"The Water in Which We Swim:" A Unique, Post-Clerkship Multidisciplinary Course.

OBJECTIVE: To improve patient outcomes and promote health equity, medical students must be taught not only biomedicine, but also the social sciences to understand the larger contexts in which patients live and health care operates. Yet, most undergraduate medical education does not explicitly cover these topics in a required, longitudinal curriculum. METHODS: In January 2015 at Harvard Medical School, we created a two-part sequence (pre- and post-clerkship) of required, 4-week multidisciplinary courses-"Essentials of the Profession I and II"-to fill this gap. "Essentials of the Profession II (EOP2)" is an advanced social sciences course anchored in patient narratives and the lived experiences of students and includes clinical epidemiology and population health, healthcare delivery and leadership, health policy, medical ethics and professionalism, and social medicine that engages students to conduct structural analyses to be effective healers, advocates, and leaders. RESULTS: Per student course evaluations, the overall course rating was 1.7 (SD 0.9, 1 = excellent and 5 = poor); its overall rating has improved over time; and it has scored well even when run virtually. It was rated highly in application of critical thinking, integration of the disciplines, and relevance for clinical work. Qualitative analyses of student responses revealed the following key course strengths: breadth of topics, teaching faculty and guest speakers, and small group discussions. The weaknesses included workload, lack of diversity of opinions, repetition, and time spent in lectures. CONCLUSIONS: We argue that EOP2 is "essential" for post-clerkship medical education. It offers an opportunity to re-ignite and enhance humanism and activism; remind students why they chose the medical profession; equip them with frameworks and toolkits to help them to overcome challenges; and devise solutions to improve health care and patient outcomes that are applicable to their future training and ongoing practice of medicine.

Responding to Suicide in School Communities: An Examination of Postvention Guidance from Expert Recommendations and Empirical Studies.

PURPOSE OF REVIEW: We review the published literature on a school's response after a student dies by suicide ("postvention"). We examine published recommendations based on expert guidance and empirical studies that have evaluated postvention measures. RECENT FINDINGS: Experts recommend careful communication with family, staff, and students that adheres to published suicide reporting guidelines. Experts also emphasize the importance of identifying and supporting high-risk students. Few robust, controlled studies have identified effective postvention measures. Effective measures tended to occur in group settings (e.g., group therapy), focus on improving grief symptoms, and involve mental health professionals. Postvention has not been robustly studied in the school context. Expert recommendations and a few evidence-backed studies provide the frame for a coherent, school-based postvention response. Further research is needed to strengthen and expand our collective understanding of effective postvention measures in the school context as youth suicide attempts continue to rise.

Dataset on mucin 1 and 4 proteins and SialyT and T antigens staining patterns in cervical cancer primary tumors and metastatic lymph nodes.

The objective was to find an association between abnormal glycosylation, represented by Tn and STn antigens on mucin (MUC) proteins, in primary tumor specimens with lymph node metastasis or recurrence of cervical cancer patients. Prospectively collected specimens were obtained from the NRG Oncology/GOG clinical trial GOG 0221 patients with previously untreated stage IB-IVA primary cervical cancer, who underwent surgical resection and removal of associated para-aortic and pelvic lymph nodes. Immunohistochemical staining for mucin 1 and 4 (MUC1 and MUC4) proteins and surface glycoproteins Tn and Sialyl Tn were performed on sections cut from formalin-fixed, paraffin-embedded specimen blocks. Loss vs no loss, of immunohistochemical stain upon neuraminidase treatment was used to verify STn vs Tn positivity, respectively, in patient specimens and in colon tissue from wild-type and T-synthase knockout transgenic mice, which served as STn positive versus STn negative controls, respectively. H-scores of staining intensity and percentage of cells stained was performed by experienced gynecologic pathologists. An experienced gynecologic pathologist also selected photographed regions of interest associated with these cases. The photomicrographs presented in this data set highlight the spectrum of morphologic expression and variability in glycoprotein expression in primary tumors and cancer-positive lymph node specimens. Findings may prove useful in furthering the understanding of cervical cancer glycoproteins, creation of artificial intelligence immunohistochemical scoring systems, and the development of targeted drug therapy.

Factors Associated With Utilization of Electroconvulsive Therapy During Psychiatric Hospitalization Among Children and Adolescents in China.

PURPOSE: Based on a nationally representative sample in China, we examined the demographic and clinical correlates of utilization of electroconvulsive therapy (ECT) in child and adolescent (C/A) patients younger than 18 years during psychiatric hospitalization. METHODS: As part of a national survey, 41 provincial tertiary psychiatric hospitals in mainland China were selected. Data from 196 C/A patients who were discharged from these psychiatric hospitals from March 19 to 31, 2019, were retrieved and analyzed. RESULTS: (1) The overall rate of ECT among C/A patients during psychiatric hospitalization was 15.6% (n = 30). (2) Between ECT and non-ECT groups, significant differences were found in sex, age, length of stay, Global Assessment of Functioning at admission, treatment outcome, and self-injurious behavior during hospitalization, and the ratio of marked improvement on discharge. (3) Multiple logistic regression analysis revealed that ECT use was independently and positively associated with an older age, male sex, lower Global Assessment of Functioning, and self-injurious behavior during hospitalization. CONCLUSIONS: The frequency of ECT use was relatively frequent in C/A patients during psychiatric hospitalization in our nationally representative sample in China. Developing more specific and operational criteria for the use of ECT for C/A patients is needed to provide guidance for the optimal use of ECT in this patient population.

Association of Sialyl Tn antigen with cervical cancer lymph node status: An NRG oncology/GOG study.

OBJECTIVE: Detection of lymph node metastases in cervical cancer patients is important for guiding treatment decisions, however accuracies of current detection methods are limited. We evaluated associations of abnormal glycosylation, represented by Tn and STn antigens on mucin (MUC) proteins, in primary tumor specimens with lymph node metastasis or recurrence of cervical cancer patients. METHODS: Surgical specimens were prospectively collected from 139 patients with locally-advanced cervical cancer undergoing lymphadenectomy enrolled in a nation-wide clinical trial (NCT00460356). Of these patients, 133 had primary cervix tumor, 67 had pelvic lymph node (PLN) and 28 had para-aortic lymph node (PALN) specimens. Fixed tissue serial sections were immunohistochemically stained for Tn, STn, MUC1 or MUC4. Neuraminidase was used to validate Tn versus STn antibody specificity. Stain scores were compared with clinical characteristics. RESULTS: Primary tumor STn expression above the median was associated with negative PLN status (p-value: 0.0387; odds ratio 0.439, 95% CI: 0.206 to 0.935). PLN had higher STn compared to primary tumor, while primary tumor had higher MUC1 compared to PALN, and MUC4 compared to PALN or PLN (p = 0.017, p = 0.011, p = 0.016 and p < 0.001, respectively). Tn and STn expression correlated in primary tumor, PALN, and PLN, Tn and MUC1 expression correlated in primary tumors only (Spearman correlation coefficient [r] = 0.301, r = 0.686, r = 0.603 and r = 0.249, respectively). CONCLUSIONS: STn antigen expression in primary cervical tumors is a candidate biomarker for guiding treatment decisions and for mechanistic involvement in PLN metastases.

Secreted peptidases contribute to virulence of fish pathogen Flavobacterium columnare.

Flavobacterium columnare causes columnaris disease in freshwater fish in both natural and aquaculture settings. This disease is often lethal, especially when fish population density is high, and control options such as vaccines are limited. The type IX secretion system (T9SS) is required for F. columnare virulence, but secreted virulence factors have not been fully identified. Many T9SS-secreted proteins are predicted peptidases, and peptidases are common virulence factors of other pathogens. T9SS-deficient mutants, such as ΔgldN and ΔporV, exhibit strong defects in secreted proteolytic activity. The F. columnare genome has many peptidase-encoding genes that may be involved in nutrient acquisition and/or virulence. Mutants lacking individual peptidase-encoding genes, or lacking up to ten peptidase-encoding genes, were constructed and examined for extracellular proteolytic activity, for growth defects, and for virulence in zebrafish and rainbow trout. Most of the mutants retained virulence, but a mutant lacking 10 peptidases, and a mutant lacking the single peptidase TspA exhibited decreased virulence in rainbow trout fry, suggesting that peptidases contribute to F. columnare virulence.

Flavobacterium columnare ferric iron uptake systems are required for virulence.

Flavobacterium columnare, which causes columnaris disease, is one of the costliest pathogens in the freshwater fish-farming industry. The virulence mechanisms of F. columnare are not well understood and current methods to control columnaris outbreaks are inadequate. Iron is an essential nutrient needed for metabolic processes and is often required for bacterial virulence. F. columnare produces siderophores that bind ferric iron for transport into the cell. The genes needed for siderophore production have been identified, but other components involved in F. columnare iron uptake have not been studied in detail. We identified the genes encoding the predicted secreted heme-binding protein HmuY, the outer membrane iron receptors FhuA, FhuE, and FecA, and components of an ATP binding cassette (ABC) transporter predicted to transport ferric iron across the cytoplasmic membrane. Deletion mutants were constructed and examined for growth defects under iron-limited conditions and for virulence against zebrafish and rainbow trout. Mutants with deletions in genes encoding outer membrane receptors, and ABC transporter components exhibited growth defects under iron-limited conditions. Mutants lacking multiple outer membrane receptors, the ABC transporter, or HmuY retained virulence against zebrafish and rainbow trout mirroring that exhibited by the wild type. Some mutants predicted to be deficient in multiple steps of iron uptake exhibited decreased virulence. Survivors of exposure to such mutants were partially protected against later infection by wild-type F. columnare.

Siderophores Produced by the Fish Pathogen Flavobacterium columnare Strain MS-FC-4 Are Not Essential for Its Virulence.

Flavobacterium columnare causes columnaris disease in wild and aquaculture-reared freshwater fish. F. columnare virulence mechanisms are not well understood, and current methods to control columnaris disease are inadequate. Iron acquisition from the host is important for the pathogenicity and virulence of many bacterial pathogens. F. columnare iron acquisition has not been studied in detail. We identified genes predicted to function in siderophore production for ferric iron uptake. Genes predicted to encode the proteins needed for siderophore synthesis, export, uptake, and regulation were deleted from F. columnare strain MS-FC-4. The mutants were examined for defects in siderophore production, for growth defects in iron-limited conditions, and for virulence against zebrafish and rainbow trout. Mutants lacking all siderophore activity were obtained. These mutants displayed growth defects when cultured under iron-limited conditions, but they retained virulence against zebrafish and rainbow trout similar to that exhibited by the wild type, indicating that the F. columnare MS-FC-4 siderophores are not required for virulence under the conditions tested. IMPORTANCE Columnaris disease, which is caused by Flavobacterium columnare, is a major problem for freshwater aquaculture. Little is known regarding F. columnare virulence factors, and control measures are limited. Iron acquisition mechanisms such as siderophores are important for virulence of other pathogens. We identified F. columnare siderophore biosynthesis, export, and uptake genes. Deletion of these genes eliminated siderophore production and resulted in growth defects under iron-limited conditions but did not alter virulence in rainbow trout or zebrafish. The results indicate that the F. columnare strain MS-FC-4 siderophores are not critical virulence factors under the conditions tested but may be important for survival under iron-limited conditions in natural aquatic environments or aquaculture systems.

Type IX Secretion System Effectors and Virulence of the Model Flavobacterium columnare Strain MS-FC-4.

Flavobacterium columnare causes columnaris disease in wild and cultured freshwater fish and is a major problem for sustainable aquaculture worldwide. The F. columnare type IX secretion system (T9SS) secretes many proteins and is required for virulence. The T9SS component GldN is required for secretion and gliding motility over surfaces. Genetic manipulation of F. columnare is inefficient, which has impeded identification of secreted proteins that are critical for virulence. Here, we identified a virulent wild-type F. columnare strain (MS-FC-4) that is highly amenable to genetic manipulation. This facilitated isolation and characterization of two deletion mutants lacking core components of the T9SS. Deletion of gldN disrupted protein secretion and gliding motility and eliminated virulence in zebrafish and rainbow trout. Deletion of porV disrupted secretion and virulence but not motility. Both mutants exhibited decreased extracellular proteolytic, hemolytic, and chondroitin sulfate lyase activities. They also exhibited decreased biofilm formation and decreased attachment to fish fins and other surfaces. Using genomic and proteomic approaches, we identified proteins secreted by the T9SS. We deleted 10 genes encoding secreted proteins and characterized the virulence of mutants lacking individual or multiple secreted proteins. A mutant lacking two genes encoding predicted peptidases exhibited reduced virulence in rainbow trout, and mutants lacking a predicted cytolysin showed reduced virulence in zebrafish and rainbow trout. The results establish F. columnare strain MS-FC-4 as a genetically amenable model to identify virulence factors. This may aid development of measures to control columnaris disease and impact fish health and sustainable aquaculture. IMPORTANCE Flavobacterium columnare causes columnaris disease in wild and aquaculture-reared freshwater fish and is a major problem for aquaculture. Little is known regarding the virulence factors involved in this disease, and control measures are inadequate. The type IX secretion system (T9SS) secretes many proteins and is required for virulence, but the secreted virulence factors are not known. We identified a strain of F. columnare (MS-FC-4) that is well suited for genetic manipulation. The components of the T9SS and the proteins secreted by this system were identified. Deletion of core T9SS genes eliminated virulence. Genes encoding 10 secreted proteins were deleted. Deletion of two peptidase-encoding genes resulted in decreased virulence in rainbow trout, and deletion of a cytolysin-encoding gene resulted in decreased virulence in rainbow trout and zebrafish. Secreted peptidases and cytolysins are likely virulence factors and are targets for the development of control measures.

Factors Associated With Non-suicidal Self-Injury in Chinese Adolescents: A Meta-Analysis.

Non-suicidal self-injury (NSSI) in adolescents is an increasing public health problem in China. We conducted a meta-analysis of studies on NSSI in Chinese adolescents (between 10 and 19 years) to examine factors associated with NSSI. Twenty-five papers including 30 separate studies with 186,447 participants were included for analysis. The results from a random-effects model showed a weak, but significant overall prediction of NSSI (OR = 1.734). There were significant associations between the following seven factors and NSSI (ranking by the effect sizes, in descending order): adverse life events (OR = 2.284), negative coping style (OR = 2.040), problematic internet use (OR = 2.023), sleep disturbance (OR = 1.734), traumatic experiences (OR = 1.728), problematic parent-child relationship (OR = 1.585), mental health problems (OR = 1.578). Additionally, NSSI sample type moderated these effects. These findings highlight factors significantly associated with NSSI in Chinese adolescents. Parent-child relationship and mental health of the only children and left-behind children in China deserve more attention. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019123508.

Respect for Persons in the Psychiatric Treatment of Children and Adolescents.

Child and adolescent psychiatry involves simultaneously balancing duties to various vulnerable parties. Balancing autonomy and protection for adolescents is complex; state laws governing these situations often add confusion. Common prescribing patterns in child psychiatry lack robust evidence, and utilization of stimulants, atypical antipsychotics, and polypharmacy has skyrocketed. Significant concerns about distributive justice arise from alarming patterns in psychiatric treatment of vulnerable populations, like those affected by poverty, racism, adverse childhood experiences, and certain legal statuses. Principles of justice and respect for persons support the need for safe, adequate, and appropriate psychiatric treatment, including psychosocial interventions and resources, for all children.

The Impact of Social Media on College Mental Health During the COVID-19 Pandemic: a Multinational Review of the Existing Literature.

PURPOSE OF REVIEW: During the COVID-19 pandemic, both social media use and rates of anxiety and depression among college students have increased significantly. This begs the question, what is the relationship between social media use and college student mental health during the COVID-19 pandemic? RECENT FINDINGS: Prior studies have found mixed results regarding the relationship between social media use and college student mental health. This relationship has become increasingly complex during the COVID-19 pandemic. We found that excessive or problematic social media use during the COVID-19 pandemic was correlated with worse mental health outcomes that could be mitigated by dialectical thinking, optimism, mindfulness, and cognitive reappraisal. The COVID-19 pandemic acts as a moderator by strengthening the relationship between social media use and mental health. Future studies should consider the impact of social media on college student mental health and concentrate on intervention initiatives to ensure the psychological well-being of college students during a global pandemic outbreak.

Recurrence risk of occult micrometastases and isolated tumor cells in early stage endometrial cancer: A case control study.

OBJECTIVES: To determine whether previously undetected occult micrometastasis (MM) or isolated tumor cells (ITC) is associated with increased recurrence odds in stage I-II endometrioid adenocarcinoma. METHODS: Women with recurrent stage I/II EC who had complete pelvic and para-aortic were identified as the outcome of interest. A case-control study was designed with the exposure defined as occult MM/ITC not seen on original nodal pathology. Controls were found by frequency-matching in a 1:2 case control ratio. Original nodal slides were re-reviewed, stained and tested with immunohistochemical to detect occult MM/ITC and the odds of associated recurrence was calculated. RESULTS: Of 153 included, 50 with and 103 without recurrence, there was no difference in age (p = 0.46), race (p = 0.24), stage (p = 0.75), FIGO grade (p = 0.64), lymphovascular space invasion (LVSI); p = 1.00, or GOG 99 high-intermediate risk (HIR) criteria (p = 0.35). A total of 18 ITC (11.8%) and 3 MM (2.0%) not previously identified were found in 19 patients. Finding occult MM/ITC was not associated with more lymph nodes (LN) removed (p = 0.67) or tumor grade (p = 0.48) but was significantly associated with stage (p < 0.01). LVSI (p = 0.09) and meeting high-intermediate risk criteria (p = 0.09), were closely associated but not statistically significant. Isolated ITC were not associated with increased odds for recurrence (OR 0.71, CL: 0.20 - 2.22, p = 0.57), recurrence free survival (RFS) (p = 0.85) or overall survival (OS) (p = 0.92). CONCLUSIONS: In early-stage EC, identification of occult MM or ITC is uncommon and associated with stage. The presence of ITC was not associated with increased odds of recurrence. Adjusting stage or treatment may avoided based on ITC alone. Isolated MM were rare in our population, and further investigation is warranted.

CaV ß controls the endocytic turnover of CaV 1.2 L-type calcium channel.

Membrane depolarization activates the multisubunit CaV 1.2 L-type calcium channel initiating various excitation coupling responses. Intracellular trafficking into and out of the plasma membrane regulates the channel's surface expression and stability, and thus, the strength of CaV 1.2-mediated Ca2+ signals. The mechanisms regulating the residency time of the channel at the cell membrane are unclear. Here, we coexpressed the channel core complex CaV 1.2α1 pore-forming and auxiliary CaV ß subunits and analyzed their trafficking dynamics from single-particle-tracking trajectories. Speed histograms obtained for each subunit were best fitted to a sum of diffusive and directed motion terms. The same mean speed for the highest-mobility state underlying directed motion was found for all subunits. The frequency of this component increased by covalent linkage of CaV ß to CaV 1.2α1 suggesting that high-speed transport occurs in association with CaV ß. Selective tracking of CaV 1.2α1 along the postendocytic pathway failed to show the highly mobile state, implying CaV ß-independent retrograde transport. Retrograde speeds of CaV 1.2α1 are compatible with myosin VI-mediated backward transport. Moreover, residency time at the cell surface was significantly prolonged when CaV 1.2α1 was covalently linked to CaV ß. Thus, CaV ß promotes fast transport speed along anterograde trafficking and acts as a molecular switch controlling the endocytic turnover of L-type calcium channels.

Cooperation between Different CRISPR-Cas Types Enables Adaptation in an RNA-Targeting System.

CRISPR-Cas immune systems adapt to new threats by acquiring new spacers from invading nucleic acids such as phage genomes. However, some CRISPR-Cas loci lack genes necessary for spacer acquisition despite variation in spacer content between microbial strains. It has been suggested that such loci may use acquisition machinery from cooccurring CRISPR-Cas systems within the same strain. Here, following infection by a virulent phage with a double-stranded DNA (dsDNA) genome, we observed spacer acquisition in the native host Flavobacterium columnare that carries an acquisition-deficient CRISPR-Cas subtype VI-B system and a complete subtype II-C system. We show that the VI-B locus acquires spacers from both the bacterial and phage genomes, while the newly acquired II-C spacers mainly target the viral genome. Both loci preferably target the terminal end of the phage genome, with priming-like patterns around a preexisting II-C protospacer. Through gene deletion, we show that the RNA-cleaving VI-B system acquires spacers in trans using acquisition machinery from the DNA-cleaving II-C system. Our observations support the concept of cross talk between CRISPR-Cas systems and raise further questions regarding the plasticity of adaptation modules.IMPORTANCE CRISPR-Cas systems are immune systems that protect bacteria and archaea against their viruses, bacteriophages. Immunity is achieved through the acquisition of short DNA fragments from the viral invader's genome. These fragments, called spacers, are integrated into a memory bank on the bacterial genome called the CRISPR array. The spacers allow for the recognition of the same invader upon subsequent infection. Most CRISPR-Cas systems target DNA, but recently, systems that exclusively target RNA have been discovered. RNA-targeting CRISPR-Cas systems often lack genes necessary for spacer acquisition, and it is thus unknown how new spacers are acquired and if they can be acquired from DNA phages. Here, we show that an RNA-targeting system "borrows" acquisition machinery from another CRISPR-Cas locus in the genome. Most new spacers in this locus are unable to target phage mRNA and are therefore likely redundant. Our results reveal collaboration between distinct CRISPR-Cas types and raise further questions on how other CRISPR-Cas loci may cooperate.

College student mental health risks during the COVID-19 pandemic: Implications of campus relocation.

PURPOSE: During the COVID-19 pandemic, many universities evacuated their campuses, requiring students to vacate on campus residences. The psychological outcomes of students who relocated during the pandemic remains unknown. We examined mandated relocation experiences related to self-reported worry, grief, loneliness, and depressive, generalized anxiety, and post-traumatic stress disorder (PTSD) symptoms among college students during the COVID-19 pandemic. METHODS: We analyzed cross-sectional survey data obtained from April 9 to August 4, 2020 on 791 young adults (ages 18-30 years) who were enrolled at a U.S. university. The CARES 2020 Project (COVID-19 Adult Resilience Experiences Study) is an online survey of young adults' mental health during the COVID-19 pandemic. Recruitment relied on snowball sampling. Participants were asked if they were required to relocate from campus and among those who did, their experiences in moving. COVID-19-related worry and grief, loneliness, and depressive, anxiety, and PTSD symptoms were assessed. RESULTS: Approximately one-third of students reported being mandated to relocate. Students mandated to relocate reported more COVID-19-related grief, loneliness, and generalized anxiety symptoms compared to those who did not even after controlling for the severity level of local COVID-19 outbreaks. Students who had to leave behind valuable personal belongings reported more COVID-19-related worries, grief, and depressive, generalized anxiety, and PTSD symptoms. CONCLUSIONS: Students who were mandated to relocate reported worse psychological outcomes compared to students who were not mandated to relocate. Our findings have implications for addressing the psychological impact of evacuating college campuses during public health emergencies and other disasters.