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Complicating factors such as time pressures, anatomic variants in the spine, and similarities in adjacent vertebrae are associated with incorrect level treatments of the spine. The purpose of this work was to mitigate such challenges by fully automating the treatment planning process for diagnostic and simulation computed tomography (CT) scans.Vertebral bodies are labeled on CT scans of any length using 2 intendent deep-learning models-mirroring 2 different experts labeling the spine. Then, a U-Net++ architecture was trained, validated, and tested to contour each vertebra (n = 220 CT scans). Features from the CT and auto-contours were input into a random forest classifier to predict whether vertebrae were correctly labeled. This classifier was trained using auto-contours from cone beam computed tomography, positron emission tomography/CT, simulation CT, and diagnostic CT images (n = 56 CT scans, 751 contours). Auto-plans were generated via scripting. Each model was combined into a framework to make a fully automated clinical tool. A retrospective planning study was conducted in which 3 radiation oncologists scored auto-plan quality on an unseen patient cohort (n = 60) on a 5-point scale. CT scans varied in scan length, presence of surgical implants, imaging protocol, and metastatic burden.The results showed that the uniquely designed convolutional neural networks accurately labeled and segmented vertebral bodies C1-L5 regardless of imaging protocol or metastatic burden. Mean dice-similarity coefficient was 85.0% (cervical), 90.3% (thoracic), and 93.7% (lumbar). The random forest classifier predicted mislabeling across various CT scan types with an area under the curve of 0.82. All contouring and labeling errors within treatment regions (11 of 11), including errors from patient plans with atypical anatomy (eg, T13, L6) were detected. Radiation oncologists scored 98% of simulation CT-based plans and 92% of diagnostic CT-based plans as clinically acceptable or needing minor edits for patients with typical anatomy. On average, end-to-end treatment planning time of the clinical tool was less than 8 minutes.This novel method to automatically verify, contour, and plan palliative spine treatments is efficient and effective across various CT scan types. Furthermore, it is the first to create a clinical tool that can automatically verify vertebral level in CT images.

Quantify differences in acoustics and intraglottal flow fields between Thyroplasty Type 1 (TT1) with and without arytenoid adduction (AA) using excised canine larynx model.Basic science experiments using excised larynges.Surgical procedures were implemented in eight excised canine larynges. Acoustics and intraglottal flow measurements were taken at low and high subglottal pressures in each experimental setup.In all larynges, vocal efficiency (VE) and cepstrum peak prominence (CPP) were higher, and the mean phonatory flow rate was lower in TT1 with AA than without AA. The glottal asymmetry is reduced with AA and promotes the formation of stronger vortices in the glottal flow during the closing phase of the vibrating folds.Findings suggest a clear acoustic and aerodynamic benefit to the addition of AA when performing TT1. It shows significant improvement in CPP, translating to decreased breathiness and dysphonia and increased VE, leading to easier and more sustainable phonation. Stronger intraglottal vortices are known to be correlated with the loudness of voice produced by phonation.N/A Laryngoscope, 2022.

Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas.(1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis?The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys.More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups.There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient.Level III, therapeutic study.

Purpose: Pediatric patients with medulloblastoma in LMICs are most treated with 3D conformal photon craniospinal irradiation (CSI), a time-consuming, complex treatment to plan, especially in resource-constrained settings. Therefore, we developed and tested a 3D conformal CSI autoplanning tool for varying patient lengths. Methods and Materials: Autocontours were generated with a deep learning model trained:tested (80:20 ratio) on 143 pediatric medulloblastoma CT scans (patient ages, 2-19 years, median=7 years). Using the verified autocontours, the autoplanning tool generated 2 lateral brain fields matched to a single spine field, an extended single spine field, or 2 matched spine fields. Additional spine sub-fields were added to optimize the corresponding dose distribution. Feathering was implemented (yielding 9-12 fields) to give a composite plan. Each planning approach was tested on 6 patients (ages, 3-10 years). A pediatric radiation oncologist assessed clinical acceptability of each autoplan. Results: The autocontoured structures’ average Dice similarity coefficient ranged from 0.65-0.98. The average V95 for the brain/spinal canal for single, extended, and multi-field spine configurations was 99.9±0.06%/99.9±0.10%, 99.9±0.07%/99.4±0.30%, and 99.9±0.06%/99.4±0.40%, respectively. The average maximum dose across all field configurations to the brainstem, eyes (L/R), lenses (L/R) and spinal cord were 23.7±0.08 Gy, 24.1±0.28 Gy, 13.3±5.27 Gy, 25.5±0.34 Gy, respectively (prescription=23.4 Gy/13 fractions). Of the 18 plans tested, all were scored as clinically acceptable as-is or clinically acceptable with minor, time-efficient edits preferred or required. No plans were scored as clinically unacceptable. Conclusion: The autoplanning tool successfully generated pediatric CSI plans for varying patient lengths in 3.50 ± 0.4 minutes on average, indicating potential for an efficient planning aid in resource-constrained settings.

To assess barium esophagram (BAS) as a diagnostic marker for patients with Killian Jamieson diverticula (KJD).Prospective, multicenter cohort study of individuals enrolled in the Prospective OUtcomes of Cricopharyngeus Hypertonicity (POUCH) Collaborative. Patient demographics, comorbidities, radiographic imaging reports, laryngoscopy findings, patient-reported outcome measures (PROM), and operative reporting were abstracted from a REDCap database and summarized using means, medians, percentages, frequencies. Paired t-tests and Wilcoxon Signed Rank test were used to test pre- to post-operative differences in RSI, EAT-10, and VHI-10 scores. Diagnostic test evaluation including sensitivity, specificity, positive, and negative predictive value with 95% confidence intervals were calculated comparing BAS findings to operative report.A total of 287 persons were enrolled; 13 (4%) patients were identified with confirmed KJD on operative reports. 100% underwent open transcervical excision. BAS has a 46.2% (95% confidence interval [CI]: 23.2, 70.9) sensitivity and 97.8% (95% CI: 95.3, 99.0) specificity in detecting a KJD and 50% (95% CI: 25.4, 74.6) positive predictive value but 97.4% (95%CI: 94.8, 98.7) negative predictive value. Preoperatively, patients reported mean (SD) RSI and EAT-10 of 19.4 (9) and 8.3 (7.5) accordingly. Postoperatively, patients reported mean (SD) RSI and EAT-10 as 5.4 (6.2) and 2.3 (3.3). Both changes in RSI and EAT-10 were statistically significant (p = 0.008, p = 0.03).KJD are rare and represent5% of hypopharyngeal diverticula undergoing surgical intervention. Open transcervical surgery significantly improves symptoms of dysphagia. BAS has high specificity but low sensitivity in detecting KJD.Level 4 Laryngoscope, 2022.

Acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition defined by rapid onset respiratory failure following acute lung injury (ALI). Its increased incidence due to COVID-19 and high mortality rate (∼40%) make the study of ARDS pathogenesis a crucial research priority. CRTH2 is a G protein-coupled receptor with established roles in type 2 immunity and well-characterized inhibitors. Prior studies have shown it also promotes neutrophilic inflammation, indicating that CRTH2 inhibition may be a potential therapeutic strategy for ARDS. To test this hypothesis, we first examined the expression pattern of CRTH2 on murine neutrophils. We found it is expressed on neutrophils, but only after extravasation into the lung. Next, we showed that extravasated lung neutrophils generate inflammatory responses upon stimulation with the CRTH2-specific agonist DK-PGD2, as demonstrated by reactive oxygen species (ROS) production. This response was abrogated in CRTH2 KO neutrophils. Inhibition of CRTH2 with fevipiprant suppressed baseline ROS production, indicating an autocrine PGD2-CRTH2 signaling loop. We then evaluated the role of CRTH2 in vivo using a murine model of LPS-induced ALI. Despite the pro-inflammatory effects of CRTH2 on neutrophils in vitro, we observed worsening of lung injury in CRTH2-deficient mice in terms of neutrophilic inflammation, vascular leak, and survival. Bulk RNAseq of lung tissue indicated an impairment in type 2 immune signaling; qPCR and ELISA confirmed downregulation of the key type 2 effector cytokine, IL-4. Thus, CRTH2 appears to play a dual role in ALI, directly promoting neutrophil effector responses, but indirectly suppressing lung injury and neutrophilic inflammation through type 2 immunity. These findings reveal a novel protective function for CRTH2 during lung injury and argue against the use of CRTH2 inhibitors in ARDS.

Purpose: Target delineation for radiation therapy is a time-consuming and complex task. Autocontouring gross tumor volumes (GTVs) has been shown to increase efficiency. However, there is limited literature on post-operative target delineation, particularly for CT-based studies. To this end, we trained a CT-based autocontouring model to contour the post-operative GTV of pediatric patients with medulloblastoma. Methods: 104 retrospective pediatric CT scans were used to train a GTV auto-contouring model. 80 patients were then preselected for contour visibility, continuity, and location to train an additional model. Each GTV was manually annotated with a visibility score based on the number of slices with a visible GTV (1 = 50%-75%, and 4 = >75%-100%). Contrast and the contrast-to-noise ratio (CNR) were calculated for the GTV contour with respect to a cropped background image. Both models were tested on the original and pre-selected testing sets. The resulting surface and overlap metrics were calculated comparing the clinical and autocontoured GTVs and the corresponding clinical target volumes (CTVs). Results: 80 patients were pre-selected to have a continuous GTV within the posterior fossa. Of these, 7, 41, 21, and 11 were visibly scored as 4, 3, 2, and 1, respectively. The contrast and CNR removed an additional 11 and 20 patients from the dataset, respectively. The Dice similarity coefficients (DSC) were 0.61 +/- 0.29 and 0.67 +/- 0.22 on the models without pre-selected training data and 0.55 +/- 13.01 and 0.83 +/- 0.17 on the models with pre-selected data, respectively. The DSC on the CTV expansions were 0.90 +/- 0.13. Conclusion: We automatically contoured continuous GTVs within the posterior fossa on scans that had contrast >=10 HU. CT-Based auto-contouring algorithms have potential to positively impact centers with limited MRI access., 14 pages, 6 figures

PURPOSE: Pediatric low-grade glioma therapy has evolved to delay or eliminate radiation. The impact of therapy changes on long-term outcomes remains unknown. METHODS: Cumulative incidence of late mortality (death >5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, CTCAE grading criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed 1970-1999. Outcomes were evaluated by diagnosis decade and by treatment exposures received ≤5 years following diagnosis (surgery-only, chemotherapy ± surgery, and cranial radiation ± surgery or chemotherapy). Relative risk (RRs) with 95%CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 2,684 eligible survivors (age at diagnosis (median [range]), 7 years [0-20 years]; time from diagnosis, 24 years [5-48 years]), exposure to cranial radiation decreased [51% (1970s), 45% (1980s), 25% (1990s)] along with late tumor recurrence (>5 & ≤15 years from diagnosis) [9.8% (1970s), 8.8% (1980s), 5.0% (1990s)]. The 15-year cumulative incidence of late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p

Metformin is the first-line therapy for the management of type 2 diabetes. After 3 months of metformin, add-on therapy can be considered if an individual's glycemic control has not been achieved for hemoglobin A1c, fasting blood glucose levels, and postprandial blood glucose levels. Liraglutide is a potential second-line option for the management of type 2 diabetes mellitus, particularly for those who are or may be at a high risk of cardiovascular disease. It can also be used an add-on therapy for those individuals with established cardiovascular disease. Liraglutide has additional benefits, such as no to minimal risk of hypoglycemia and promotion of weight loss through its mechanism of action. This particular article summarizes evidence on cardiovascular biomarkers and surrogate endpoints, along with macrovascular events, with liraglutide therapy. Overall, liraglutide has extensive cardiovascular evidence based on which it could be used as a desirable agent for glycemic control while lowering the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization from heart failure.

OBJECTIVE To provide evidence of the effectiveness of a brief relapse prevention intervention using implementation intentions (Self-Management after Therapy, SMArT), following remission from depression and to identify effective relapse prevention strategies. METHOD The SMArT intervention was provided to 107 patients who were recovered after psychological therapy for depression. Relapse events were calculated as reliable and clinically significant increases in PHQ-scores. Sixteen patients receiving the intervention and eight practitioners providing it were interviewed. Framework Analysis identified seven themes which highlighted effective relapse prevention strategies and effective implementation of the SMArT intervention. RESULTS Relapse rates at the final SMArT session (four months after the end of acute stage therapy) were 11%. Seven themes were identified that supported effective self-management: (1) Relationship with the practitioner-feeling supported; (2) Support networks; (3) Setting goals, implementing plans and routine; (4) Changing views of recovery; (5) The SMArT sessions-mode, content, timing, duration; (6) Suitability for the person; and (7) Suitability for the service. CONCLUSION The study provides some support for the effectiveness of the SMArT intervention, although a randomized controlled trial is required; and identifies important relapse prevention strategies.

The past two decades have witnessed a resurgence in neutrophil research, inspired in part by the discovery of neutrophil extracellular traps (NETs) and their myriad roles in health and disease. Within the lung, dysregulation of neutrophils and NETosis have been linked to an array of diseases including pneumonia, cystic fibrosis, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), and severe asthma. However, our understanding of pathologic neutrophil responses in the lung remains incomplete. Two methodologic issues have contributed to this gap: first, an emphasis on studying neutrophils from blood rather than the lung and second, the technical difficulties of interrogating neutrophil responses in mice, which has largely restricted basic murine research to specialized laboratories. To address these limitations, we have developed a suite of techniques for studying neutrophil effector functions specifically in the mouse lung. These include ex vivo assays for phagocytosis and NETosis using bronchoalveolar neutrophils and in situ evaluation of NETosis in a murine model of pneumonia. Throughout, we have prioritized technical ease and robust, quantitative readouts. We hope these assays will help to standardize research on lung neutrophils and improve accessibility to this burgeoning field.

Deaths from coronavirus disease (COVID-19) have exceeded 300,000 persons globally, calling for rapid development of mobile diagnostics that can assay widespread prevalence and infection rates. Data provided in this study supports the utility of a newly-designed lateral flow immunoassay (LFA) for detecting SARS-CoV-2 IgM and IgG antibodies. We employed a clinical cohort of 1,892 SARS-CoV-2 patients and controls, including individuals diagnosed by RT-qPCR at Yale New Haven Hospital, The First Affiliated Hospital of Anhui Medical University, the Chinese Center for Disease Control and Prevention of Hefei City (Hefei CDC), Anhui Province (Anhui Province CDC), and Fuyang City (Fuyang CDC). The LFA studied here detects SARS-CoV-2 IgM and IgG antibodies with a specificity of 97.9–100% for IgM, 99.7–100% for IgG, and sensitivities ranging from 94.1–100% for patients >14-days post symptom onset. Sensitivity decreases in patients

Metformin is the first-line therapy for the management of type 2 diabetes. After 3 months of metformin, add-on therapy can be considered if an individual’s glycemic control has not been achieved for hemoglobin A1c, fasting blood glucose levels, and postprandial blood glucose levels. Liraglutide is a potential second-line option for the management of type 2 diabetes mellitus, particularly for those who are or may be at a high risk of cardiovascular disease. It can also be used an add-on therapy for those individuals with established cardiovascular disease. Liraglutide has additional benefits, such as no to minimal risk of hypoglycemia and promotion of weight loss through its mechanism of action. This particular article summarizes evidence on cardiovascular biomarkers and surrogate endpoints, along with macrovascular events, with liraglutide therapy. Overall, liraglutide has extensive cardiovascular evidence based on which it could be used as a desirable agent for glycemic control while lowering the risk of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization from heart failure.

Children's packed lunches contain more sugar than school-provided meals. Interventions to improve the provision of healthier packed lunches have modest effects on lunch contents. This cluster randomised controlled trial tested an intervention to encourage healthier provision of packed lunches by parents of primary school children in Derby. Schools were randomised to intervention (n = 8) or control (n = 9) using blocked random allocation. In the intervention group, parents of children who brought packed lunches to school in years 3–6 (age 7–11 years) received three bundles of materials (including packed lunch planner, shopping list, information on sugar content of popular lunchbox items and suggestions for healthier swap alternatives) in bookbags/lunchboxes over a 4-week period. Control parents received no materials. Photos of lunchbox contents were taken at baseline, immediately post-intervention and at three-month follow-up. A parental survey aimed to assess capability, opportunity and motivation for packing a healthier lunchbox. No intervention effects were observed for primary outcomes (presence and number of sugary snacks or chilled sugary desserts). The intervention had a significant impact on one secondary outcome (increased number of healthier “swap” items suggested in intervention materials) immediately post-intervention, but this effect had disappeared at three-month follow-up. No intervention effects were found on survey variables. Parent comments revealed that materials were either received positively (as they reinforced existing behaviours) or negatively (as they were not perceived to be helpful or appropriate). The results of this study suggest that providing educational materials and resources to parents of primary school children in Derby was not sufficient to increase provision of healthier packed lunches. Future research should investigate how behavioural science can support families to improve the nutritional content of primary school children's lunchboxes.

Highlights • We monitor HPV infection in sexually active young women in England. • The prevalence of HPV 16/18 has reduced within 3 years of HPV immunisation. • Reductions in HPV 16/18 were greatest at ages with highest immunisation coverage. • The data suggest reductions in HPV 16/18 amongst unvaccinated young women and men., Background Reduction in the prevalence of vaccine type HPV infection in young women is an early indication of the impact of the HPV immunisation programme and a necessary outcome if the subsequent impact on cervical cancer is to be realised. Methods Residual vulva-vaginal swab (VVS) specimens from young women aged 16–24 years undergoing chlamydia screening in community sexual health services (formerly known as family planning clinics), general practice (GP), and youth clinics in 2010–2012 were submitted from 10 laboratories in seven regions around England. These specimens were linked to demographic and sexual behaviour data reported with the chlamydia test, anonymised, and tested for type-specific HPV DNA using a multiplex PCR and Luminex-based genotyping test. Estimated immunisation coverage was calculated and findings were compared to a baseline survey conducted prior to the introduction of HPV immunisation in 2008. Results A total of 4664 eligible specimens were collected and 4178 had a valid test result. The post-immunisation prevalence of HPV 16/18 infection was lowest in this youngest age group (16–18 years) and increased with age. This increase with age was a reversal of the pattern seen prior to immunisation and was inversely associated with estimates of age-specific immunisation coverage (65% for 16–18 year olds). The prevalence of HPV 16/18 infection in the post-immunisation survey was 6.5% amongst 16–18 year olds, compared to 19.1% in the similar survey conducted prior to the introduction of HPV immunisation. Conclusions These findings are the first indication that the national HPV immunisation programme is successfully preventing HPV 16/18 infection in sexually active young women in England. The reductions seen suggest, for the estimated coverage, high vaccine effectiveness and some herd-protection benefits. Continued surveillance is needed to determine the effects of immunisation on non-vaccine HPV types.

Genotyping may improve risk stratification of high-risk (HR) human papillomavirus (HPV)-positive women in cervical screening programs; however, prospective data comparing the natural history and carcinogenic potential of individual HR types remain limited. A meta-analysis of cross-sectional HR HPV-type distribution in 115,789 HPV-positive women was performed, including 33,154 normal cytology, 6,810 atypical squamous cells of undetermined significance (ASCUS), 13,480 low-grade squamous intraepithelial lesions (LSIL) and 6,616 high-grade SIL (HSIL) diagnosed cytologically, 8,106 cervical intraepithelial neoplasia grade 1 (CIN1), 4,068 CIN2 and 10,753 CIN3 diagnosed histologically and 36,374 invasive cervical cancers (ICCs) from 423 PCR-based studies worldwide. No strong differences in HPV-type distribution were apparent between normal cytology, ASCUS, LSIL or CIN1. However, HPV16 positivity increased steeply from normal/ASCUS/LSIL/CIN1 (20-28%), through CIN2/HSIL (40/47%) to CIN3/ICC (58/63%). HPV16, 18 and 45 accounted for a greater or equal proportion of HPV infections in ICC compared to normal cytology (ICC:normal ratios = 3.07, 1.87 and 1.10, respectively) and to CIN3 (ICC:CIN3 ratios = 1.08, 2.11 and 1.47, respectively). Other HR types accounted for important proportions of HPV-positive CIN2 and CIN3, but their contribution dropped in ICC, with ICC:normal ratios ranging from 0.94 for HPV33 down to 0.16 for HPV51. ICC:normal ratios were particularly high for HPV45 in Africa (1.85) and South/Central America (1.79) and for HPV58 in Eastern Asia (1.36). ASCUS and LSIL appear proxies of HPV infection rather than cancer precursors, and even CIN3 is not entirely representative of the types causing ICC. HPV16 in particular, but also HPV18 and 45, warrant special attention in HPV-based screening programs.

Objectives Using a prospective interrupted time series design, our goal was to determine whether a change in urine antibiotic susceptibility reporting from co-amoxiclav to cefalexin to community clinicians served by Southmead General Hospital led to a change in antibiotic prescribing. Methods We used longitudinal data on antibiotic prescribing using a clinician questionnaire to identify prescribing for urinary tract infections (UTIs) when a urine specimen was submitted to microbiology; MIQUEST computer search in general practices for prescribing for all UTIs in the community; and Prescribing Analysis and Cost (PACT) data to determine antibiotic prescribing for all infections. Results Cefalexin and cephalosporin prescribing increased when cefalexin was reported and co-amoxiclav prescribing decreased when co-amoxiclav was not reported by the laboratory. This was seen for episodes of UTI in which a general practitioner (GP) sent a specimen as determined with: the questionnaire results (9-fold rise in cephalosporins, 70% fall in co-amoxiclav); episodes of UTI identified by MIQUEST searches in the practice (50% increase in cefalexin, 25% reduction in co-amoxiclav); and overall antibiotic prescribing in the practice determined with PACT data (20% increase in cefalexin, 8% reduction in co-amoxiclav). MIQUEST data indicated that prescribing reverted to pre-intervention levels once the change in antibiotic reporting had stopped. Conclusions Our data provide more evidence that changing laboratory antibiotic susceptibility reporting has a direct effect on antibiotic prescribing by GPs. Our data indicate that much of the change in prescribing was attributable to the use of cefalexin and co-amoxiclav for persistent or recurrent infections. Microbiology laboratories can influence antibiotic use by selectively reporting antibiotics they would prefer GPs to prescribe.

Otitis externa is a ubiquitous inflammatory disease; although it arises most commonly from an infection, there is no consensus in the UK for the reporting of ear swab culture results. This study aims to review current microbiology laboratory reporting of ear swab specimens to primary care and reach an evidence-based consensus for a reporting policy. Fifty consecutive ear swab reports were reviewed from each of 12 laboratories in the South West region to determine and discuss reporting practice. The Health Protection Agency (HPA) GP Microbiology Laboratory Use Group reviewed the underlying evidence and worked towards a consensus of expert microbiology opinion for laboratory reporting of ear swab results using a modified version of the Delphi technique. A total of 487 reports from primary care were reviewed (54% female; 46% male). Cultures most commonly yielded Pseudomonas species (36%), Staphylococcus species (21%), Streptococcus species (15%) and fungi (11%). Five reporting policies were agreed: Policy 1: Common pathogens such as group A beta-haemolytic streptococci, Streptococcus pneumoniae, Staphylococcus aureus - Always reported by name with antibiotic susceptibilities. Policy 2: Pseudomonas species - Always reported, but antibiotic susceptibilities only reported in severe disease. Policy 3: Aspergillus, Candida, coliforms and Proteus species, as well as non-group A streptococci and anaerobes - Only reported if moderate numbers of colonies and it is the predominant organism present; if appropriate report antibiotic susceptibilities. Policy 4: Coagulase-negative staphylococci, diphtheroids and enterococci - Not reported by name; generic terms used and antibiotic susceptibilities not reported. Policy 5: When antibiotic susceptibilities reported these must include susceptibility to a topical antibiotic. It is suggested that laboratories should consider adopting this evidence-based reporting consensus for ear swab culture results from primary care patients with otitis externa.

Summary: Isolated methylmalonic acidemia/aciduria (MMA) is a devastating metabolic disorder with poor outcomes despite current medical treatments. Like other mitochondrial enzymopathies, enzyme replacement therapy (ERT) is not available, and although promising, AAV gene therapy can be limited by pre-existing immunity and has been associated with genotoxicity in mice. To develop a new class of therapy for MMA, we generated a 5-methoxyU-modified codon-optimized mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, and encapsulated it into biodegradable lipid nanoparticles (LNPs). Intravenous (i.v.) administration of hMUT mRNA in two different mouse models of MMA resulted in a 75%–85% reduction in plasma methylmalonic acid and was associated with increased hMUT protein expression and activity in liver. Repeat dosing of hMUT mRNA reduced circulating metabolites and dramatically improved survival and weight gain. Additionally, repeat i.v. dosing did not increase markers of liver toxicity or inflammation in heterozygote MMA mice. : An et al. find that systemically delivered LNP-encapsulated mRNA results in hepatic protein expression. hMUT mRNA expresses functional mitochondrial MUT enzyme, and MMA mouse models show a metabolic and clinical response after mRNA therapy. Keywords: methylmalonic acidemia/aciduria, methylmalonyl-CoA mutase, methylmalonic acid, mRNA therapy, lipid nanoparticle, liver

Pooled data on human papillomavirus (HPV) type distribution in invasive cervical cancer (ICC) can help to predict the potential impact of HPV type-specific vaccines and screening tests, and to understand the carcinogenicity of HPV types. We performed a meta-analysis of HPV type-specific prevalence data published from 1990 to 2010, including a total of 243 studies and 30,848 ICC. The proportion of ICC associated with HPV16 and/or 18 (HPV16/18) was between 70 and 76% in all world regions except Asia. In Western/Central Asia, 82% of ICC was HPV16/18-associated compared to only 68% in Eastern Asia. The 12 most common HPV types identified, in order of decreasing prevalence, were HPV16 (57%), 18 (16%), 58, 33, 45, 31, 52, 35, 59, 39, 51 and 56. The prevalence of other types, phylogenetically related to those above, ranged from

(See the major article by Szarewski et al on pages 1391–6.) The annual rate of genital warts (GW) cases diagnosed in genitourinary medicine (GUM) clinics in England has, for the most part, been increasing since the early 1970s [1, 2]. A lessening in the rate of increase was observed between 1987 and 1995 and was associated with AIDS awareness campaigns [3]. However, in 2009 there was a slight but notable decrease in diagnoses in females reported by GUM clinics, from 37 062 in 2008 to 35 925 in 2009, which has continued into 2010 and 2011 (

Background The current generation of Human Papillomavirus (HPV) vaccines, Cervarix® and Gardasil®, exhibit a high degree of efficacy in clinical trials against the two high-risk (HR) genotypes represented in the vaccines (HPV16 and HPV18). High levels of neutralizing antibodies are elicited against the vaccine types, consistent with preclinical data showing that neutralizing antibodies can mediate type-specific protection in the absence of other immune effectors. The vaccines also confer protection against some closely related non-vaccine HR HPV types, although the vaccines appear to differ in their degree of cross-protection. The mechanism of vaccine-induced cross-protection is unknown. This study sought to compare the breadth and magnitudes of neutralizing antibodies against non-vaccine types elicited by both vaccines and establish whether such antibodies could be detected in the genital secretions of vaccinated individuals. Methods and Findings Serum and genital samples were collected from 12–15 year old girls following vaccination with either Cervarix® (n = 96) or Gardasil® (n = 102) HPV vaccine. Serum-neutralizing antibody responses against non-vaccine HPV types were broader and of higher magnitude in the Cervarix®, compared to the Gardasil®, vaccinated individuals. Levels of neutralizing and binding antibodies in genital secretions were closely associated with those found in the serum (r = 0.869), with Cervarix® having a median 2.5 (inter-quartile range, 1.7–3.5) fold higher geometric mean HPV-specific IgG ratio in serum and genital samples than Gardasil® (p = 0.0047). There was a strong positive association between cross-neutralizing antibody seropositivity and available HPV vaccine trial efficacy data against non-vaccine types. Conclusions These data demonstrate for the first time that cross-neutralizing antibodies can be detected at the genital site of infection and support the possibility that cross-neutralizing antibodies play a role in the cross-protection against HPV infection and disease that has been reported for the current HPV vaccines. Trial Registration ClinicalTrials.gov NCT00956553

OBJECTIVE: To investigate frequency and risk factors for prevalent, incident, and persistent carcinogenic human papillomavirus (HPV) in young women before the introduction of immunisation against HPV types 16 and 18 for schoolgirls. DESIGN: Cohort study SETTING: 20 London universities and further education colleges. PARTICIPANTS: 2185 sexually active female students, mean age 21 years (range 16-27), 38% from ethnic minorities, who took part in the POPI (prevention of pelvic infection) chlamydia screening trial in 2004-08 and who provided duplicate, self taken vaginal swabs and completed questionnaires at baseline. At follow-up, a median of 16 months later, 821 women (38%) returned repeat vaginal swabs by post. In 2009-10, stored samples were tested for HPV. RESULTS: Samples from 404/2185 (18.5% (95% CI 16.9% to 20.2%)) of the cohort were positive for carcinogenic HPV at baseline, including 15.0% (327) positive for non-vaccine carcinogenic genotypes. Reporting two or more sexual partners in the previous year and concurrent Chlamydia trachomatis or bacterial vaginosis were independent risk factors for prevalent vaginal HPV infection. Infection with one or more new HPV types was found in 17.7% (145/821) of follow-up samples, giving an estimated annual incidence of carcinogenic HPV infection of 12.9% (95% CI 11.0% to 15.0%). Incident infection was more common in women reporting two or more partners in the previous year, aged

The purpose of this study was to verify the dosimetric performance of Acuros XB (AXB), a grid-based Boltzmann solver, in intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy (VMAT).The Radiological Physics Center (RPC) head and neck (HN) phantom was used for all calculations and measurements in this study. Clinically equivalent IMRT and VMAT plans were created on the RPC HN phantom in the Eclipse treatment planning system (version 10.0) by using RPC dose prescription specifications. The dose distributions were calculated with two different algorithms, AXB 11.0.03 and anisotropic analytical algorithm (AAA) 10.0.24. Two dose report modes of AXB were recorded: dose-to-medium in medium (D(m,m)) and dose-to-water in medium (D(w,m)). Each treatment plan was delivered to the RPC phantom three times for reproducibility by using a Varian Clinac iX linear accelerator. Absolute point dose and planar dose were measured with thermoluminescent dosimeters (TLDs) and GafChromic® EBT2 film, respectively. Profile comparison and 2D gamma analysis were used to quantify the agreement between the film measurements and the calculated dose distributions from both AXB and AAA. The computation times for AAA and AXB were also evaluated.Good agreement was observed between measured doses and those calculated with AAA or AXB. Both AAA and AXB calculated doses within 5% of TLD measurements in both the IMRT and VMAT plans. Results of AXB_D(m,m) (0.1% to 3.6%) were slightly better than AAA (0.2% to 4.6%) or AXB_D(w,m) (0.3% to 5.1%). The gamma analysis for both AAA and AXB met the RPC 7%/4 mm criteria (over 90% passed), whereas AXB_D(m,m) met 5%/3 mm criteria in most cases. AAA was 2 to 3 times faster than AXB for IMRT, whereas AXB was 4-6 times faster than AAA for VMAT.AXB was found to be satisfactorily accurate when compared to measurements in the RPC HN phantom. Compared with AAA, AXB results were equal to or better than those obtained with film measurements for IMRT and VMAT plans. The AXB_D(m,m) reporting mode was found to be closer to TLD and film measurements than was the AXB_D(w,m) mode. AXB calculation time was found to be significantly shorter (× 4) than AAA for VMAT.

Objective: To review current microbiology laboratory reporting of ear swab specimens in primary care and reach an evidence-based reporting policy consensus.Method: Prospective primary care study commenced June 2006. Analyzed 50 consecutive ear swab reports of otitis externa from 12 laboratories in the southwest UK to determine reporting practice. The HPA GP Laboratory Use Group achieved consensus of expert microbiology opinion for reporting using a modified version of the Delphi technique.Results: 487 reports were reviewed (54% female; 46% male). Pseudomonas species (36%), Staphylococcus species (21%), Streptococcus species (15%), and fungi (11%) predominated. Five reporting policies agreed. Policy 1: Common pathogens (above) — “Reported by name with antibiotic susceptibilities.” Policy 2: Pseudomonas species— “Always reported; antibiotic susceptibilities in severe disease.” Policy 3: Aspergillus, Candida, coliform etc— “Only reported if moderate numbers of colonies and predominant organism present; if ap...

BACKGROUND: There is low uptake of chlamydia screening in general practices registered with the English National Chlamydia Screening Programme (NCSP). Aims. To explore staff's attitudes and behaviour around chlamydia screening and how screening could be optimized in general practice. METHODS: A qualitative study with focus groups and interviews, in general practices in seven NCSP areas. Twenty-five focus groups and 12 interviews undertaken with a purposively selected diverse group of high and low chlamydia-screening practices in 2006-08. Data were collected and analysed using a framework analytical approach. RESULTS: Higher screening practices had more staff with greater belief in patient and population benefits of screening and, as screening was a subjective norm, it was part of every day practice. Many staff in the majority of other practices were uncomfortable raising chlamydia opportunistically and time pressures meant that any extra public health issues covered within a consultation were determined by Quality Outcomes Framework (QOF) targets. All practices would value more training and feedback about their screening rates and results. Practices suggested that use of computer prompts, simplified request forms and more accessible kits could increase screening. CONCLUSION: Practice staff need more evidence of the value of opportunistic chlamydia screening in men and women; staff development to reduce the barriers to broaching sexual health; simpler request forms and easily accessible kits to increase their ability to offer it within the time pressures of general practice. Increased awareness of chlamydia could be attained through practice meetings, computer templates and reminders, targets and incentives or QOF points with feedback.

SUMMARYThe aim of this study was to investigate the prevalence and associated risk factors of methicillin-susceptible and methicillin-resistant Staphylocccus aureus (MSSA and MRSA) carriage in care homes, with particular focus on dementia. A point-prevalence survey of 748 residents in 51 care homes in Gloucestershire and Greater Bristol was undertaken. Dementia was assessed by the clock test or abbreviated mini-mental test. Nasal swabs were cultured for S. aureus on selective agar media. Multivariable analysis indicated that dementia was not a significant risk factor for MSSA (16·2%) or MRSA (7·8%); and that residents able to move around the home unassisted were at a lower risk of MRSA (P=0·04). MSSA carriage increased with increasing age (P=0·03) but MRSA carriage decreased with increasing age (P=0·05). Hospitalization in the last 6 months increased the risk of MSSA (P=0·04) and MRSA (P=0·10). We concluded that cross-infection through staff caring for more dependent residents may spread MRSA within care homes and from the recently hospitalized. Control of MSSA and MRSA in care homes requires focused infection control interventions.

Introduction There is a lack of data on the sexual behaviour of patients between being tested for chlamydia, receiving the test result, and being treated. This time-period may be important in the transmission of chlamydia, as infection could continue to be spread to sexual partners whilst awaiting the test result and treatment. We aimed to investigate the sexual behaviours of patients in this time-period in order to investigate the benefits a point-of-care test (POCT) might bring to clinical practice. Methods A cross-sectional clinical audit of Genito-Urinary Medicine (GUM) clinic attendees in England. Clinic staff conducted a notes review of patients returning for chlamydia treatment following a positive chlamydia test result, and of age- and sex-matched chlamydia negatives attending for initial consultation. Initial consultation data were available for all patients; data on behaviour between test and treatment were available only for chlamydia-positives. The data also served as a sexual history taking audit for the GUM clinics, following British Association of Sexual Health and HIV (BASHH) guidelines. Results Five of nine GUM clinics approached participated (July–December 2014). The sexual history BASHH auditable outcomes completion rates varied from 0–100%. 775 patients (442 females, 353 males) were included in analyses. Males with 2–4 partners, and those who reported never using a condom, were more likely to be chlamydia positive. For 21/143 (14.7%) positive patients who provided data, last new sexual contact was in the period between test and treatment. Conclusion The BASHH 97% data recording target was only consistently met for one of six auditable outcomes, indicating required improvements in sexual history recording by GUM clinics. Patients continue to form new sexual partnerships whilst awaiting chlamydia test results, allowing for the possibility of infecting new sexual partners. POCTs which remove the test to treatment delay could prevent this onward transmission.

Background/introduction There is a lack of data on the sexual behaviour of patients between being tested for chlamydia, receiving the test result, and being treated. This time-period may be important in the transmission of chlamydia, as infection could continue to be spread to sexual partners whilst awaiting the test result and treatment. Aim(s)/objectives To investigate the sexual behaviours of patients between the time of being tested for chlamydia and receiving test result and treatment in order to investigate the benefits that a point-of-care test (POCT) might bring to clinical practice. Methods We conducted a cross-sectional clinical audit of GUM clinic attendees. Clinic staff conducted a notes review of patients returning for chlamydia treatment following a positive chlamydia test result, and of age- and sex-matched chlamydia negatives. The data also served as an audit for the GUM clinics, following BASHH guidelines. Results Five of nine GUM clinics approached participated, in July–December 2014. Data from 775 patients were included in analyses, 365 of whom were chlamydia-positive. Males with 2–4 partners, and those who reported never using a condom, were more likely to be chlamydia positive. For 21/143 (14.7%) positive patients who provided data, last new sexual contact was in the period between test and treatment. Data were missing on condom use (22%) and recent new partners (81%). Discussion/conclusion Patients continue to form new sexual partnerships whilst awaiting chlamydia test results, allowing for the possibility of infecting new sexual partners. POCTs which remove the test to treatment delay could prevent this onward transmission.

Background/introduction Control of STIs is challenged by inadequate access to prompt diagnosis and treatment for patients and partners. Novel point-of-care diagnostics have real potential to address some of these challenges but their robust evaluation, and hence utility, is hampered by the ethics and regulatory landscape that confronts industry and academia. Aim(s)/objectives To develop a diagnostics and clinical facility to deliver high-quality, time-efficient diagnostic evaluations for STIs. Methods A multi-institutional and disciplinary group ( e STI 2 ) including clinical, public health and social scientists, microbiologists, clinicians, trial coordinators, and North American and European regulatory expertise was established. An ‘overarching’ ethics, favourable costing, and regulatory framework was carefully developed and put in place to enable any new diagnostic evaluation involving residual and/or additional-to-routine patient-consented samples to start promptly without requiring lengthy ethics applications. Strong working relationships with multiple GUM clinics were developed to overcome the potential for clinic fatigue, and Good Clinical Laboratory Practice Standard Operating Procedures were enabled. Results Since February 2012, the network has conducted several evaluations with both academia and industry, spanning initial ‘proof of concept’ projects using residual samples, multi-site diagnostic evaluations involving >800 additional-to-routine patient samples completed in four months, and service evaluations of CE-marked assays. A diagnostic evaluation to support an application for regulatory approval will be taking place in 2015. Discussion/conclusion The development of a diagnostic facility for STIs that fast-tracks high quality diagnostic evaluations is feasible and has potential for supporting promising diagnostic technologies towards NHS adoption.

Background Effective Sexually Transmitted Infection (STI) control is being challenged by inadequate access to prompt diagnosis and treatment for patients and relatively poor community STI surveillance. This work forms part of a larger eSTI 2 (Electronic Self-Testing Instrument for Sexually Transmitted Infections) consortium developing diagnostic devices for pathogen detection and integrating point-of-care tests with mobile technology. Aim(s)/Objective(s) Harnessing the widespread mobile phone use, this research develops innovative eSTI 2 technologies for reducing STIs transmission and providing greater personal control of sexual health. The aim of this study is to develop a wireless web-based management system that links chlamydia self-test diagnostics to further patient care pathways. Methods This research adopts a user centred approach to the development of a Human Technology Interface for self-managing STI diagnosis. The research methodology begins primarily with initial exploratory pilot studies to gather functional and user requirements regarding ethical and regulatory requirements of the Human Technology Interface. Iterative development of functional prototypes exploring design possibilities and technology features will be followed by the formative evaluation of interface design through qualitative and controlled usability studies with target users. Results In this paper we report on a user centred approach that allows for the successful capture and integration of social science methods to encapsulate user requirements with usability principles in order to develop an effective and user acceptable self-managing STI system. Discussion and/or Conclusions Working in a cross-discipline collaboration the overall aim is to investigate the impact of user-centred methods in the design of innovative mobile phone and web technology based rapid testing.