Translation and psychometric properties of the Arabic version of the ageism scale for dental students (ASDS-Ar): A multi-institutional validation.

BACKGROUND AND OBJECTIVE: Ageism represents an important barrier to high-quality healthcare for older adults. The present study sought to translate and validate the Arabic version of the Ageism Scale for Dental Students (ASDS-Arabic). MATERIALS AND METHODS: The 27-item ASDS tool was translated from English into Arabic following recommended cross-sectional forward and backward translation guidelines. The translated version was subjected to the content validity ratio (CVR) and sent to dental students in 21 institutes from 10 different Arab countries. Principal components analysis (PCA) was used to assess the dimensionality of the scale, and Cronbach's alpha was used to determine internal consistency reliability. The discriminant validity of the scale was assessed using the independent t-test. Confirmatory factor analysis (CFA) was also undertaken. RESULTS: Based on CVR, three items were removed. The 24-item Arabic version was completed by 3284 dental students. PCA and CFA retained 17 items in six components, explaining 50.3% of the total variance, with acceptable reliability, validity and discrimination. The first component "Adherence of older patients with dental treatment and instructions," included four items with a Cronbach α of 0.64 and scored 4.3 ± 0.8. The second component "Feasibility of the treatment plan," included three items with a Cronbach α of 0.66 and scored from 2.6 ± 1.2 to 2.9 ± 1.1. The third component "Cost of and responsibility for the dental treatment" included four items with a Cronbach α of 0.47 and scored 4.4 ± 0.8 to 4.5 ± 0.8. The fourth component "Medical history of older patients" included two items with a Cronbach α of 0.70 and scored 4.0 ± 1.0 to 4.1 ± 1.0. The fifth Component "Feeling towards older patients" included two items with a Cronbach α of 0.672 and scored 2.6 ± 1.2 to 2.0 ± 1.4. The sixth Component "Confidence and experience in treating older patients" included two items with a Cronbach α of 0.33 and scored 4.4 ± 1 to 4.6 ± 1. CONCLUSION: This preliminary validation of the ASDS-Ar resulted in a new 17-item scale with six components with acceptable validity, reliability and discrimination.

Enhanced Surface Accessibility of SARS-CoV-2 Omicron Spike Protein Due to an Altered Glycosylation Profile.

SARS-CoV-2 spike (S) proteins undergo extensive glycosylation, aiding in proper folding, enhancing stability, and evading host immune surveillance. In this study, we used mass spectrometric analysis to elucidate the N-glycosylation characteristics and disulfide bonding of recombinant spike proteins derived from the SARS-CoV-2 Omicron variant (B.1.1.529) in comparison with the D614G spike variant. Furthermore, we conducted microsecond-long molecular dynamics simulations on spike proteins to resolve how the different N-glycans impact spike conformational sampling in the two variants. Our findings reveal that the Omicron spike protein maintains an overall resemblance to the D614G spike variant in terms of site-specific glycan processing and disulfide bond formation. Nonetheless, alterations in glycans were observed at certain N-glycosylation sites. These changes, in synergy with mutations within the Omicron spike protein, result in increased surface accessibility of the macromolecule, including the ectodomain, receptor-binding domain, and N-terminal domain. Additionally, mutagenesis and pull-down assays reveal the role of glycosylation of a specific sequon (N149); furthermore, the correlation of MD simulation and HDX-MS identified several high-dynamic areas of the spike proteins. These insights contribute to our understanding of the interplay between structure and function, thereby advancing effective vaccination and therapeutic strategies.

Retraining transplant pharmacy staff to reduce Medicare Part B prescription billing errors post-transplant.

BACKGROUND: Medicare Part B (MedB) imposes penalties for certain errors in prescription billing of post-transplant medications, which can greatly affect pharmacy revenue. To prevent MedB billing fines, pharmacy staff must be cognizant of specific MedB requirements. OBJECTIVE: This quality improvement project aimed to retrain certified pharmacy technicians (CPhTs) on common billing errors and evaluate changes in error rates and potential fines after retraining. We aimed to determine whether retraining CPhTs minimizes MedB prescription billing errors and reduces potential fines owed by the Vanderbilt Transplant Pharmacy (VTP) to the Centers for Medicare and Medicaid Services (CMS). METHODS: This was a single-center, quality improvement study including post-transplant patients with at least one MedB prescription billing error who filled prescriptions through VTP. All CPhTs involved in MedB prescription billing received retraining focused on the top 3 errors in MedB billing identified at VTP: early refills, missing relationship of caller to patient and residence of patient on order documentation, or no day supply remaining recorded on the order file. Retraining consisted of developing a training checklist, testing current knowledge levels, individualized nonpunitive coaching based on technician specific errors, and retesting for knowledge retention. Outcomes included the number of prescriptions with at least one MedB prescription billing error and the projected amount of dollars fined owing to errors recorded during the 3 months before and 3 months after retraining. RESULTS: Fourteen CPhTs received retraining. Average refill too soon errors decreased by 37.5% (10.7% vs. 6.7%), average missing relationship by 21.7% (7.7% vs. 6%), and day supply errors by 39.7% (1.7% vs. 1%). Error reductions equaled a 28.2% decrease (approximately $12,700) in potential fines. CONCLUSION: Retraining focused on MedB billing error successfully reduced error frequency and fines from CMS. MedB billing error fines can be costly for pharmacies dispensing high-cost medications; therefore, identifying common errors and training staff can be useful and financially prudent.

War and education: the attacks on medical schools amidst ongoing armed conflict, Sudan 2023.

BACKGROUND: War results in widespread destruction of a country's infrastructure, healthcare facilities, and educational institutions. This study aims to assess the attacks on medical schools amidst the ongoing conflict in Sudan. METHODS: A descriptive cross-sectional study was conducted across 58 medical schools located in the states of Khartoum, Darfur, and Kordofan. Data on attacks between April 15, 2023, and July 15th 2023, were collected using online data collection form. RESULTS: All medical schools in conflict areas were included in the study. More than half (58.6%) of these medical schools were attacked. Private schools, constituting the majority of the study sample, were the most frequently attacked (70.6%). Of these, 52.9% were located in Khartoum city. More than one form of attack was reported in 64.7% of the affected schools. Looting occurred in 73.5% of the attacked faculties, while 67.6% of them were converted into military bases. Despite these challenges, 60.3% of the schools in the conflict zone managed to restore the educational process through online learning and collaboration with other institutions. CONCLUSION: During a three-month period of warfare, most medical schools within conflict zones were attacked. This emphasizes the vulnerability of medical education institutions during war and highlights the urgent need of the Ministry of Higher Education interventions to provide leadership, support, and oversight for the educational process in medical schools across the country.

Inclusion of deuterated glycopeptides provides increased sequence coverage in hydrogen/deuterium exchange mass spectrometry analysis of SARS-CoV-2 spike glycoprotein.

RATIONALE: Hydrogen/deuterium exchange mass spectrometry (HDX-MS) can provide precise analysis of a protein's conformational dynamics across varied states, such as heat-denatured versus native protein structures, localizing regions that are specifically affected by such conditional changes. Maximizing protein sequence coverage provides high confidence that regions of interest were located by HDX-MS, but one challenge for complete sequence coverage is N-glycosylation sites. The deuteration of peptides post-translationally modified by asparagine-bound glycans (glycopeptides) has not always been identified in previous reports of HDX-MS analyses, causing significant sequence coverage gaps in heavily glycosylated proteins and uncertainty in structural dynamics in many regions throughout a glycoprotein. METHODS: We detected deuterated glycopeptides with a Tribrid Orbitrap Eclipse mass spectrometer performing data-dependent acquisition. An MS scan was used to identify precursor ions; if high-energy collision-induced dissociation MS/MS of the precursor indicated oxonium ions diagnostic for complex glycans, then electron transfer low-energy collision-induced dissociation MS/MS scans of the precursor identified the modified asparagine residue and the glycan's mass. As in traditional HDX-MS, the identified glycopeptides were then analyzed at the MS level in samples labeled with D2 O. RESULTS: We report HDX-MS analysis of the SARS-CoV-2 spike protein ectodomain in its trimeric prefusion form, which has 22 predicted N-glycosylation sites per monomer, with and without heat treatment. We identified glycopeptides and calculated their average isotopic mass shifts from deuteration. Inclusion of the deuterated glycopeptides increased sequence coverage of spike ectodomain from 76% to 84%, demonstrated that glycopeptides had been deuterated, and improved confidence in results localizing structural rearrangements. CONCLUSION: Inclusion of deuterated glycopeptides improves the analysis of the conformational dynamics of glycoproteins such as viral surface antigens and cellular receptors.

Examining the use, confidence, and barriers to follow Advanced Life Support in Obstetrics (ALSO) course guides in managing obstetric emergencies in Sudan.

BACKGROUND: The Advanced Life Support in Obstetrics (ALSO) course is a globally recognized interprofessional training program designed to assist healthcare professionals in acquiring and sustaining the necessary knowledge and skills to handle obstetric emergencies effectively. This survey aimed to assess the use, barriers, and confidence in using the ALSO course guidelines in managing obstetric emergencies in Sudan. METHODS: This descriptive cross-sectional study involved 103 physicians from the Sudan ALSO group in Sudan. A structured, close-ended questionnaire was distributed electronically to the participants. Data analysis was conducted using Statistical Package of Social Sciences Software version 26. RESULTS: More than half of the participants were specialists (54.4%). Although all respondents claimed to adhere to the ALSO guidelines for managing shoulder dystocia, a lower percentage followed them for neonatal resuscitation (75.0%) and maternal venous thrombosis management (68.9%). Only 62.1% of participants felt confident performing neonatal resuscitation. The main barriers to implementing the ALSO course guidelines were the respondents' preference for other guidelines and their belief that the guidelines were not applicable in their specific settings. CONCLUSION: The majority of participants displayed a high level of confidence, indicating a positive perception of the guide's effectiveness. However, there is room for improvement, particularly in areas such as neonatal resuscitation and forceps-assisted births, where confidence levels were lower. Addressing barriers, including the preference for other guidelines and the applicability of the guide in specific settings, is crucial to ensure widespread adoption. Refresher training programs, contextual adaptations, and the integration of guidelines may help overcome these barriers and enhance the overall implementation of the ALSO guide in managing obstetric emergencies in Sudan.

Structural basis of the American mink ACE2 binding by Y453F trimeric spike glycoproteins of SARS-CoV-2.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) enters the host cell by binding to angiotensin-converting enzyme 2 (ACE2). While evolutionarily conserved, ACE2 receptors differ across various species and differential interactions with Spike (S) glycoproteins of SARS-CoV-2 viruses impact species specificity. Reverse zoonoses led to SARS-CoV-2 outbreaks on multiple American mink (Mustela vison) farms during the pandemic and gave rise to mink-associated S substitutions known for transmissibility between mink and zoonotic transmission to humans. In this study, we used bio-layer interferometry (BLI) to discern the differences in binding affinity between multiple human and mink-derived S glycoproteins of SARS-CoV-2 and their respective ACE2 receptors. Further, we conducted a structural analysis of a mink variant S glycoprotein and American mink ACE2 (mvACE2) using cryo-electron microscopy (cryo-EM), revealing four distinct conformations. We discovered a novel intermediary conformation where the mvACE2 receptor is bound to the receptor-binding domain (RBD) of the S glycoprotein in a "down" position, approximately 34° lower than previously reported "up" RBD. Finally, we compared residue interactions in the S-ACE2 complex interface of S glycoprotein conformations with varying RBD orientations. These findings provide valuable insights into the molecular mechanisms of SARS-CoV-2 entry.

Prioritizing children's mental health amidst Sudan's humanitarian crisis: policy recommendations for immediate action.

The humanitarian crisis precipitated by the ongoing conflict in Sudan poses profound risks to the health and welfare of the country's children. This paper explores essential policy interventions to safeguard child mental health services under these challenging circumstances. Crucial strategies include enhancing healthcare accessibility for children and their caregivers, promoting education, and improving household living conditions. Additionally, it is vital to provide improved access to information about nutritious food and strengthen health systems in areas directly exposed to conflict. Cooperation with international aid organizations is paramount to delivering medical supplies to functioning health facilities. The paper also recommends partnerships with local non-governmental and humanitarian organizations to execute public health programs effectively. These multi-faceted policy measures underscore the importance of a comprehensive response to ensure the health and well-being of children amid the turmoil in Sudan. Through these strategies, we aim to provide a blueprint for policymakers and humanitarian organizations to mitigate the devastating impacts of the conflict on the country's most vulnerable population.

Violence in Sudan: A Looming Public Health Disaster.

Sudan's ongoing conflict, rooted in colonial-era policies and resource competition, has led to widespread displacement, poverty, and social service breakdowns. The escalating power struggle between the Sudanese Army Forces (SAF) and the paramilitary Rapid Support Forces (RSF) exacerbates the humanitarian crisis by severely undermining the nation's health services and infrastructure. This leads to long-lasting social and economic consequences, creating a need for a coordinated response from national and international organizations to provide emergency healthcare, rebuild infrastructure, and train and retain healthcare workers. Moreover, the recent takeover of a National Public Health Laboratory in Khartoum, which contains dangerous biological material, is considered extremely dangerous. The expulsion of technicians and power cuts prevent the proper management of biological materials (e.g., polio, measles, and cholera isolates). This editorial sheds light on the deep-seated repercussions of the conflict in Sudan, with a specific focus on the toll it takes on health services and infrastructure. It calls for an all-encompassing, synergistic approach that places the health and welfare of impacted communities at the forefront. Through concerted collaboration between national entities and the global community, there lies the potential to pave the way for recuperation, fortitude, and enduring stability in regions ravaged by conflict.

Analysis of the N-glycosylation profiles of the spike proteins from the Alpha, Beta, Gamma, and Delta variants of SARS-CoV-2.

N-Glycosylation plays an important role in the structure and function of membrane and secreted proteins. Viral proteins used in cell entry are often extensively glycosylated to assist in protein folding, provide stability, and shield the virus from immune recognition by its host (described as a "glycan shield"). The SARS-CoV-2 spike protein (S) is a prime example, having 22 potential sites of N-glycosylation per protein protomer, as predicted from the primary sequence. In this report, we conducted mass spectrometric analysis of the N-glycosylation profiles of recombinant spike proteins derived from four common SARS-CoV-2 variants classified as Variant of Concern, including Alpha, Beta, Gamma, and Delta along with D614G variant spike as a control. Our data reveal that the amino acid substitutions and deletions between variants impact the abundance and type of glycans on glycosylation sites of the spike protein. Some of the N-glycosylation sequons in S show differences between SARS-CoV-2 variants in the distribution of glycan forms. In comparison with our previously reported site-specific glycan analysis on the S-D614G and its ancestral protein, glycan types on later variants showed high similarity on the site-specific glycan content to S-D614G. Additionally, we applied multiple digestion methods on each sample, and confirmed the results for individual glycosylation sites from different experiment conditions to improve the identification and quantification of glycopeptides. Detailed site-specific glycan analysis of a wide variety of SARS-CoV-2 variants provides useful information toward the understanding of the role of protein glycosylation on viral protein structure and function and development of effective vaccines and therapeutics.

Development and optimisation of a preclinical cone beam computed tomography-based radiomics workflow for radiation oncology research.

Background and purpose: Radiomics features derived from medical images have the potential to act as imaging biomarkers to improve diagnosis and predict treatment response in oncology. However, the complex relationships between radiomics features and the biological characteristics of tumours are yet to be fully determined. In this study, we developed a preclinical cone beam computed tomography (CBCT) radiomics workflow with the aim to use in vivo models to further develop radiomics signatures. Materials and methods: CBCT scans of a mouse phantom were acquired using onboard imaging from a small animal radiotherapy research platform (SARRP, Xstrahl). The repeatability and reproducibility of radiomics outputs were compared across different imaging protocols, segmentation sizes, pre-processing parameters and materials. Robust features were identified and used to compare scans of two xenograft mouse tumour models (A549 and H460). Results: Changes to the radiomics workflow significantly impact feature robustness. Preclinical CBCT radiomics analysis is feasible with 119 stable features identified from scans imaged at 60 kV, 25 bin width and 0.26 mm slice thickness. Large variation in segmentation volumes reduced the number of reliable radiomics features for analysis. Standardization in imaging and analysis parameters is essential in preclinical radiomics analysis to improve accuracy of outputs, leading to more consistent and reproducible findings. Conclusions: We present the first optimised workflow for preclinical CBCT radiomics to identify imaging biomarkers. Preclinical radiomics has the potential to maximise the quantity of data captured in in vivo experiments and could provide key information supporting the wider application of radiomics.

Experiences of caregivers and individuals living with traumatic brain injury in accessing health information: a qualitative investigation.

BACKGROUND/PURPOSE: Rehabilitation and treatment of chronic symptoms of traumatic brain injury (TBI) present life-long challenges. This qualitative study aimed to understand the experience of individuals with TBI and caregivers in finding and using health information and to understand their interest in participating in research. METHODS: Participants were recruited through hospital listservs, websites, social media, and word of mouth from across the US. A qualitative constructivism research method was used to analyze responses from semi-structured interviews with 24 individuals, 11 with TBI and 13 caregivers. RESULTS: Three major themes emerged from the analyses: 1) processes and resources for finding TBI-related health information, 2) reliability of information, and 3) participation in research. Study participants described using the internet, consulting with healthcare professionals, reading research articles, and seeking out information from other individuals with TBI or caregivers to search for information. Participants also shared their experiences related to evaluating the reliability of information and the impact of individuals with TBI and caregivers participating on research teams. CONCLUSION: Participants identified various needs in finding relevant health information and highlighted gaps in searching for and using health information. Participants identified an overarching need for improved dissemination of information that is both accessible and reliable.

Development and Optimization of a Machine-Learning Prediction Model for Acute Desquamation After Breast Radiation Therapy in the Multicenter REQUITE Cohort.

Purpose: Some patients with breast cancer treated by surgery and radiation therapy experience clinically significant toxicity, which may adversely affect cosmesis and quality of life. There is a paucity of validated clinical prediction models for radiation toxicity. We used machine learning (ML) algorithms to develop and optimise a clinical prediction model for acute breast desquamation after whole breast external beam radiation therapy in the prospective multicenter REQUITE cohort study. Methods and Materials: Using demographic and treatment-related features (m = 122) from patients (n = 2058) at 26 centers, we trained 8 ML algorithms with 10-fold cross-validation in a 50:50 random-split data set with class stratification to predict acute breast desquamation. Based on performance in the validation data set, the logistic model tree, random forest, and naïve Bayes models were taken forward to cost-sensitive learning optimisation. Results: One hundred and ninety-two patients experienced acute desquamation. Resampling and cost-sensitive learning optimisation facilitated an improvement in classification performance. Based on maximising sensitivity (true positives), the "hero" model was the cost-sensitive random forest algorithm with a false-negative: false-positive misclassification penalty of 90:1 containing m = 114 predictive features. Model sensitivity and specificity were 0.77 and 0.66, respectively, with an area under the curve of 0.77 in the validation cohort. Conclusions: ML algorithms with resampling and cost-sensitive learning generated clinically valid prediction models for acute desquamation using patient demographic and treatment features. Further external validation and inclusion of genomic markers in ML prediction models are worthwhile, to identify patients at increased risk of toxicity who may benefit from supportive intervention or even a change in treatment plan.

Access, Utilization, and Implementation of Research Among Rehabilitation Nurses: A Qualitative Study.

PURPOSE: This study aimed to understand rehabilitation nurses' perceptions of research information, related barriers, and avenues for future research, specifically in those caring for individuals with burn injury, spinal cord injury, or traumatic brain injury. DESIGN: Qualitative semistructured interviews were conducted. METHODS: Eighteen interviews were conducted. A thematic network approach identified codes and developed basic, organizing, and global themes. RESULTS: Researchers identified factors that facilitated research uptake, determined organizational structures that support research culture, and described nurse engagement with literature. CONCLUSIONS: Although participants desired to engage with the research literature, they identified barriers including time constraints, heavy workloads, and lack of access. To facilitate research uptake, research must be easily accessible, be easily digestible, and include clinical practice recommendations. Research must expand its scope to address issues relevant to the rehabilitation population. CLINICAL RELEVANCE: Our findings may be used to drive improvements in research competence, facilitate knowledge translation, and support evidence-based practice among rehabilitation nurses.

Simultaneous integrated boost (SIB) to dominant intra-prostatic lesions during extreme hypofractionation for prostate cancer: the impact of rectal spacers.

PURPOSE: Boosting dominant intra-prostatic lesions (DILs) has the potential to increase the therapeutic ratio in prostate cancer radiotherapy. In this study, employing 5-fraction stereotactic ablative radiotherapy (SABR) volumetric modulated arc therapy (VMAT) to deliver 40 Gy to the prostate clinical target volume (CTV) while boosting the DIL up to 50 Gy was evaluated for patients before and after rectal spacer insertion. MATERIALS AND METHODS: 24 Computed Tomography (CT) scans of 12 prostate cancer patients with unfavourable intermediate or high risk prostate cancer were employed in this study. At least two treatment plans were generated for each patient to compare pre- and post-spacer insertion plans. Plans were evaluated for target coverage, organs-at-risk doses, and the achievable boost dose level. RESULTS: The CTV coverage was significantly better in plans with a spacer, V40Gy 98.4% versus 97.0% (p = 0.012). Using spacers significantly reduced rectal dose in all 12 patients in this study. It was possible to boost DIL to 50 Gy to without violating dose constraints in 6 of 12 patients and to 47.5 Gy in 3 patients post-spacer insertion. For 3 patients (25%) it was not possible to boost DIL above 45 Gy even with a spacer in situ. Without a spacer, for 6 patient (50%) clinically acceptable plan were only achieved when the DIL dose was lowered to 45 Gy. In five of these 6 patients the dose limiting structure was the urethra (urethra planning risk volume V45Gy [cc] ≤ 0.1 cc constraint). CONCLUSIONS: Clinically acceptable plans for 5 fraction SABR, 40 Gy to the prostate CTV, with a SIB to DIL (45-50 Gy) were achieved. The boost dose achieved was DIL location dependent and primarily affected by DIL's proximity to the urethra. Compared to plans before spacer insertion, higher DIL dose were achieved with spacer in situ for 25% of the patients. Moreover, significant reduction in rectal dose and better target coverage were also achieved for all patients with spacers in situ.

Enhanced fitness of SARS-CoV-2 variant of concern Alpha but not Beta.

Emerging variants of concern (VOCs) are driving the COVID-19 pandemic1,2. Experimental assessments of replication and transmission of major VOCs and progenitors are needed to understand the mechanisms of replication and transmission of VOCs3. Here we show that the spike protein (S) from Alpha (also known as B.1.1.7) and Beta (B.1.351) VOCs had a greater affinity towards the human angiotensin-converting enzyme 2 (ACE2) receptor than that of the progenitor variant S(D614G) in vitro. Progenitor variant virus expressing S(D614G) (wt-S614G) and the Alpha variant showed similar replication kinetics in human nasal airway epithelial cultures, whereas the Beta variant was outcompeted by both. In vivo, competition experiments showed a clear fitness advantage of Alpha over wt-S614G in ferrets and two mouse models-the substitutions in S were major drivers of the fitness advantage. In hamsters, which support high viral replication levels, Alpha and wt-S614G showed similar fitness. By contrast, Beta was outcompeted by Alpha and wt-S614G in hamsters and in mice expressing human ACE2. Our study highlights the importance of using multiple models to characterize fitness of VOCs and demonstrates that Alpha is adapted for replication in the upper respiratory tract and shows enhanced transmission in vivo in restrictive models, whereas Beta does not overcome Alpha or wt-S614G in naive animals.

N-glycosylation profiles of the SARS-CoV-2 spike D614G mutant and its ancestral protein characterized by advanced mass spectrometry.

N-glycosylation plays an important role in the structure and function of membrane and secreted proteins. The spike protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is heavily glycosylated and the major target for developing vaccines, therapeutic drugs and diagnostic tests. The first major SARS-CoV-2 variant carries a D614G substitution in the spike (S-D614G) that has been associated with altered conformation, enhanced ACE2 binding, and increased infectivity and transmission. In this report, we used mass spectrometry techniques to characterize and compare the N-glycosylation of the wild type (S-614D) or variant (S-614G) SARS-CoV-2 spike glycoproteins prepared under identical conditions. The data showed that half of the N-glycosylation sequons changed their distribution of glycans in the S-614G variant. The S-614G variant showed a decrease in the relative abundance of complex-type glycans (up to 45%) and an increase in oligomannose glycans (up to 33%) on all altered sequons. These changes led to a reduction in the overall complexity of the total N-glycosylation profile. All the glycosylation sites with altered patterns were in the spike head while the glycosylation of three sites in the stalk remained unchanged between S-614G and S-614D proteins.

A data science approach for early-stage prediction of Patient's susceptibility to acute side effects of advanced radiotherapy.

The prediction by classification of side effects incidence in a given medical treatment is a common challenge in medical research. Machine Learning (ML) methods are widely used in the areas of risk prediction and classification. The primary objective of such algorithms is to use several features to predict dichotomous responses (e.g., disease positive/negative). Similar to statistical inference modelling, ML modelling is subject to the class imbalance problem and is affected by the majority class, increasing the false-negative rate. In this study, seventy-nine ML models were built and evaluated to classify approximately 2000 participants from 26 hospitals in eight different countries into two groups of radiotherapy (RT) side effects incidence based on recorded observations from the international study of RT related toxicity "REQUITE". We also examined the effect of sampling techniques and cost-sensitive learning methods on the models when dealing with class imbalance. The combinations of such techniques used had a significant impact on the classification. They resulted in an improvement in incidence status prediction by shifting classifiers' attention to the minority group. The best classification model for RT acute toxicity prediction was identified based on domain experts' success criteria. The Area Under Receiver Operator Characteristic curve of the models tested with an isolated dataset ranged from 0.50 to 0.77. The scale of improved results is promising and will guide further development of models to predict RT acute toxicities. One model was optimised and found to be beneficial to identify patients who are at risk of developing acute RT early-stage toxicities as a result of undergoing breast RT ensuring relevant treatment interventions can be appropriately targeted. The design of the approach presented in this paper resulted in producing a preclinical-valid prediction model. The study was developed by a multi-disciplinary collaboration of data scientists, medical physicists, oncologists and surgeons in the UK Radiotherapy Machine Learning Network.

Membrane-partitioned cell wall synthesis in mycobacteria.

Many antibiotics target the assembly of cell wall peptidoglycan, an essential, heteropolymeric mesh that encases most bacteria. In rod-shaped bacteria, cell wall elongation is spatially precise yet relies on limited pools of lipid-linked precursors that generate and are attracted to membrane disorder. By tracking enzymes, substrates, and products of peptidoglycan biosynthesis in Mycobacterium smegmatis, we show that precursors are made in plasma membrane domains that are laterally and biochemically distinct from sites of cell wall assembly. Membrane partitioning likely contributes to robust, orderly peptidoglycan synthesis, suggesting that these domains help template peptidoglycan synthesis. The cell wall-organizing protein DivIVA and the cell wall itself promote domain homeostasis. These data support a model in which the peptidoglycan polymer feeds back on its membrane template to maintain an environment conducive to directional synthesis. Our findings are applicable to rod-shaped bacteria that are phylogenetically distant from M. smegmatis, indicating that horizontal compartmentalization of precursors may be a general feature of bacillary cell wall biogenesis.

Mini review: Personalization of the radiation therapy management of prostate cancer using MRI-based radiomics.

Decisions on how to treat prostate cancer with radiation therapy are guideline-based but as such guidelines have been developed for populations of patients, this invariably leads to overly aggressive treatment in some patients and insufficient treatment in others. Heterogeneity within prostate tumors and in metastatic sites, even within the same patient, is believed to be a major cause of treatment failure. Radiomics biomarkers, more commonly referred to as radiomics 'features", provide readily available, cost-effective, non-invasive tools for screening, detecting tumors and serial monitoring of patients, including assessments of response to therapy and identification of therapeutic complications. Radiomics offers the potential to analyse whole tumors in 3D, as well as sub-regions or 'habitats' within tumors. Combining quantitative information from imaging with pathology, demographic details and other biomarkers will pave the way for personalised treatment selection and monitoring in prostate cancer. The aim of this review is to consider if MRI-based radiomics can bridge the gap between population-based management and personalised management of prostate cancer.