ uses measles incidence as an indicator of the strength of immunization systems. The Measles-Rubella Strategic Framework 2021-2030¶ and the Measles Outbreaks Strategic Response Plan 2021-2023** are aligned with the IA2030 and highlight robust measles surveillance systems to document immunity gaps, identify root causes of undervaccination, and develop locally tailored solutions to ensure administration of 2 doses of measles-containing vaccine (MCV) to all children. This report describes progress toward World Health Assembly milestones and measles elimination objectives during 2000-2020 and updates a previous report (2). During 2000-2010, estimated MCV first dose (MCV1) coverage increased globally from 72% to 84%, peaked at 86% in 2019, but declined to 84% in 2020 during the COVID-19 pandemic. All countries conducted measles surveillance, although fewer than one third achieved the sensitivity indicator target of ≥2 discarded†† cases per 100,000 population in 2020. Annual reported measles incidence decreased 88% during 2000-2016, from 145 to 18 cases per 1 million population, rebounded to 120 in 2019, before falling to 22 in 2020. During 2000-2020, the annual number of estimated measles deaths decreased 94%, from 1,072,800 to 60,700, averting an estimated 31.7 million measles deaths. To achieve regional measles elimination targets, enhanced efforts are needed to reach all children with 2 MCV doses, implement robust surveillance, and identify and close immunity gaps.

Low Referral Rates for Genetic Assessment of Patients With Multiple Adenomas in United Kingdom Bowel Cancer Screening Programs.

BACKGROUND: Approximately 1 in 20 cases of colorectal cancer are caused by monogenic syndromes. Published guidelines recommend that patients with 10 or more adenomas be referred for genetic testing, based on evidence that colorectal cancer risk is associated with adenoma multiplicity. OBJECTIVE: The aim of this study was to determine adherence to guidelines on referral for genetic screening in patients with 10 or more adenomas. DESIGN: A cross-sectional study was performed of prospectively collected data from the UK Bowel Cancer Screening Programme between May 2007 and June 2018. Only histologically confirmed adenomas were included. Clinicopathological data were recorded from patient records, and referrals to clinical genetics services were ascertained. SETTING: Data were obtained from 3 centers in London, United Kingdom. PATIENTS: A total of 17,450 subjects underwent colonoscopy following an abnormal fecal occult blood test. MAIN OUTCOME MEASURES: We quantified patients with 10 or more adenomas and the proportion referred for genetic screening. RESULTS: The adenoma detection rate was 50.6% among 17,450 patients who underwent colonoscopy (8831 had 1 or more adenomas). Three hundred forty-seven patients (2.0%) had 10 or more adenomas. Patients with 10 or more adenomas were more likely to be male than those with fewer than 10 adenomas (76.9% vs 53.4%; p < 0.0001). A family history was collected in 37.8% of the multiple adenoma population. Of 347 patients with 10 or more adenomas, 28 (8.1%) were referred for genetic assessment. LIMITATIONS: All 3 screening centers were in a single city. No genetic outcome data were available to permit analysis of actual rates of inherited cancer syndromes in this population. CONCLUSIONS: In this study, almost 1 in 50 patients had 10 or more adenomas. Despite guidelines advising genetic testing in this group, referral rates are low. A referral pathway and management strategies should be established to address this patient population. See Video Abstract at http://links.lww.com/DCR/B630. TASAS BAJAS DE DERIVACIN PARA LA EVALUACIN GENTICA DE PACIENTES CON ADENOMAS MLTIPLES EN LOS PROGRAMAS DE DETECCIN DEL CNCER DE INTESTINO DEL REINO UNIDO: ANTECEDENTES:Aproximadamente uno de cada veinte casos de cáncer colorrectal son causados por síndromes monogénicos. Las pautas publicadas recomiendan que los pacientes con diez o más adenomas sean derivados para pruebas genéticas, basándose en la evidencia de que el riesgo de cáncer colorrectal está asociado con la multiplicidad de adenomas.OBJETIVO:El objetivo de este estudio fue determinar la adherencia a las guías de derivación para cribado genético en pacientes con diez o más adenomas.DISEÑO:Se realizó un estudio transversal de datos recolectados prospectivamente del Programa de Detección de Cáncer de Intestino del Reino Unido entre mayo de 2007 y junio de 2018. Solo se incluyeron los adenomas confirmados histológicamente. Los datos clínico-patológicos se registraron a partir de los registros de los pacientes y se determinaron las derivaciones a los servicios de genética clínica.AJUSTE ENTORNO CLINICO:Los datos se obtuvieron de tres centros en Londres, Reino Unido.PACIENTES:Un total de 17.450 17450 sujetos pacientes se sometieron a una colonoscopia después de una prueba de sangre oculta en heces anormal positiva.PRINCIPALES MEDIDAS DE RESULTADO VOLARACION:cuantificamos los pacientes con diez o más adenomas y la proporción remitida para cribado genético.RESULTADOS:La tasa de detección de adenomas fue del 50,6% entre 17.450 17450 pacientes que se sometieron a colonoscopia (8.831 8831 tenían uno o más adenomas). 347 pacientes (2,0%) tenían 10 o más adenomas. Los pacientes con 10 o más adenomas tenían más probabilidades de ser hombres que aquellos con menos de 10 adenomas (76,9% frente versus a 53,4%; p <0,0001). Se recogieron antecedentes familiares en el 37,8% de la población de adenomas múltiples. De 347 pacientes con 10 o más adenomas, 28 (8,1%) fueron remitidos para evaluación genética.LIMITACIONES:Los tres centros de detección se encontraban en una sola ciudad. No se disponía de datos de resultados genéticos que permitieran el análisis de las tasas reales de síndromes de cáncer hereditario en esta población.CONCLUSIONES:En este estudio, casi uno de cada cincuenta pacientes tenía diez o más adenomas. A pesar de las pautas que recomiendan las pruebas genéticas en este grupo, las tasas de derivación son bajas. Se debe establecer una vía de derivación y estrategias de manejo para abordar esta población de pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B630.

In situ investigation of oxidation across a heterogeneous nanoparticle-support interface during metal support interactions.

Interactions between oxide supports and noble metal nanoparticles (NPs) is an area of intense research interest across all fields of catalysis. Oxygen spillover, metal support interactions (MSIs) and charge transfer are among many mechanisms observed and proposed as to how NP-support interfaces assist and enhance catalysis. This work studies the migration of oxygen across the Pd NP-CuO nanowire (NW) interface and beyond. X-ray photoelectron spectroscopy (XPS) and Kelvin probe force microscopy (KPFM) found an interaction between the Pd NP and CuO NW support, via the formation of PdO at the Pd-CuO interface. It was found, through in situ irradiation at high vacuum transmission electron microscopy (TEM), that oxygen enters the Pd NP lattice from the Pd-CuO interface via amorphization of the NP. Varying the amount of irradiation highlighted the different rates of amorphization of NPs, with full amorphization of a NP leading to the formation of an epitaxially driven PdO across the NPs. Interestingly, in situ heating in XPS observed a reduction to metallic Pd, found to be similarly amorphous during TEM investigation. On comparison with Pd supported on a non-reducible substrate - in which oxidation was found to proceed from the outer surface in, rather than the support interface (resulting in a PdO shell) - it is theorized that the oxidation and reduction of Pd on CuO forms a PdO NP surface full of Pd-PdO sites allowing for synergistic effects, of great use in the oxidation and hydrogenation of organic species.