Prophylactic immunization to Helicobacter pylori infection using spore vectored vaccines.

BACKGROUND: Helicobacter pylori infection remains a major public health threat leading to gastrointestinal illness and increased risk of gastric cancer. Mostly affecting populations in developing countries no vaccines are yet available and the disease is controlled by antimicrobials which, in turn, are driving the emergence of AMR. MATERIALS AND METHODS: We have engineered spores of Bacillus subtilis to display putative H. pylori protective antigens, urease subunit A (UreA) and subunit B (UreB) on the spore surface. Following oral dosing of mice with these spores, we evaluated immunity and colonization in animals challenged with H. pylori. RESULTS: Oral immunization with spores expressing either UreA or UreB showed antigen-specific mucosal responses (fecal sIgA) including seroconversion and hyperimmunity. Following challenge, colonization by H. pylori was significantly reduced by up to 1-log. CONCLUSIONS: This study demonstrates the utility of bacterial spores for mucosal vaccination to H. pylori infection. The heat stability and robustness of Bacillus spores coupled with their existing use as probiotics make them an attractive solution for either protection against H. pylori infection or potentially for therapy and control of active infection.

A Women in Medicine Trainees' Council: a model for women trainee professional development.

Women physicians are promoted less often, more likely to experience harassment and bias, and paid less than their male peers. Although many institutions have developed initiatives to help women physicians overcome these professional hurdles, few are specifically geared toward physicians-in-training. The Women in Medicine Trainees' Council (WIMTC) was created in 2015 to support the professional advancement of women physicians-in-training in the Massachusetts General Hospital Department of Medicine (MGH-DOM). In a 2021 survey, the majority of respondents agreed that the WIMTC ameliorated the challenges of being a woman physician-in-training and contributed positively to overall wellness. Nearly all agreed that they would advise other training programs to implement a similar program. We present our model for women-trainee support to further the collective advancement of women physicians.

Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders.

Mutations of the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2) cause classical forms of Rett syndrome (RTT) in girls. A subset of patients who are recognized to have an overlapping neurological phenotype with RTT but are lacking a mutation in a gene that causes classical or atypical RTT can be described as having a 'Rett-syndrome-like phenotype (RTT-L). Here, we report eight patients from our cohort diagnosed as having RTT-L who carry mutations in genes unrelated to RTT. We annotated the list of genes associated with RTT-L from our patient cohort, considered them in the light of peer-reviewed articles on the genetics of RTT-L, and constructed an integrated protein-protein interaction network (PPIN) consisting of 2871 interactions connecting 2192 neighboring proteins among RTT- and RTT-L-associated genes. Functional enrichment analysis of RTT and RTT-L genes identified a number of intuitive biological processes. We also identified transcription factors (TFs) whose binding sites are common across the set of RTT and RTT-L genes and appear as important regulatory motifs for them. Investigation of the most significant over-represented pathway analysis suggests that HDAC1 and CHD4 likely play a central role in the interactome between RTT and RTT-L genes.

Tuning riboflavin derivatives for photodynamic inactivation of pathogens.

The development of effective pathogen reduction strategies is required due to the rise in antibiotic-resistant bacteria and zoonotic viral pandemics. Photodynamic inactivation (PDI) of bacteria and viruses is a potent reduction strategy that bypasses typical resistance mechanisms. Naturally occurring riboflavin has been widely used in PDI applications due to efficient light-induced reactive oxygen species (ROS) release. By rational design of its core structure to alter (photo)physical properties, we obtained derivatives capable of outperforming riboflavin's visible light-induced PDI against E. coli and a SARS-CoV-2 surrogate, revealing functional group dependency for each pathogen. Bacterial PDI was influenced mainly by guanidino substitution, whereas viral PDI increased through bromination of the flavin. These observations were related to enhanced uptake and ROS-specific nucleic acid cleavage mechanisms. Trends in the derivatives' toxicity towards human fibroblast cells were also investigated to assess viable therapeutic derivatives and help guide further design of PDI agents to combat pathogenic organisms.

Exploring genome-wide DNA methylation patterns in Aicardi syndrome.

AIM: To explore differential DNA methylation (DNAm) in Aicardi syndrome (AIC), a severe neurodevelopmental disorder with largely unknown etiology. PATIENTS & METHODS: We characterized DNAm in AIC female patients and parents using the Illumina 450 K array. Differential DNAm was assessed using the local outlier factor algorithm, and results were validated via qPCR in a larger set of AIC female patients, parents and unrelated young female controls. Functional epigenetic modules analysis was used to detect pathways integrating both genome-wide DNAm and RNA-seq data. RESULTS & CONCLUSION: We detected differential methylation patterns in AIC patients in several neurodevelopmental and/or neuroimmunological networks. These networks may be part of the underlying pathogenic mechanisms involved in the disease.

Beyond Continuing Medical Education: Clinical Coaching as a Tool for Ongoing Professional Development.

PROBLEM: For most physicians, the period of official apprenticeship ends with the completion of residency or fellowship, yet the acquisition of expertise requires ongoing opportunities to practice a given skill and obtain structured feedback on one's performance. APPROACH: In July 2013, the authors developed a clinical coaching pilot program to provide early-career hospitalists with feedback from a senior clinical advisor (SCA) at Massachusetts General Hospital. A Hospital Medicine Unit-wide retreat was held to help design the SCA role and obtain faculty buy-in. Twelve SCAs were recruited from hospitalists with more than five years of experience; each served as a clinical coach to 28 early-career hospitalists during the pilot. Clinical narratives and programmatic surveys were collected from SCAs and early-career hospitalists. OUTCOMES: Of 25 responding early-career hospitalists, 23 (92%) rated the SCA role as useful to very useful, 20 (80%) reported interactions with the SCA led to at least one change in their diagnostic approach, and 13 (52%) reported calling fewer subspecialty consults as a result of guidance from the SCA. In response to questions about professional development, 18 (72%) felt more comfortable as an independent physician following their interactions with the SCA, and 19 (76%) thought the interactions improved the quality of care they delivered. NEXT STEPS: To better understand the impact and generalizability of clinical coaching, a larger, longitudinal study is required to look at patient and provider outcomes in detail. Further refinement of the SCA role to meet faculty needs is needed and could include faculty development.