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Abstract The COVID-19 pandemic has disrupted people’s lives and caused significant economic damage around the world, but its impact on people’s mental health has not been paid due attention by the research community. According to anecdotal data, the pandemic has raised serious concerns related to mental health among the masses. However, no systematic investigations have been conducted previously on mental health monitoring and, in particular, detection of post-traumatic stress disorder (PTSD). The goal of this study is to use classical machine learning approaches to classify tweets into COVID-PTSD positive or negative categories. To this end, we employed various Machine Learning (ML) classifiers, to segregate the psychotic difficulties with the user’s PTSD in the context of COVID-19, including Random Forest Support Vector Machine, Naïve Bayes, and K-Nearest Neighbor. ML models are trained and tested using various combinations of feature selection strategies to get the best possible combination. Based on our experimentation on real-world dataset, we demonstrate our model’s effectiveness to perform classification with an accuracy of 83.29% using Support Vector Machine as classifier and unigram as a feature pattern.

Traditional approaches to marking short-answer questions face limitations in timeliness, scalability, inter-rater reliability, and faculty time costs. Harnessing generative artificial intelligence (AI) to address some of these shortcomings is attractive. This study aims to validate the use of ChatGPT for evaluating short-answer assessments in an undergraduate medical program. Ten questions from the pre-clerkship medical curriculum were randomly chosen, and for each, six previously marked student answers were collected. These sixty answers were evaluated by ChatGPT in July 2023 under four conditions: with both a rubric and standard, with only a standard, with only a rubric, and with neither. ChatGPT displayed good Spearman correlations with a single human assessor (r = 0.6–0.7, p < 0.001) across all conditions, with the absence of a standard or rubric yielding the best correlation. Scoring differences were common (65–80%), but score adjustments of more than one point were less frequent (20–38%). Notably, the absence of a rubric resulted in systematically higher scores (p < 0.001, partial η2 = 0.33). Our findings demonstrate that ChatGPT is a viable, though imperfect, assistant to human assessment, performing comparably to a single expert assessor. This study serves as a foundation for future research on AI-based assessment techniques with potential for further optimization and increased reliability.

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen’s kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan–Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026–0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001–1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

BACKGROUND Recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) is generally an incurable disease, with patients experiencing median survival of under 10 months and significant morbidity. While immune checkpoint blockade (ICB) drugs are effective in approximately 20% of patients, the remaining experience limited clinical benefit and are exposed to potential adverse effects and financial costs. Clinically approved biomarkers, such as tumor mutational burden (TMB), have a modest predictive value in HNSCC.METHODS We analyzed clinical and genomic features, generated using whole-exome sequencing, in 133 ICB-treated patients with R/M HNSCC, of whom 69 had virus-associated and 64 had non-virus-associated tumors.RESULTS Hierarchical clustering of genomic data revealed 6 molecular subtypes characterized by a wide range of objective response rates and survival after ICB therapy. The prognostic importance of these 6 subtypes was validated in an external cohort. A random forest-based predictive model, using several clinical and genomic features, predicted progression-free survival (PFS), overall survival (OS), and response with greater accuracy than did a model based on TMB alone. Recursive partitioning analysis identified 3 features (systemic inflammatory response index, TMB, and smoking signature) that classified patients into risk groups with accurate discrimination of PFS and OS.CONCLUSION These findings shed light on the immunogenomic characteristics of HNSCC tumors that drive differential responses to ICB and identify a clinical-genomic classifier that outperformed the current clinically approved biomarker of TMB. This validated predictive tool may help with clinical risk stratification in patients with R/M HNSCC for whom ICB is being considered.FUNDING Fundación Alfonso Martín Escudero, NIH R01 DE027738, US Department of Defense CA210784, The Geoffrey Beene Cancer Research Center, The MSKCC Population Science Research Program, the Jayme Flowers Fund, the Sebastian Nativo Fund, and the NIH/NCI Cancer Center Support Grant P30 CA008748.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells’ behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

World production of convenient and durable materials made of synthetic plastics during the last 70 years caused the dispersal of microplastic particles in the environment. Microplastic pollution is the focus of interest worldwide due to its global distribution and adverse effects on living organisms. The largest number of studies addressing this issue explored the aquatic environment, yet terrestrial ecosystems also suffer from microplastic pollution. Insects are crucial for most terrestrial ecosystems. Few can compete with them in biomass productivity and species diversity, which makes them targets for studying the toxic bioaccumulation. This review article presents a systematic analysis of data on bioaccumulation, degradation of microplastics by aquatic and terrestrial entomofauna, and its ecotoxicological effects.

OBJECTIVES ChatGPT is an artificial intelligence model that can interpret free-text prompts and return detailed, human-like responses across a wide domain of subjects. This study evaluated the extent of the threat posed by ChatGPT to the validity of short-answer assessment problems used to examine pre-clerkship medical students in our undergraduate medical education program. METHODS Forty problems used in prior student assessments were retrieved and stratified by levels of Bloom's Taxonomy. Thirty of these problems were submitted to ChatGPT-3.5. For the remaining 10 problems, we retrieved past minimally passing student responses. Six tutors graded each of the 40 responses. Comparison of performance between student-generated and ChatGPT-generated answers aggregated as a whole and grouped by Bloom's levels of cognitive reasoning, was done using t-tests, ANOVA, Cronbach's alpha, and Cohen's d. Scores for ChatGPT-generated responses were also compared to historical class average performance. RESULTS ChatGPT-generated responses received a mean score of 3.29 out of 5 (n = 30, 95% CI 2.93-3.65) compared to 2.38 for a group of students meeting minimum passing marks (n = 10, 95% CI 1.94-2.82), representing higher performance ( P = .008, η 2 = 0.169), but was outperformed by historical class average scores on the same 30 problems (mean 3.67, P = .018) when including all past responses regardless of student performance level. There was no statistically significant trend in performance across domains of Bloom's Taxonomy. CONCLUSION While ChatGPT was able to pass short answer assessment problems spanning the pre-clerkship curriculum, it outperformed only underperforming students. We remark that tutors in several cases were convinced that ChatGPT-produced responses were produced by students. Risks to assessment validity include uncertainty in identifying struggling students and inability to intervene in a timely manner. The performance of ChatGPT on problems requiring increasing demands of cognitive reasoning warrants further research.

In this guide, we discuss a technique that allows nipple tattooing to be done at the time of the patient’s nipple reconstruction surgery, using simple equipment available in most hospitals, without the need for a specialist tattoo machine. This simple technique reconstructs the full NAC aesthetic unit, giving a more immediate result compared to the traditional two-stage process. By allowing this step to be completed at the time of their reconstruction, one could propose their satisfaction is accelerated, and allows their treatment journey to come to an end sooner.

Abstract Introduction The magnitude and impact of rotational error is unclear in rectal cancer radiation therapy. This study evaluates rotational errors in rectal cancer patients, and investigates the feasibility of planning target volume (PTV) margin reduction to decrease organs at risk (OAR) irradiation. Methods In this study, 10 patients with rectal cancer were retrospectively selected. Rotational errors were assessed through image registration of daily cone beam computed tomography (CBCT) and planning CT scans. Two reference treatment plans (TPR) with PTV margins of 5 mm and 10 mm were generated for each patient. Pre‐determined rotational errors (±1°, ±3°, ±5°) were simulated to produce six manipulated treatment plans (TPM) from each TPR. Differences in evaluated dose‐volume metrics between TPR and TPM of each rotation were compared using Wilcoxon Signed‐Rank Test. Clinical compliance was investigated for statistically significant dose‐volume metrics. Results Mean rotational errors in pitch, roll and yaw were −0.72 ± 1.81°, −0.04 ± 1.36° and 0.38 ± 0.96° respectively. Pitch resulted in the largest potential circumferential displacement of clinical target volume (CTV) at 1.42 ± 1.06 mm. Pre‐determined rotational errors resulted in statistically significant differences in CTV, small bowel, femoral heads and iliac crests (P

Abstract Introduction Head and neck cancer (HNC) patients are at risk of weight change, due to inadequate nutrition intake or dehydration, when receiving radiotherapy (RT). This study aimed to develop methodology to measure water content changes on magnetic resonance imaging (MRI) scans of the head and neck region over the course of RT. Methods Retrospective datasets of 54 patients were analysed. Eligible patients had been treated for HNC with cisplatin chemoradiation (CRT) or RT alone and underwent a minimum of 2 MRI scans from weeks 0, 3 and 6 of their treatment. Anatomical regions consisting of ≥90% water, on T2‐weighted DIXON MRI sequences, were contoured. Water volume changes of all patients were evaluated, within an anatomically standardised external volume, by comparing the absolute water fraction volume (cc) (VEx90WF) and relative water fraction volume (%) (RelVEx90WF) at weeks 0 and 6 of RT. Results There was a statistically significant difference between the RelVEx90WF at weeks 0 and 6 (P = 0.005). However, no statistically significant difference was identified between weeks 0 and 6 VEx90WF (P = 0.064). There were no statistically significant differences identified between patients who received CRT versus RT alone. Conclusion This study developed a novel method for measuring changes in water fraction volumes over time, using T2‐weighted DIXON MRIs. The methodology created in this study requires further validation through phantom imaging, with known fat and water values.

Background: During the last decade, radiotherapy using MR Linac has gone from research to clinical implementation for different cancer locations. For head and neck cancer (HNC), target delineation based only on MR images is not yet standard, and the utilisation of MRI instead of PET/CT in radiotherapy planning is not well established. We aimed to analyse the inter-observer variation (IOV) in delineating GTV (gross tumour volume) on MR images only for patients with HNC. Material/methods: 32 HNC patients from two independent departments were included. Four clinical oncologists from Denmark and four radiation oncologists from Australia had independently contoured primary tumour GTVs (GTV-T) and nodal GTVs (GTV-N) on T2-weighted MR images obtained at the time of treatment planning. Observers were provided with sets of images, delineation guidelines and patient synopsis. Simultaneous truth and performance level estimation (STAPLE) reference volumes were generated for each structure using all observer contours. The IOV was assessed using the DICE Similarity Coefficient (DSC) and mean absolute surface distance (MASD). Results: 32 GTV-Ts and 68 GTV-Ns were contoured per observer. The median MASD for GTV-Ts and GTV-Ns across all patients was 0.17 cm (range 0.08–0.39 cm) and 0.07 cm (range 0.04–0.33 cm), respectively. Median DSC relative to a STAPLE volume for GTV-Ts and GTV-Ns across all patients were 0.73 and 0.76, respectively. A significant correlation was seen between median DSCs and median volumes of GTV-Ts (Spearman correlation coefficient 0.76, p

The DNA damage response (DDR) is critical for maintaining genome stability, and abnormal DDR—resulting from mutations in DNA damage-sensing and repair proteins—is a hallmark of cancer. Here, we aimed to investigate the predictive power of DDR gene mutations and the tumor mutational load (TML) for survival outcomes in a cohort of 22 rectal cancer patients who received pre-operative neoadjuvant therapy. Univariate analysis revealed that TML-high and TP53 mutations were significantly associated with worse overall survival (OS) with TML-high retaining significance in multivariate analyses. Kaplan–Meier survival analyses further showed TML-high was associated with worse disease-free (p = 0.036) and OS (p = 0.024) results in our patient cohort. A total of 53 somatic mutations were identified in 22 samples with eight (36%) containing mutations in DDR genes, including ATM, ATR, CHEK2, MRE11A, RAD50, NBN, ERCC2 and TP53. TP53 was the most frequently mutated gene, and TP53 mutations were significantly associated with worse OS (p = 0.023) in Kaplan–Meier survival analyses. Thus, our data indicate that TML and TP53 mutations have prognostic value for rectal cancer patients and may be important independent biomarkers for patient management. This suggests that prognostic determination for rectal cancer patients receiving pre-operative neoadjuvant therapy should include consideration of the initial TML and tumor genetic status.

KRAS and BRAF mutation rates in colorectal cancer (CRC) reported from various mono-ethnic studies vary amongst different ethnic groups. However, these differences in mutation rates may not be statistically significant or may be due to differences in environmental and/or laboratory factors across countries rather than racial genetic differences. Here, we compare the KRAS/BRAF mutation rates and survival outcomes in CRC between ethnic groups at a single institution. We also investigate the contributions of genetic, environmental, and laboratory factors to the variations in KRAS/BRAF mutation rates reported from different countries. Clinicopathological data from 453 ethnically diverse patients with CRC were retrospectively analyzed at Liverpool Hospital, NSW Australia (2014–2016). KRAS/BRAF mutations were detected using real-time PCR (Therascreen kits from Qiagen). Mismatch repair (MMR) status was determined using immunohistochemical staining. Four ethnic groups were analyzed: Caucasian, Middle Eastern, Asian, and South American. Overall survival data were available for 406 patients. There was no significant difference in KRAS mutation rates between Caucasians (41.1%), Middle Easterners (47.9%), Asians (44.8%), and South Americans (25%) (p = 0.34). BRAF mutation rates differed significantly between races (p = 0.025), with Caucasians having the highest rates (13.5%) and Middle Easterners the lowest (0%). A secondary analysis in which Caucasians were divided into three subgroups showed that ethnic grouping correlated significantly with KRAS mutation rate (p = 0.009), with central and eastern Europeans having the highest rates (58.3%). There were no significant differences in overall survival (OS) or disease-free survival (DFS) between the four races. The similarity in KRAS mutation rates across races raises the possibility that the differences in KRAS mutation rates reported from various countries may either not be statistically significant or may be due to environmental and/or laboratory factors rather than underlying racial genetic differences. In contrast, we verified that BRAF mutation rates differ significantly between races, suggesting racial genetic differences may be responsible for the discrepant BRAF mutation rates reported from different countries.

Summary: Background: Prurigo nodularis is a chronic skin disease characterised by intensely pruritic, hyperkeratotic nodules. Vixarelimab, a human monoclonal antibody, binds to the beta subunit of the oncostatin M receptor, inhibiting signalling of both interleukin 31 and oncostatin M, two cytokine pathways that contribute to pruritus and nodule formation in prurigo nodularis. Methods: This double-blind, placebo-controlled, phase 2a trial was done at both private and academic dermatology outpatient research clinics across the United States and Canada (n = 40). Patient eligibility criteria included age 18–75 years, physician-documented diagnosis of prurigo nodularis minimum 6 months duration of prurigo nodularis, presence of at least 10 pruritic nodules approximately 0.5–2 cm in size on at least two different anatomical locations (excluding face and scalp) and involving the extremities, and presence of normal-appearing skin between nodules; atopic dermatitis as a comorbidity was exclusionary. Patients were required to have moderate-to-severe pruritus, defined as Worst Itch–Numeric Rating Scale (WI-NRS) score ≥7 at screening and LS-mean weekly WI-NRS score ≥5 for each of the 2 consecutive weeks immediately before randomisation. Participants were randomly assigned (1:1) to receive weekly subcutaneous vixarelimab 360 mg (720 mg loading dose) or placebo using stratification factors (sex and presence of atopy) and block size 4 through the IWRS system. Stratification by atopy status was based on the reported high prevalence of atopy in this population and the potential impact of atopy in the immunopathologic process in prurigo nodularis. Patients, investigators, study sponsor, and site staff were masked to study treatment. The primary efficacy endpoint was least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in weekly average Worst Itch–Numeric Rating Scale (WI-NRS) score. The primary efficacy endpoint was analysed with ANCOVA including treatment as fixed effect, with baseline WI-NRS, and randomisation stratification factor as covariates. All randomised patients who had at least 1 dose of study drug or placebo were included in the Safety Analysis Set. This trial is registered at ClinicalTrials.gov, NCT03816891. Findings: Of 50 patients randomised between March 11, 2019 and January 31, 2020, 23 vixarelimab recipients and 26 placebo recipients comprised the modified intent-to-treat analysis population (baseline LS-mean [SD] WI-NRS score, 8.3 [1.05]). Outcomes at Week 8 for vixarelimab versus placebo included LS-mean PCFB in WI-NRS score, −50.6% versus −29.4% (LS-mean difference [95% CI], −21.2% [−40.82, −1.60]; p = 0.03); ≥4-point reduction in WI-NRS score, 52.2% (12/23) versus 30.8% (8/26) (p = 0.11); PN-IGA score of 0 or 1, 30.4% (7/23) versus 7.7% (2/26) (p = 0.03); LS-mean PCFB in pruritus VAS score, −54.4% versus −32.6% (p = 0.03); and LS-mean PCFB sleep loss reduction (improvement), −56.3% versus −30.0% (p = 0.02). No deaths, serious TEAEs, or TEAEs leading to dose interruption were reported. The percentage of vixarelimab recipients reporting any TEAE was 91.3% (21/23) versus 76.9% (20/26) of placebo recipients; drug-related TEAEs generally were similar between the two groups (vixarelimab, 43.5% [10/23]; placebo, 38.5% [10/26]). Interpretation: Vixarelimab demonstrated rapid reduction of pruritus and achievement of clear/almost clear skin in one-third of the patients by Week 8. Relief of itch and clearing of skin nodules represent two important potential therapeutic advances in the management of patients suffering from the debilitating disease Prurigo Nodularis. Funding: Kiniksa Pharmaceuticals, Ltd.

BackgroundNext generation sequencing (NGS) is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) Tier I-V & X. Allele frequency is also increasingly recognised as an important prognostic tool in advanced cancer. The aim of this study was to determine the genomic mutations in metastatic colorectal cancer (CRC) in an Australian multicultural population and their influence on survival outcomes.MethodsNext generation sequencing with the 50-gene panel Oncomine Precision Assay™ was used on 180 CRC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022.ResultsFrom 180 samples, 147 (82%) had at least one gene mutation identified with 68 (38%) having two or more concurrent mutations. Tier I variants included RAS wild-type [EI] in 73 (41%) and BRAF V600E [EIA] in 27 (15%). Non-tier I variants include 2 (1%) ERBB2 amplification [EIIB], 26 (15%) PIK3CA hotspot mutations [EIIIA] and 9 (5%) MET focal amplifications [EIIIA]. NGS testing revealed an additional 22% of cases with Tier II & III mutations. 43% of patients also presented with potentially actionable Tier III & IV mutations. Patients with concurrent TP53 and RAS mutations had significantly reduced overall survival (6.1 months versus 21.1 months, p ConclusionsIn addition to identifying patients with genomic alterations suitable for clinically proven standard of care therapeutic options, the 50 gene NGS panel has significant potential in identifying potentially actionable non-tier 1 mutations and therefore may become future standard clinical practice.

Abstract Milademetan is a small‐molecule inhibitor of murine double minute 2 (MDM2) that is in clinical development for advanced solid tumors and hematological cancers, including liposarcoma and acute myeloid leukemia. Milademetan is a CYP3A and P‐glycoprotein substrate and moderate CYP3A inhibitor. The current study aims to understand the drug‐drug interaction (DDI) risk of milademetan as a CYP3A substrate during its early clinical development. A clinical DDI study of milademetan (NCT03614455) showed that concomitant administration of single‐dose milademetan with the strong CYP3A inhibitor itraconazole or posaconazole increased milademetan mean area under the curve from zero to infinity (AUCinf) by 2.15‐fold (90% confidence interval [CI], 1.98–2.34) and 2.49‐fold (90% CI, 2.26–2.74), respectively, supporting that the milademetan dose should be reduced by 50% when concomitantly administered with strong CYP3A inhibitors. A physiologically‐based pharmacokinetic (PBPK) model of milademetan was subsequently developed to predict the magnitude of CYP3A‐mediated DDI potential of milademetan with moderate CYP3A inhibitors. The PBPK model predicted an increase in milademetan exposure of 1.72‐fold (90% CI, 1.69–1.76) with fluconazole, 1.91‐fold (90% CI, 1.83–1.99) with erythromycin, and 2.02‐fold (90% CI, 1.93–2.11) with verapamil. In addition, it estimated that milademetan’s original dose (160 mg once daily) could be resumed from its half‐reduced dose 3 days after discontinuation of concomitant strong CYP3A inhibitors. The established PBPK model of milademetan was qualified and considered to be robust enough to support continued development of milademetan.

Abstract Purpose The COVID‐19 pandemic gave rise to renewed concerns of the transmission risks posed by surgeries on sites of high viral colonization such as the nasopharynx. Endoscopic dacryocystorhinostomy (DCR) involves the creation of a new tear duct from the lacrimal sac to the nasal cavity. The purpose of this project is to determine if endoscopic DCR is an aerosol generating procedure (AGP). Methods An optical particle sizer (OPS) was used to intraoperatively quantify aerosol concentrations during four cases of endoscopic DCR. The OPS sampled the air once every 60 seconds throughout the operations. The time of important operative steps were documented and correlated with OPS readings. Particle concentrations during each major surgical step were compared to baseline readings by the Mann Whitney U Test. Results There were statistically significant increases in median particle concentrations during laryngeal mask airway intubations for both particles 0.3 to 5.0 μm and >5.0 μm (P

PurposeThis study assessed the delivered dose accuracy in pancreas SBRT by incorporating the real-time target position determined using an in-house position monitoring system.Methods and materialsAn online image-based position monitoring system, SeedTracker, was developed to monitor radiopaque marker positions using monoscopic x-ray images, available from the Elekta XVI imaging system. This system was applied to patients receiving SBRT for pancreatic cancer on the MASTERPLAN Pilot trial (ACTRN 12617001642370). All patients were implanted pre-treatment with at least three peri-tumoral radiopaque markers for target localisation. During treatment delivery, marker positions were compared to expected positions delineated from the planning CT. The position tolerance of ±3mm from the expected position of the markers was set to trigger a gating event (GE) during treatment. The dosimetric impact of position deviations and actual dose delivered with position corrections was assessed by convolving the plan control point dose matrices with temporal target positions determined during treatment.ResultsEight patients were treated within this study. At least one GE was observed in 38% of the treatment fractions and more than one GE was observed in 10% of the fractions. The position deviations resulted in the mean(range) difference of -0.1(-1.1 - 0.4)Gy in minimum dose to tumour and 1.9(-0.1- 4.6)Gy increase to Dmax to duodenum compared to planned dose. In actual treatment delivery with the patient realignment, the mean difference of tumour min dose and duodenal Dmax was reduced to 0.1(-1.0 – 1.1)Gy and 1.1 (-0.7 - 3.3)Gy respectively compared to the planned dose.ConclusionsThe in-house real-time position monitoring system improved the treatment accuracy of pancreatic SBRT in a general-purpose linac and enabled assessment of delivered dose by incorporating the temporal target position during delivery. The intrafraction motion impacts the dose to tumour even if target position is maintained within a 3mm position tolerance.

Abstract Background Among patients with non-metastatic pancreatic cancer, 80% have high-risk, borderline resectable or locally advanced cancer, with a 5-year overall survival of 12%. MASTERPLAN evaluates the safety and activity of stereotactic body radiotherapy (SBRT) in addition to chemotherapy in these patients. Methods and design MASTERPLAN is a multi-centre randomised phase II trial of 120 patients with histologically confirmed potentially operable pancreatic cancer (POPC) or inoperable pancreatic cancer (IPC). POPC includes patients with borderline resectable or high-risk tumours; IPC is defined as locally advanced or medically inoperable pancreatic cancer. Randomisation is 2:1 to chemotherapy + SBRT (investigational arm) or chemotherapy alone (control arm) by minimisation and stratified by patient cohort (POPC v IPC), planned induction chemotherapy and institution. Chemotherapy can have been commenced ≤28 days prior to randomisation. Both arms receive 6 × 2 weekly cycles of modified FOLFIRINOX (oxaliplatin (85 mg/m2 IV), irinotecan (150 mg/m2), 5-fluorouracil (2400 mg/m2 CIV), leucovorin (50 mg IV bolus)) plus SBRT in the investigational arm. Gemcitabine+nab-paclitaxel is permitted for patients unsuitable for mFOLFIRINOX. SBRT is 40Gy in five fractions with planning quality assurance to occur in real time. Following initial chemotherapy ± SBRT, resectability will be evaluated. For resected patients, adjuvant chemotherapy is six cycles of mFOLFIRINOX. Where gemcitabine+nab-paclitaxel was used initially, the adjuvant treatment is 12 weeks of gemcitabine and capecitabine or mFOLFIRINOX. Unresectable or medically inoperable patients with stable/responding disease will continue with a further six cycles of mFOLFIRINOX or three cycles of gemcitabine+nab-paclitaxel, whatever was used initially. The primary endpoint is 12-month locoregional control. Secondary endpoints are safety, surgical morbidity and mortality, radiological response rates, progression-free survival, pathological response rates, surgical resection rates, R0 resection rate, quality of life, deterioration-free survival and overall survival. Tertiary/correlative objectives are radiological measures of nutrition and sarcopenia, and serial tissue, blood and microbiome samples to be assessed for associations between clinical endpoints and potential predictive/prognostic biomarkers. Interim analysis will review rates of locoregional recurrence, distant failure and death after 40 patients complete 12 months follow-up. Fifteen Australian and New Zealand sites will recruit over a 4-year period, with minimum follow-up period of 12 months. Discussion MASTERPLAN evaluates SBRT in both resectable and unresectable patients with pancreatic ductal adenocarcinoma. Trial registration Australia New Zealand Clinical Trials Registry ACTRN12619000409178 , 13/03/2019. Protocol version: 2.0, 19 May 2019

Background: Since the implementation of competency-based medical education (CBME) across residency training programs in Canada, there has been limited research understanding how entrustable professional activity (EPA) assessments are used by faculty supervisors and residents. Objective: This study examines how EPA assessments are used in an Obstetrics and Gynecology residency program and the impact of implementation on both groups. Methods: A mixed methods study design was used. Part one involved the aggregation of descriptive data of EPA assessment completion for postgraduate year 1 and 2 residents from July 2019 to May 2020. Part two involved a thematic analysis of semi-structured interviews of residents and faculty. Results: There was significant uptake of EPA assessments across community and teaching hospitals with widespread contribution of assessment data from faculty. However, both residents and faculty reported that the intended design of EPA assessments as low-stakes assessments to provide formative feedback is not how EPA assessments are experienced. Residents and faculty noted the increased level of administrative burden and related perceived stress amongst the resident group. Conclusions: The implementation of EPA assessments is feasible across a variety of sites. However, previous measurement challenges remain. Neither residents nor faculty perceive the value of EPAs to improve feedback, despite their intended nature.

Meiotic recombination 11 (MRE11) plays a critical role in the DNA damage response and maintenance of genome stability and is associated with the prognosis for numerous malignancies. Here, we explored the clinicopathological significance and prognostic value of MRE11 expression in colorectal cancer (CRC), a leading cause of cancer-related deaths worldwide. Samples from 408 patients who underwent surgery for colon and rectal cancer between 2006 and 2011, including a sub-cohort of 127 (31%) patients treated with adjuvant therapy, were analyzed. In Kaplan–Meier survival analyses, we found that high MRE11 expression in the tumor center (TC) was significantly associated with poor disease-free survival (DFS; p = 0.045) and overall survival (OS; p = 0.039). Intriguingly, high MRE11 expression in the TC was also significantly correlated with reduced DFS (p = 0.005) and OS (p = 0.010) in the subgroup with right-sided primary CRC. In multivariate analyses, high MRE11 expression (hazard ratio [HR] = 1.697, 95% confidence interval [CI]: 1.034–2.785; p = 0.036) and lymphovascular/perineural invasion (LVI/PNI; HR = 1.922, 95% CI 1.122–3.293; p = 0.017) showed significant association with worse OS in patients with right-sided tumors but not those with left-sided tumors. Moreover, in patients with right-sided tumors, high MRE11 was associated with worse OS for those with lymph node involvement (p = 0.006) and LVI/PNI (p = 0.049). Collectively, our results suggest that MRE11 may serve as an independent prognostic marker in those with right-sided severe CRC, with clinical value in the management of these patients.

Background and purpose: Prediction of chemoradiotherapy response (CRT) in locally advanced rectal cancer would enable stratification of management. The purpose was to prospectively evaluate multi-parametric magnetic resonance imaging (MRI) assessment of tumour heterogeneity combining diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) MRI for the prediction of CRT response in locally advanced rectal cancer. Materials and methods: Patients with Stage II or III rectal adenocarcinoma undergoing neoadjuvant CRT and surgery underwent MRI (DWI and DCE) before, during (week 3), and after CRT (1 week before surgery). Patients with histopathology tumour regression grade (TRG) 0–1 were classified as responders, and TRG 2–3 were classified as non-responders. A whole tumour voxel-wise technique was used to produce apparent diffusion coefficient (ADC) and Ktrans (Tofts model) histograms derived from DWI and DCE-MRI, respectively. Logistic regression was used to predict response status for ADC and Ktrans quantiles. Results: Thirty-three patients were included in this analysis; 16 responders, and 17 non-responders. On heterogeneity analysis, odds of being a responder were significantly higher after CRT (before surgery) for higher ADC 75th (p = 0.049) and ADC 90th (p = 0.034) percentile values. The Ktrans quantiles were lower in non-responders than responders before and during CRT, and higher after CRT although no significant association with response status was observed (p ≥ 0.10). Conclusions: DWI-MRI after CRT (before surgery) incorporating a histogram analysis of whole tumour heterogeneity was predictive of CRT response in patients with locally advanced rectal cancer. DCE-MRI did not add value in response prediction. Clinical trial registration: Australian New Zealand Clinical Trials Registry (ANZCTR) number ACTRN12616001690448.

BackgroundResidents receive a numeric performance rating (eg, 1-7 scoring scale) along with a narrative (ie, qualitative) feedback based on their performance in each workplace-based assessment (WBA). Aggregated qualitative data from WBA can be overwhelming to process and fairly adjudicate as part of a global decision about learner competence. Current approaches with qualitative data require a human rater to maintain attention and appropriately weigh various data inputs within the constraints of working memory before rendering a global judgment of performance. ObjectiveThis study explores natural language processing (NLP) and machine learning (ML) applications for identifying trainees at risk using a large WBA narrative comment data set associated with numerical ratings. MethodsNLP was performed retrospectively on a complete data set of narrative comments (ie, text-based feedback to residents based on their performance on a task) derived from WBAs completed by faculty members from multiple hospitals associated with a single, large, residency program at McMaster University, Canada. Narrative comments were vectorized to quantitative ratings using the bag-of-n-grams technique with 3 input types: unigram, bigrams, and trigrams. Supervised ML models using linear regression were trained with the quantitative ratings, performed binary classification, and output a prediction of whether a resident fell into the category of at risk or not at risk. Sensitivity, specificity, and accuracy metrics are reported. ResultsThe database comprised 7199 unique direct observation assessments, containing both narrative comments and a rating between 3 and 7 in imbalanced distribution (scores 3-5: 726 ratings; and scores 6-7: 4871 ratings). A total of 141 unique raters from 5 different hospitals and 45 unique residents participated over the course of 5 academic years. When comparing the 3 different input types for diagnosing if a trainee would be rated low (ie, 1-5) or high (ie, 6 or 7), our accuracy for trigrams was 87%, bigrams 86%, and unigrams 82%. We also found that all 3 input types had better prediction accuracy when using a bimodal cut (eg, lower or higher) compared with predicting performance along the full 7-point rating scale (50%-52%). ConclusionsThe ML models can accurately identify underperforming residents via narrative comments provided for WBAs. The words generated in WBAs can be a worthy data set to augment human decisions for educators tasked with processing large volumes of narrative assessments.

There is an unmet clinical need for simple, accessible biomarkers to select patients who are more likely to respond to immune checkpoint therapy. Here the authors show that a lower neutrophil-to-lymphocyte ratio is associated with better overall and progressive-free survival, as well as higher rate of response, in a multi-cancer cohort of patients treated with immune checkpoint inhibitors.

Introduction: Lead exposure negatively affects cognitive functioning among children. However, there is limited evidence about whether exposure to lead in early life impairs later life cognitive functioning. Methods: Participants in the prospective Wisconsin Longitudinal Study cohort (N = 8583) were linked to the 1940 Census, which was taken when they were young children. We estimated the effect of living near a lead mine in childhood on late life memory/attention and language/executive function in 2004 (mean age 64) and 2011 (mean age 71). Results: Lead-exposed children had significantly steeper memory/attention decline between 2004 and 2011 and worse language/executive function at baseline in late life. These long-term effects of lead were not mediated through adolescent IQ or late life SES and health factors. Discussion: Proximity to lead mining in childhood had long-term effects on late life memory/attention decline and language/executive function, reflecting a possible latent influence of lead exposure. More research is needed to understand behavioral and biological pathways underlying this relationship.

Solid polymer electrolyte has been extensively studied as an alternative to liquid electrolyte that is often affected by the leakage, deformation and limited range of operating temperature issues. The present study was conducted in an attempt to synthesize polyurethane acrylate (PUA) as a host polymer to evaluate polymer performance supplemented with Li salt as polymer electrolytes. PUA was prepared by the reaction of jatropha oil polyol with toluene 2,4-diisocyanate and hydroxylethylmethylacrylate. Lithium perchlorate (LiClO4) salt with different percentage of weight in the range of 5 wt. % to 25 wt. % was added to PUA to produce the PUA electrolyte. The mixtures were cured under UV radiation to obtain thin polymeric films with good thermal stability and ionic conductivity. PUA with 25 wt. % lithium salt has the highest conductivity of 6.40 × 10−5 S cm−1 at room temperature. The finding was supported by Fourier transform infrared (FTIR). Electrode polarization occurrence was interpreted by the complex dielectric constant (Ɛr), dielectric loss (Ɛi), real electrical modulus (Mr), imaginary electrical modulus (Mi) and tan σ. The effect of lithium salt addition was investigated by differential scanning calorimeter (DSC), thermogravimetric analysis (TGA), X-ray diffraction (XRD) and scanning electron microscopy (SEM) analyses. Additionally, the ionic transport properties, transference number measurement and electrochemical stability were presented.

Thermoelectric generators with a small size are unable to produce enough high voltage and power levels to run Si integrated circuits using commonly encountered temperature differences. Here, the authors present microelectronic thermoelectric generators using Si0.97Ge0.03 to solve the problem.

Currently, there is a paucity of evidence to guide the management of antipsychotic therapy at the end of life for patients with schizophrenia. A 51-year-old female with a diagnosis of palliative squamous cell carcinoma of the tonsils was admitted to her local hospice for end-of-life care. She had a history of treatment-resistant schizophrenia, which was ordinarily managed with oral clozapine and aripiprazole. Owing to a deteriorating swallow and the inappropriateness of other enteral administration routes for this patient however, it became necessary to consider alternative means by which to give essential antipsychotic medicine. A subcutaneous infusion of olanzapine was chosen as the most viable solution. During the course of the admission, her schizophrenia began to relapse with the onset of positive psychotic symptoms (paranoia and hallucinations). This was posited as likely due to interruption of her regular oral antipsychotic medication combined with insufficient olanzapine dosing. The olanzapine dose was thus subsequently titrated over the course of a week with close monitoring, and her psychotic symptoms abated. Owing to a protracted dying phase, the patient remained on subcutaneous olanzapine for a total of 56 days, which allowed for accurate assessment of her psychiatric symptoms and evaluation of therapeutic response. The findings of this case report suggest that subcutaneous olanzapine may be an appropriate alternative for patients who are unable to take their complex oral antipsychotic regimens through enteral routes at the end of life.

Immune checkpoint inhibitor (ICI) therapies can achieve meaningful tumor responses in a subset of patients with most types of cancer that have been investigated. However, the majority of patients treated with these drugs do not experience any clinical benefit. Because not all patients benefit from ICIs, and some may experience more meaningful tumor response if treated with chemotherapy or other treatments, there is a compelling need for predictive biomarkers to facilitate more informed selection of therapy. Tumor mutational burden (TMB) is one feature of a tumor that has predictive value for ICI therapy across multiple cancer types. In a pan-cancer analysis of over 1,600 patients, higher TMB was associated with longer survival and higher response rates with ICI therapy. While this effect was seen in the majority of cancer types, indicating that TMB underlies fundamental aspects of immune-mediated tumor rejection, the optimal predictive cut-point varied widely by histology, suggesting that there is unlikely to be one tissue-agnostic definition of high TMB that is useful for predicting ICI response. More comprehensive predictive models integrating TMB with other factors – including genetic, immunologic, and clinicopathologic markers – will be needed to potentially achieve a tissue-agnostic predictor of benefit from ICIs.

Abstract Background Limited access to, understanding of, and trust in paper-based patient information is a key factor influencing paramedic decisions to transfer patients nearing end-of-life to hospital. Practical solutions to this problem are rarely examined in research. This paper explores the extent to which access to, and quality of, patient information affects the care paramedics provide to patients nearing end-of-life, and their views on a shared electronic record as a means of accessing up-to-date patient information. Method Semi-structured interviews with paramedics (n = 10) based in the north of England, drawn from a group of health and social care professionals (n = 61) participating in a study exploring data recording and sharing practices in end-of-life care. Data were analysed using thematic analysis. Results Two key themes were identified regarding paramedic views of patient information: 1) access to information on patients nearing end-of-life, and 2) views on the proposed EPaCCS. Paramedics reported they are typically unable to access up-to-date patient information, particularly advance care planning documents, and consequently often feel they have little option but to actively treat and transport patients to hospital – a decision not always appropriate for, or desired by, the patient. While paramedics acknowledged a shared electronic record (such as EPaCCs) could support them to provide community-based care where desired and appropriate, numerous practical and technical issues must be overcome to ensure the successful implementation of such a record. Conclusions Access to up-to-date patient information is a barrier to paramedics delivering appropriate end-of-life care. Current approaches to information recording are often inconsistent, inaccurate, and inaccessible to paramedics. Whilst a shared electronic record may provide paramedics with greater and timelier access to patient information, meaning they are better able to facilitate community-based care, this is only one of a series of improvements required to enable this to become routine practice.

Interleukin 17C (IL-17C) modulates epithelial inflammation and has a possible role in atopic dermatitis (AD) pathology. Four randomized clinical studies (Phase 1 and 2) investigated the safety, tolerability, efficacy, and pharmacokinetic profile of the anti-IL-17C monoclonal antibody MOR106 for up to 12 weeks (NCT03568071: n = 207 adults with moderate–severe AD; NCT03689829 Part 1: n = 32 healthy males; NCT03689829 Part 2: n = 44 adults with moderate–severe AD; and NCT03864627: n = 76 adults with moderate–severe AD). In these studies, MOR106 was either administered intravenously (i.v.) every 2 or 4 weeks at doses between 1–10 mg/kg, or subcutaneously (s.c.), either as a single dose or doses every 2 weeks at 320 mg. Overall, MOR106 was well-tolerated, and the safety profile was consistent with monoclonal antibodies approved for AD. Bioavailability following s.c. dosing was 55%, and steady-state drug levels were reached at 2–4 weeks. Ongoing studies were terminated following a futility analysis of the Phase 2 placebo-controlled dose-finding study (NCT03568071) due to a low probability for achieving the primary efficacy endpoint. Cumulatively, MOR106 demonstrated ineffectiveness for the treatment of AD, but its safety and pharmacokinetic characteristics warrant further drug development in other indications. Funding: sponsored by Galapagos NV; funded by Novartis AG.

Introduction: As academia begins to incorporate modern communication technologies into its scholarly structures, there are both enablers and barriers which foster academics’ uptake of these innovations. Those who are early adopters of academic social media - whether it be for education, research-related networking, or knowledge translation - may therefore be best positioned to highlight both enablers and barriers within their work environments. Methods: The authors conducted a constructivist grounded theory study to discern what prominent practitioners of academic social media (e.g. Twitter) have encountered in their careers. Participants were recruited via a snowball sampling technique and invited to participate in semi-structured interviews. Three investigators engaged in constant comparative analysis of incoming transcripts. To enhance rigour, we conducted an audit of the analysis and a participant member check. Results: Seventeen emerging influencers in the field of academic social media were recruited. After axial coding, the 30 enablers and 21 barriers to academic social media use were mapped to three spheres of influence: personal, institutional, and virtual. The investigators propose a framework that organizes these enablers and barriers around a tipping point where sustainability becomes possible. Conclusions: Multiple enablers and barriers were described to influence social media users within academic medicine. By organizing these facets into a personal, institutional, and virtual framework along a spectrum, we can begin to understand the underlying structures that potentiate the academic ecosystems in which social media and similar innovations may flourish.

Introduction Approximately 7.2% of children in the world suffer from attention-deficit/hyperactivity disorder (ADHD). Due to the availability of the osmotic-release oral-system methylphenidate, ADHD currently has a remission rate of up to 30.72%. Nevertheless, it has been reported that patients with ADHD tend to exhibit vitamin A and vitamin D deficiency, which may aggravate the symptoms of ADHD. This study aims to determine the effect of vitamin A and vitamin D supplementation as adjunctive therapy to methylphenidate on the symptoms of ADHD.Methods and analysis This is a parallel, prospective, interventional multicentric study. Patients will be enrolled from the southern, central and northern parts of China. A target of 504 patients will be followed for 8 weeks. They will be allocated into three groups (vitamin AD, vitamin D and placebo) and administered the interventions accordingly. Data on changes in the symptoms of ADHD as well as changes in the serum concentrations of vitamin A and vitamin D will be recorded. Both responders and nonresponders based on the sociodemographic and clinical data will also be described to mitigate selection bias.Ethics and dissemination This study is performed in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University, China (approval number: (2019) IRB (STUDY) number 262). The results of the trial will be reported in peer-reviewed scientific journals and academic conferences regardless of the outcomes.Trial registration number NCT04284059.

Purpose: This retrospective patient study assessed the consistency of abdominal gas presence throughout radiation therapy for patients with upper gastrointestinal cancer and determined the impact of variations in gas volume on the calculated dose distribution of volumetric modulated arc therapy. Methods and Materials: Eight patients with pancreatic cancer were included for analysis. A plan library consisting of 3 reference plans per patient (Ref0.0, Ref0.5, and Ref1.0) was created based on planning computed tomography (CT) with density overrides of 0.0, 0.5, and 1.0 applied to gas volumes, respectively. Corresponding cone beam CT (CBCT) data sets were obtained and density overrides were applied to enable fractional dose calculation. Variation in gas volume relative to initial volume determined from CT was assessed. Dose metrics for targets and organs at risk were compared between the accumulated CBCT dose and the planned dose of the 3 reference plans for each patient. Results: There was a significant decrease in gas present from CT to treatment CBCT, with a mean decrease in volume of 48.6% for the entire cohort. Dosimetrically, all accumulated target and organ-at-risk parameters, aside from the kidneys, exhibited the smallest mean deviation from the Ref0.0 plan and largest mean deviation from the Ref1.0 plan. A statistically significant difference in mean accumulated dose to Ref0.0 and Ref1.0 was observed for the dose delivered to 95% of the planning target volume. Conclusions: Significant variation in gas volumes from CT to treatment can occur throughout volumetric modulated arc therapy for pancreatic cancer. Through the use of a plan library, it was determined that initial assessment of a patient’s treatment plan with an assigned gas density of 0.0 provided the most accurate prediction of the accumulated dose.

Objective Multiple System Atrophy (MSA) and progressive supranuclear palsy (PSP) are rapidly progressive forms of degenerative Parkinsonism. The difficulties of diagnosing MSA and PSP in their early stages may lead to delayed referral to appropriate specialists and distress to patients, as well as delaying symptomatic treatment and participation in clinical trials. This work aimed to describe the symptoms that patients with MSA and PSP developed and plot their emergence relative to final diagnosis using a median onset in months. Methods Forty-seven patients from the United Kingdom with MSA or PSP diagnosed by a movement disorder specialist were interviewed with carers or relatives to establish milestone onset. This was corroborated using clinical notes and letters. Results In the MSA cohort (n = 23), autonomic symptoms (median 5.5 months before diagnosis) and falls (median 1 month before diagnosis) were the two clinical milestones which occurred before diagnosis. In the PSP cohort (n = 24), falling was the only milestone which occurred before diagnosis (median of 18.5 months). Conclusion This Study Shows That Psp Patients Experience Falling More Than A Year And A Half An Average Before Receiving A Diagnosis And Although Msa Patients Also Tended To Fall, This Was Much Closer To The Time Of Diagnosis. Further Work With Larger Cohorts May Illustrate Whether These Preliminary Findings Can Be Generalised To Guide Diagnosis And Management.

Background: The number of people in the UK with three or more long-term conditions continues to grow and the management of patients with co-morbidities is complex. In treating patients with multimorbidities, a fundamental problem is understanding and detecting points of conflict between different guidelines which to date has relied on individual clinicians collating disparate information. Objective: We will develop a framework for modelling a diverse set of care pathways, and investigate how conflicts can be detected and resolved automatically. We will use this knowledge to develop a software tool for use by clinicians that can map guidelines, highlight root causes of conflict between these guidelines and suggest ways they might be resolved. Method: Our work consists of three phases. First, we will accurately model clinical pathways for six of the most common chronic diseases; second, we will automatically identify and detect sources of conflict across the pathways and howthey might be resolved. Third, we will present a case study to prove the validity of our approach using a team of clinicians to detect and resolve the conflicts in the treatment of a fictional patient with multiple common morbidities and compare their findings and recommendations with those derived automatically using our novel software. Discussion: This paper describes the development of an important software-based method for identifying a conflict between clinical guidelines. Our findings will support clinicians treating patients with multimorbidity in both primary and secondary care settings.

ObjectivesThis study considers whether orphans' experiences with physically and psychologically violent discipline differ from non-orphans in sub-Saharan Africa, and to what extent national, community, household, caretaker, and child characteristics explain those differences.MethodsWe use cross-sectional Multiple Indicator Cluster Surveys (MICS) administered between 2010-2017 in 14 sub-Saharan African countries. The sample included 125,197 children, of which 2,937 were maternal orphans, 9,113 were paternal orphans, and 1,858 were double orphans. We estimate the difference between orphans and non-orphans experience of harsh discipline using multivariable logistic regressions with country fixed effects and clustered standard errors.ResultsFindings show that orphaned children experience less harsh discipline in the home. With the exception of double orphans' experience with physically violent discipline, these differences persisted even after controlling for a rich set of child, household, and caretaker characteristics.ConclusionsWe propose two alternative explanations for our surprising findings and provide a supplementary analysis to help arbitrate between them. The evidence suggests that orphaned children (especially those with a deceased mother) are less likely to experience harsh discipline because of lower caretaker investment in their upbringing. We encourage future research to draw on in-depth interviews or household surveys with discipline data from multiple children in a home to further unpack why orphans tend to experience less harsh punishment than other children.

Background:. “Breast implant illness” (BII) is a poorly defined cluster of nonspecific symptoms, attributed by patients as being caused by their breast implants. These symptoms can include joint pain, skin and hair changes, concentration, and fatigue. Many patients complaining of BII symptoms are dismissed as psychosomatic. There are currently over 10,000 peer-reviewed articles on breast implants, but at the time of commencing this study, only 2 articles discussed this entity. At the same time, mainstream media and social media are exploding with nonscientific discussion about BII. Methods:. We have prospectively followed 50 consecutive patients, self-referring for explantation due to BII. We analyzed their preoperative symptoms and followed up each patient with a Patient-Reported Outcome Questionnaire. All implants and capsules were, if possible, removed en bloc. Explanted implants were photographed. Implant shell and capsule sent for histology and microbiological culture. Results:. BII symptoms were not shown to correlate with any particular implant type, surface, or fill. There was no significant finding as to duration of implant or location of original surgery. Chronic infection was found in 36% of cases with Propionibacterium acnes the most common finding. Histologically, synoviocyte metaplasia was found in a significantly greater incidence than a matched cohort that had no BII symptoms (P = 0.0164). Eighty-four percent of patients reported partial or complete resolution of BII symptoms on Patient-Reported Outcome Questionnaire. None of the 50 patients would consider having breast implants again. Conclusion:. The authors believe BII to be a genuine entity worthy of further study. We have identified microbiological and histological abnormalities in a significant number of patients identifying as having BII. A large proportion of these patients have reported resolution or improvement of their symptoms in patient-reported outcomes. Improved microbiology culture techniques may identify a larger proportion of chronic infection, and further investigation of immune phenotypes and toxicology may also be warranted in this group.

Abstract Background The MRE11/RAD50/NBS1 (MRN) complex plays an essential role in detecting and repairing double-stranded breaks, and thus the potential roles of MRE11, RAD50 and NBS1 proteins in the pathogenesis of various cancers is the subject of investigation. This study was aimed at assessing the three-protein panel of MRN complex subunits as a potential radiosensitivity marker and evaluating the prognostic and clinicopathological implications of MRN expression in rectal cancer. Methods Samples from 265 rectal cancer patients treated with surgery and adjuvant chemoradiotherapy, including samples from 55 patients who were treated with neoadjuvant radiotherapy between 2000 and 2011, were analyzed. Expression of MRN complex proteins in tissue samples was determined by immunohistochemistry. Univariate and multivariate analyses were carried out to identify clinicopathological characteristics that are associated with the MRN three-protein panel expression in rectal cancer samples. Results In Kaplan–Meier survival analyses, we found that high level expression of MRN complex proteins in postoperative samples was associated with poor disease-free (p = 0.021) and overall (P = 0.002) survival. Interestingly, high MRN expression also correlated with poor disease-free (P = 0.047) and overall (P = 0.024) survival in the neoadjuvant radiotherapy subgroup. In multivariate analysis, combined MRN expression (hazard ratio = 2.114, 95% confidence interval 1.096–4.078, P = 0.026) and perineural invasion (hazard ratio = 2.160, 95% confidence interval 1.209–3.859, P = 0.009) were significantly associated with a worse disease-free survival. Conclusions Expression levels of MRN complex proteins significantly predict disease-free survival in rectal cancer patients, including those treated with neoadjuvant radiotherapy, and may have value in the management of these patients.

Background and Purpose: Four-dimensional (4D) computed tomography (CT) is widely used in radiotherapy (RT) planning and remains the current standard for motion evaluation. We assess a 4D magnetic resonance imaging (MRI) sequence in terms of motion and image quality in a phantom, healthy volunteers and patients undergoing RT. Materials and Methods: The 4D-MRI sequence is a prototype T1-weighted 3D gradient echo with radial acquisition with self-gating. The accuracy of the 4D-MRI respiratory sorting based method was assessed using a MRI-CT compatible respiratory simulation phantom. In volunteers, abdominal viscera were evaluated for artefact, noise, structure delineation and overall image quality using a previously published four-point scoring system. In patients undergoing abdominal RT, the tumour (or a surrogate) was utilized to assess the range of motion on both 4D-CT and 4D-MRI. Furthermore, imaging quality was evaluated for both 4D-CT and 4D-MRI. Results: In phantom studies 4D-MRI demonstrated amplitude of motion error of less than 0.2 mm for five, seven and ten bins. 4D-MRI provided excellent image quality for liver, kidney and pancreas. In patients, the median amplitude of motion seen on 4D-CT and 4D-MRI was 11.2 mm (range 2.8–20.3 mm) and 10.1 mm (range 0.7–20.7 mm) respectively. The median difference in amplitude between 4D-CT and 4D-MRI was −0.6 mm (range −3.4–5.2 mm). 4D-MRI demonstrated superior edge detection (median score 3 versus 1) and overall image quality (median score 2 versus 1) compared to 4D-CT. Conclusions: The prototype 4D-MRI sequence demonstrated promising results and may be used in abdominal targeting, motion gating, and towards implementing MRI-based adaptive RT. Keywords: MRI, Motion management, 4D-MRI, abdominal radiotherapy, Four dimensional magnetic resonance imaging