Some Perceptions Differ, Match Outcomes Do Not: A Multisite Retrospective Cross-Sectional Comparison of Virtual vs. In-Person Recruitment.

BACKGROUND: Virtual interviewing for residency provides considerable savings. Its impact on match outcomes remains unclear. OBJECTIVE: Evaluate the impact of virtual residency recruitment on program and applicant assessment and match outcomes. DESIGN: Cross-sectional survey, September 2020-July 2021 PARTICIPANTS: Faculty interviewers and 2019 and 2020 PGY-1 classes at three academic internal medicine residencies. MAIN MEASURES: Survey items rating effectiveness of interview format, preference for future interview format, and perceived impact on diversity. KEY RESULTS: A total of 247/436 faculty (57%) interviewers responded. Faculty perceived that in-person interviews enhanced applicant assessment (3.23 ± 0.38, p < 0.01) and recruitment of the most qualified applicants (p < 0.01) but did not impact recruitment of a racially or gender diverse class (3.03 ± 0.99, p = 0.95 and 3.09 ± 0.76, p = 0.14 respectively). They also did not demonstrate a preference for future interview formats. A total of 259/364 matched applicants responded, corresponding to a 76% response rate in the in-person cohort and a 66% response rate for virtual. Trainees were equally likely to match at their top choice when interviewing virtually vs. in-person (p = 0.56), and racial/ethnic and gender composition of the incoming class also did not differ (p = 0.81 and p = 0.19 respectively). Trainees perceived many aspects of the institution were better assessed in-person, though the impact varied according to assessment domain. Trainees who interviewed in-person preferred in-person formats. Of those who interviewed virtually, 47% preferred virtual and 54% preferred in-person. There were no predictors of virtual preference for future interview formats. CONCLUSIONS: Faculty and applicants who experienced virtual recruitment had no preference for future recruitment format. Virtual recruitment had no impact on the racial/gender diversity of matched classes or on applicants matching at their top-ranked institution. Institutions should consider the potential non-inferiority of virtual interviews with financial and other benefits when making decisions about future interview formats.

Vitamin D Deficiency (VDD) and Benefits of Supplementation in Veterans with IBS-D.

Many veterans deployed to Gulf War areas suffer from persistent chronic diarrhea that is disabling and affects their quality of life. The causes for this condition have eluded investigators until recently and recent literature has shed light on the effect of vitamin D on the brain-gut axis. This study focused on determining clinical causes contributing to diarrhea and assessed whether reversing the identified causes, specifically vitamin D deficiency (VDD), could reduce the incidence of diarrhea in Gulf War veterans (GWVs). All patients completed a workup that included serologies (IBD, celiac), routine laboratory tests (CBC, chemistry panels, TSH, T4, CRP), cultures for enteric pathogens (C diff, bacteria, viruses, small intestinal bacterial overgrowth (SIBO)), and upper and lower endoscopies with histology and a trial of cholestyramine to exclude choleretic diarrhea and rifaximin for dysbiosis. A total of 4221 veterans were screened for chronic diarrhea, yielding 105 GWVs, of which 69 GWVs had irritable bowel syndrome with diarrhea (IBS-D). Paired t-tests demonstrated that all GWVs had VDD (t-11.62, df68 and sig(2-tailed) 0.0001) (defined as a vitamin D level less than 30 ng/mL with normal ranges of 30-100 ng/mL) but no positive serologies, inflammatory markers, abnormal endoscopies, cultures, or histology to explain their persistent diarrhea. There was no correlation with age, BMI, or inflammation. Some zip codes had a higher frequency of GWVs with VDD, but the number of deployments had no impact. Treatment with vitamin D supplementation (3000-5000 units), given in the morning, based on weight, reduced the number of bowel movements per day (p < 0.0001) without causing hypercalcemia. We suggest that VDD is important in the etiology of IBS-D in GWVs and that vitamin D supplementation significantly reduces diarrhea.

Cas13d-mediated isoform-specific RNA knockdown with a unified computational and experimental toolbox.

Alternative splicing is an essential mechanism for diversifying proteins, in which mature RNA isoforms produce proteins with potentially distinct functions. Two major challenges in characterizing the cellular function of isoforms are the lack of experimental methods to specifically and efficiently modulate isoform expression and computational tools for complex experimental design. To address these gaps, we developed and methodically tested a strategy which pairs the RNA-targeting CRISPR/Cas13d system with guide RNAs that span exon-exon junctions in the mature RNA. We performed a high-throughput essentiality screen, quantitative RT-PCR assays, and PacBio long read sequencing to affirm our ability to specifically target and robustly knockdown individual RNA isoforms. In parallel, we provide computational tools for experimental design and screen analysis. Considering all possible splice junctions annotated in GENCODE for multi-isoform genes and our gRNA efficacy predictions, we estimate that our junction-centric strategy can uniquely target up to 89% of human RNA isoforms, including 50,066 protein-coding and 11,415 lncRNA isoforms. Importantly, this specificity spans all splicing and transcriptional events, including exon skipping and inclusion, alternative 5' and 3' splice sites, and alternative starts and ends.

Synthetic α-Helical Nanopore Reactor for Chemical Sensing.

The use of nanopores for the single-molecule sensing of folded proteins and biomacromolecules has recently gained attention. Here, we introduce a simplified synthetic α-helical transmembrane pore, pPorA, as a nanoreactor and sensor that exhibits functional versatility comparable to that of engineered protein and DNA nanopores. The pore, built from the assembly of synthetic 40-amino-acid-long peptides, is designed to contain cysteine residues within the lumen and at the pore terminus for site-specific chemical modification probed using single-channel electrical recordings. The reaction of the pore with differently charged activated thiol reagents was studied, wherein positively charged reagents electrophoretically driven into the pore resulted in pore blocking in discrete steps upon covalent bond formation. The asymmetric blockage patterns resulting from cis and trans-side addition of reagents reveal the pore orientation in the lipid membrane. Furthermore, activated PEG thiols covalently blocked the pores over a longer duration in a charge-independent manner, establishing the large diameter and orientation of the formed pores. While the covalent binding of thiol reagents caused a drop in the pore conductance, cationic cyclic octasaccharides produced time-resolved translocation events, confirming the structural flexibility and tunability of the pores. The ability of the pore to accommodate large analytes and the considerable current amplitude variation following bond formation events are promising for developing platforms to resolve multistep chemical reactions at the single-molecule level for applications in synthetic nanobiotechnology.

Recent advances in BCRP-induced breast cancer resistance treatment with marine-based natural products.

Breast cancer is the prominent cause of cancer-related death in women globally in terms of incidence and mortality. Despite, recent advances in the management of breast cancer, there are still a lot of cases of resistance to medicines, which is currently one of the biggest problems faced by researchers across the globe. Out of several mechanisms, breast cancer resistance protein (BCRP) arbitrated drug resistance is a major concern. Hormonal, cytotoxic and immunotherapeutic drugs are used in the systemic therapy of breast cancer. It is vital to choose drugs based on the clinical and molecular attributes of the tumor to provide better treatment with greater efficacy and minimal harm. Given the aforementioned necessity, the use of marine flora in treating breast cancer cannot be neglected. The scientists also stressed the value of marine-derived goods in avoiding breast cancer resistance. Future research into the identification of anticancer drugs will heavily draw upon the marine environment's ample supply of marine-derived natural products (MNPs), which have a wide range of biological functions. Cell cycle arrest, induction of apoptosis and anti-angiogenic, anti-proliferative and anti-metastasis actions are all part of their processes. The overview of breast cancer, the mechanisms underlying its resistance, recent clinical trials based on marine-derived products in breast cancer and the use of marine products in the treatment of breast cancer are highlighted in this paper. Moreover, the authors also emphasised the importance of marine-derived products in preventing breast cancer resistance.

Strategic Management of Bleeding Small Bowel Gastrointestinal Angiodysplasias (GIADs): A 12 Year Retrospective Review in a Veteran Population and Cost Comparison.

BACKGROUND: Gastrointestinal angiodysplasias (GIADs), also known as gastrointestinal angioectasias, are dilated, abnormally thin-walled blood vessels that occur in the mucosa and submucosa throughout the gastrointestinal tract. As a common cause of small bowel bleeding, GIADs have a significant impact on patient's morbidity and healthcare costs. Presently, somatostatin has been used widely to treat GIADs, but it is unclear if other therapies are as beneficial and cost-effective as somatostatin in managing GIADs. (2) Methods: A retrospective chart review was performed, which included subjects treated with Lanreotide, a somatostatin analog, and other therapies at the VA Loma Linda Healthcare System (VALLHCC) from January 2006 to December 2018. Patients who had symptomatic GIADs were detected by video capsule endoscopy (VCE), a device-assisted enteroscopy (DAE) or, in our case, push enteroscopy (PE) with an Endocuff. (3) Results: Three hundred twelve patients were diagnosed with GIADs. In this group of patients, 72 underwent ablation (endoscopic BICAP) with the addition of Lanreotide (SST), 63 underwent ablation therapy, eight were treated with SST only, 128 received iron replacement only, 25 received iron plus SST therapy, and 61 were observed with no therapy. Each group was followed via their hemoglobin (Hgb) level immediately thereafter, and Hgb levels were then obtained every 3 months for a 12-month period. After ablation therapy, 63 patients maintained stable Hgb levels over the course of the study, suggesting a significant therapeutic effect by controlling active bleeding. The 27 patients receiving ablation +SST therapy did not show improvements when compared to ablation only and the 128 patients who received iron therapy alone. (4) Conclusions: Importantly, 12 years of managing these patients has given us a cost- and time-sensitive strategy to maintain the patients' Hgb levels and avoid hospital admissions for acute bleeding. Iron treatment alone is effective compared to SST treatment in recovering from GIADs. Eliminating SST treatment from therapeutic intervention would save $89,100-445,550 per patient, depending on the number of doses for private care patients and $14,286-28,772 for VA patients, respectively. A suggested therapy would be to perform DAE on actively bleeding patients, ablate the lesions using a coagulation method, and place the patient on iron. If that fails, gastroenterologists should repeat VCE and perform either PE with Endocuff or balloon enteroscopy (all DAEs).

Electrostatic Filtering of Polypeptides Through Membrane Protein Pores.

Naturally-occurring membrane proteins have been engineered as nanopore sensors for the single-molecule detection of various biochemical molecules. Here, we present a natural bacterial porin, CymA containing a dynamic component and densely packed charged residues in the pore, shaping a unique structural conformation and charge feature. Using single-channel recordings, we investigated the translocation of charged polypeptides through native CymA and truncated CymA lacking the dynamic element. Cationic polypeptides bind to the pore with high affinity, specifically at low salt conditions indicating an electrostatic charge and voltage-dependent translocation. Anionic peptides did not bind to the pore, confirming the selective binding of polypeptides with the pore due to their specific charge distribution. Further, the distinct peptide translocation kinetics between native and truncated indicated the role of the dynamic segment in molecular transport. We suggest that these natural membrane pores that permit the selective translocation of cationic polypeptides are advantageous for nanopore proteomics applications.

Assembly of transmembrane pores from mirror-image peptides.

Tailored transmembrane alpha-helical pores with desired structural and functional versatility have promising applications in nanobiotechnology. Herein, we present a transmembrane pore DpPorA, based on the natural pore PorACj, built from D-amino acid α-helical peptides. Using single-channel current recordings, we show that DpPorA peptides self-assemble into uniform cation-selective pores in lipid membranes and exhibit properties distinct from their L-amino acid counterparts. DpPorA shows resistance to protease and acts as a functional nanopore sensor to detect cyclic sugars, polypeptides, and polymers. Fluorescence imaging reveals that DpPorA forms well-defined pores in giant unilamellar vesicles facilitating the transport of hydrophilic molecules. A second D-amino acid peptide based on the polysaccharide transporter Wza forms transient pores confirming sequence specificity in stable, functional pore formation. Finally, molecular dynamics simulations reveal the specific alpha-helical packing and surface charge conformation of the D-pores consistent with experimental observations. Our findings will aid the design of sophisticated pores for single-molecule sensing related technologies.

Genome-wide association and multi-omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women.

INTRODUCTION: Variants in the tau gene (MAPT) region are associated with breast cancer in women and Alzheimer's disease (AD) among persons lacking apolipoprotein E ε4 (ε4-). METHODS: To identify novel genes associated with tau-related pathology, we conducted two genome-wide association studies (GWAS) for AD, one among 10,340 ε4- women in the Alzheimer's Disease Genetics Consortium (ADGC) and another in 31 members (22 women) of a consanguineous Hutterite kindred. RESULTS: We identified novel associations of AD with MGMT variants in the ADGC (rs12775171, odds ratio [OR] = 1.4, P = 4.9 × 10-8 ) and Hutterite (rs12256016 and rs2803456, OR = 2.0, P = 1.9 × 10-14 ) datasets. Multi-omics analyses showed that the most significant and largest number of associations among the single nucleotide polymorphisms (SNPs), DNA-methylated CpGs, MGMT expression, and AD-related neuropathological traits were observed among women. Furthermore, promoter capture Hi-C analyses revealed long-range interactions of the MGMT promoter with MGMT SNPs and CpG sites. DISCUSSION: These findings suggest that epigenetically regulated MGMT expression is involved in AD pathogenesis, especially in women.

The Impact of Virtual Interviews on Recruitment in Hospice and Palliative Medicine Fellowship Training.

CONTEXT: The ongoing COVID-19 pandemic has led many leaders to reassess how recruitment into the medical field is conducted. In Hospice and Palliative Medicine, many training programs are moving to virtual recruitment as a more permanent strategy. However, virtual recruitment disproportionately affects smaller training programs as well as those in smaller cities or those whose location is less well-known. OBJECTIVES: To assess faculty perspective regarding the value of virtual vs. face-to-face recruitment methods in a well-established program located in a mid-sized city that is lesser known than many comparable programs. METHODS: After virtual recruitment season in 2020, we assessed our faculty regarding the process of virtual interviews. Survey items were based on results of the 2020 NRMP Internal Medicine Program Director Survey to include the most highly cited factors used to rank internal medicine applicants. Faculty was asked whether virtual or face-to-face interviews were more effective and were asked to make an overall choice between face to face and virtual recruitment formats and to explain the reason behind their decision. RESULTS: Twenty-three faculty received the survey and 17 completed. Although more faculty felt that in-person interviews allowed for better ability to recruit the most qualified trainees than virtual interviews, nine out of the 17 faculty chose virtual as their preferred format. CONCLUSION: While acknowledging benefits that can only be achieved in-person, our faculty believe that virtual interviews for future Hospice and Palliative Medicine fellows is an effective and potentially advantageous way to recruit the future work force of Hospice and Palliative Medicine.

Encapsulation of Trimethine Cyanine in Cucurbit[8]uril: Solution versus Solid-State Inclusion Behavior.

Inclusion of polymethine cyanine dyes in the cavity of macrocyclic receptors is an effective strategy to alter their absorption and emission behavior in aqueous solution. In this paper, the effect of the host-guest interaction between cucurbit[8]uril (CB[8]) and a model trimethine indocyanine (Cy3) on dye spectral properties and aggregation in water is investigated. Solution studies, performed by a combination of spectroscopic and calorimetric techniques, indicate that the addition of CB[8] disrupts Cy3 aggregates, leading to the formation of a 1 : 1 host-guest complex with an association constant of 1.5×106  M-1 . At concentrations suitable for NMR experiments, the slow formation of a supramolecular polymer was observed, followed by precipitation. Single crystals X-ray structure elucidation confirmed the formation of a polymer with 1 : 1 stoichiometry in the solid state.

Endocuff-assisted push enteroscopy increases the detection of proximal small-bowel gastrointestinal angiodysplasias.

Gastrointestinal angiodysplasias (GIADs) are the most common causes for suspected small bowel bleeding. Fifty percent of GIADs do not need treatment due to bleeding cessation, while 45% have high re-bleeding rates, that significantly impact patient outcome and health resource utilization. We suspected that this high re-bleeding rate occurs because not all lesions are detected with present standard of care. This study evaluates whether device-assisted enteroscopy (DAE) utilizing the Endocuff (EC) device could improve GIAD detection. A retrospective chart review of a prospective data collection was performed from January 2006 to December 2018 at VA Loma Linda Healthcare System (VALLHCS) on both inpatients and outpatients referred for active and chronic suspected small bowel bleeding. The patients were initially monitored for bleeding lesions via video capsule endoscopy (VCE) after negative upper and lower endoscopy. GIADs observed between 0% to 40% small bowel transit time (SBTT) were referred for push enteroscopy (PE) with and without (±) the EC device. Twenty-five consecutive patients underwent PE ± EC. No patient had VCE done after PE ± EC. Using PE-EC, GIADs were detected in 9 of 25 (36%) of patients. Importantly, PE+EC detected GIADs in 23 of 25 (92%) patients. The sum of GIADs detected without EC was 26 ± 0.06 vs. 112 ± 0.2 using EC. The average detection rate for PE without EC was significantly lower (1.04 ± 0.06, mean ± SE) as compared to PE with EC (4.48 ± 0.23, mean ± SE, p<0.0005). Additionally, a positive correlation (r=0.51) between capsule enteroscopy (CE) location of GIADs and SBTT was found. The EC device increases the detection of GIADs in the proximal small bowel. We also reconfirm that the location of bleeding GIADs are within the reach of the push enteroscope (PE). Finally, PE + EC may also reduce GIAD miss rates, which may play a role in the reduction of re-bleeding episodes.

Residency and Fellowship Program Leaders' Perceptions of Virtual Recruitment and Interviewing.

Background: Virtual recruitment is a new and more cost-effective alternative to traditional in-person recruitment in academic medicine. However, little is known about the perceived repercussions of the switch across a variety of training settings. Objective: To describe the perceptions of graduate medical education program leaders about virtual matching and preferred format for future recruitment within an integrated health care delivery system sponsoring residency and fellowship programs at both university- and community-based primary teaching sites. Methods: We surveyed program leadership of 136 Accreditation Council for Graduate Medical Education programs at a single sponsoring institution in April 2021, following residency match results but before matched applicants began programs. The 40-item survey pertained to various aspects of recruitment. Select questions were assessed using a 5-point Likert scale. Descriptive statistics, Student's t test, and ordinal linear regression models were used for analysis. Results: Out of 136 programs, 129 (94.8%) responded. Overall, preferred format for recruitment was neutral, although there was wide heterogeneity of responses. Programs felt that virtual recruitment marginally decreased their ability to describe strengths but did not affect the strength or diversity of their matched class. Community sites preferred in-person recruitment. Conclusions: Programs did not perceive that virtual recruitment affected the strength or diversity of their 2021 matched class, although community programs were more likely to prefer in-person formats.

Transient dormant monomer states for supramolecular polymers with low dispersity.

Temporally controlled cooperative and living supramolecular polymerization by the buffered release of monomers has been recently introduced as an important concept towards obtaining monodisperse and multicomponent self-assembled materials. In synthetic, dynamic supramolecular polymers, this requires efficient design strategies for the dormant, inactive states of the monomers to kinetically retard the otherwise spontaneous nucleation process. However, a generalized design principle for the dormant monomer states to expand the scope of precision supramolecular polymers has not been established yet, due to the enormous differences in the mechanism, energetic parameters of self-assembly and monomer exchange dynamics of the diverse class of supramolecular polymers. Here we report the concept of transient dormant states of monomers generated by redox reactions as a predictive general design to achieve monodisperse supramolecular polymers of electronically active, chromophoric or donor-acceptor, monomers. The concept has been demonstrated with charge-transfer supramolecular polymers with an alternating donor-acceptor sequence.

Chiral Plasmons: Au Nanoparticle Assemblies on Thermoresponsive Organic Templates.

Template-assisted strategies are widely used to fabricate nanostructured materials. By taking these strategies a step forward, herein we report the design of two chiral plasmonic nanostructures based on Au nanoparticle (NP) assemblies organized in clockwise and anticlockwise directions, having opposite response to circularly polarized light. The chiral plasmonic nanostructures are obtained by growing Au NPs on chiral templates based on d- and l-forms of alanine functionalized phenyleneethynylenes. Interestingly, Au NP assemblies show mirror symmetrical electronic circular dichroism (ECD) bands at their surface plasmon frequency originating through their asymmetric organization. Upon increasing the temperature, the chiral templates dissociate as evident from the disappearance of their ECD signal. The profound advantage of the thermoresponsive nature of the templates is employed to obtain free-standing chiral plasmonic nanostructures. The tilt angle high-resolution transmission electron microscopic measurements indicate that the NP assemblies, grown on a template based on the d-isomer, organize in clockwise direction ( P-form) and on l-isomer in anticlockwise direction ( M-form). The inherent chirality prevailing on the surface of the template drives the helical growth of the Au NPs in opposite directions. Experimental results are rationalized by a model which accounts for the large polarizability of Au NPs. The large polarizability leads to large oscillating dipole moments whose effects become prominent when interparticle distances are comparable to the particle size.

Proteomic Analysis and Immuno-Profiling of Eastern India Russell's Viper ( Daboia russelii) Venom: Correlation between RVV Composition and Clinical Manifestations Post RV Bite.

The proteomes of Russell's viper venom (RVV) from Burdwan (RVV B) and Nadia (RVV N), the two districts of West Bengal, eastern India (EI), were investigated by gel-filtration chromatography (GFC) followed by tandem mass spectrometry of tryptic fragments of the fractions. A total of 73 and 69 proteins belonging to 15 snake venom protein families were identified in RVV B and RVV N, respectively, by MS/MS search against Viperidae (taxid 8689) protein entries of the nonredundant NCBI database. The minor differences in venom composition of both the EI RV were established unequivocally by their biochemical and pharmacological properties and by SDS-PAGE, gel filtration chromatography, and LC-MS/MS analyses. The composition of EI RVVs was well correlated with published reports on the pathophysiology of RV-envenomed patients from this part of the country. Venom-antivenom cross-reactivity determined by ELISA, Western blotting, and antivenomics approaches demonstrated poor recognition of low molecular mass (<20 kDa) RVV proteins by commercial polyvalent antivenoms, which was substantiated by neutralization of RVV enzymes by antivenom.

Disrupting Dimerization Translocates Soluble Epoxide Hydrolase to Peroxisomes.

The epoxyeicosatrienoic acid (EET) neutralizing enzyme soluble epoxide hydrolase (sEH) is a neuronal enzyme, which has been localized in both the cytosol and peroxisomes. The molecular basis for its dual localization remains unclear as sEH contains a functional peroxisomal targeting sequence (PTS). Recently, a missense polymorphism was identified in human sEH (R287Q) that enhances its peroxisomal localization. This same polymorphism has also been shown to generate weaker sEH homo-dimers. Taken together, these observations suggest that dimerization may mask the sEH PTS and prevent peroxisome translocation. In the current study, we test the hypothesis that dimerization is a key regulator of sEH subcellular localization. Specifically, we altered the dimerization state of sEH by introducing substitutions in amino acids responsible for the dimer-stabilizing salt-bridge. Green Fluorescent Protein (GFP) fusions of each of mutants were co-transfected into mouse primary cultured cortical neurons together with a PTS-linked red fluorescent protein to constitutively label peroxisomes. Labeled neurons were analyzed using confocal microscopy and co-localization of sEH with peroxisomes was quantified using Pearson's correlation coefficient. We find that dimer-competent sEH constructs preferentially localize to the cytosol, whereas constructs with weakened or disrupted dimerization were preferentially targeted to peroxisomes. We conclude that the sEH dimerization status is a key regulator of its peroxisomal localization.