Predictors and Etiologies of Clinical Relapse Among Patients With Ulcerative Colitis in Deep Remission.

GOAL: The objective of this study was to evaluate for potential predictors and etiologies of clinical relapse among patients with ulcerative colitis in deep remission. BACKGROUND: Patients displaying deep (endoscopic and histologic) remission have a decreased cumulative risk of relapse in ulcerative colitis of <10% per year, but predictors and etiologies of relapse in this population are poorly understood. MATERIALS AND METHODS: We performed a retrospective cohort study utilizing electronic medical records at Tufts Medical Center to identify patients in deep remission, classified as having both endoscopic remission (Mayo Endoscopic Score of 0 or 1) and histologic remission (Simplified Geboes Score 0.2). We evaluated the cumulative risk of clinical relapse following attainment of deep remission and examined predictors and etiologies of relapse. RESULTS: Among 139 patients with ulcerative colitis in deep remission, the cumulative risk of relapse was <10% and <20% at 1 and 2 years. Patients with complete normalization of mucosa (Geboes=0) and normalization of C-reactive protein (<7.48 mg/dL) at the time of remission were associated with a lower risk of relapse. Discontinuation of therapy was the most commonly identified etiology of relapse. CONCLUSIONS: Patients in deep remission have a 1-year risk of clinical relapse of <10%, with those demonstrating a non-normalized mucosa or elevated C-reactive protein predictive of persistent relapse risk. Discontinuation of therapy or minor histologic changes may drive relapse among those in deep remission.

Lymphocytic Choriomeningitis Virus in Person Living with HIV, Connecticut, USA, 2021.

Lymphocytic choriomeningitis virus is an underreported cause of miscarriage and neurologic disease. Surveillance remains challenging because of nonspecific symptomatology, inconsistent case reporting, and difficulties with diagnostic testing. We describe a case of acute lymphocytic choriomeningitis virus disease in a person living with HIV in Connecticut, USA, identified by using quantitative reverse transcription PCR.

Inhaled Bacteriophage Therapy for Multi-Drug Resistant Achromobacter.

The rise of antimicrobial resistant (AMR) bacteria is a global public health threat. AMR Achromobacter bacteria pose a challenging clinical problem, particularly for those with cystic fibrosis (CF) who are predisposed to chronic bacterial lung infections. Lytic bacteriophages (phages) offer a potential alternative to treat AMR infections, with the possible benefit that phage selection for resistance in target bacteria might coincide with reduced pathogenicity. The result is a genetic "trade-off," such as increased sensitivity to chemical antibiotics, and/or decreased virulence of surviving bacteria that are phage resistant. Here, we show that two newly discovered lytic phages against Achromobacter were associated with stabilization of respiratory status when deployed to treat a chronic pulmonary infection in a CF patient using inhaled (nebulized) phage therapy. The two phages demonstrate traits that could be generally useful in their development as therapeutics, especially the possibility that the phages can select for clinically useful trade-offs if bacteria evolve phage resistance following therapy. We discuss the limitations of the current study and suggest further work that should explore whether the phages could be generally useful in targeting pulmonary or other Achromobacter infections in CF patients.

A Trichomonas vaginalis Rhomboid Protease and Its Substrate Modulate Parasite Attachment and Cytolysis of Host Cells.

Trichomonas vaginalis is an extracellular eukaryotic parasite that causes the most common, non-viral sexually transmitted infection worldwide. Although disease burden is high, molecular mechanisms underlying T. vaginalis pathogenesis are poorly understood. Here, we identify a family of putative T. vaginalis rhomboid proteases and demonstrate catalytic activity for two, TvROM1 and TvROM3, using a heterologous cell cleavage assay. The two T. vaginalis intramembrane serine proteases display different subcellular localization and substrate specificities. TvROM1 is a cell surface membrane protein and cleaves atypical model rhomboid protease substrates, whereas TvROM3 appears to localize to the Golgi apparatus and recognizes a typical model substrate. To identify TvROM substrates, we interrogated the T. vaginalis surface proteome using both quantitative proteomic and bioinformatic approaches. Of the nine candidates identified, TVAG_166850 and TVAG_280090 were shown to be cleaved by TvROM1. Comparison of amino acid residues surrounding the predicted cleavage sites of TvROM1 substrates revealed a preference for small amino acids in the predicted transmembrane domain. Over-expression of TvROM1 increased attachment to and cytolysis of host ectocervical cells. Similarly, mutations that block the cleavage of a TvROM1 substrate lead to its accumulation on the cell surface and increased parasite adherence to host cells. Together, these data indicate a role for TvROM1 and its substrate(s) in modulating attachment to and lysis of host cells, which are key processes in T. vaginalis pathogenesis.

Dorsal versus lateral plate fixation of finger proximal phalangeal fractures: a retrospective study.

INTRODUCTION: Unstable proximal phalanx fractures are relatively common injuries but consensus of standard treatment is lacking. Outcomes following plate fixation are highly variable, and it remains unclear which factors are predictive for poorer results. The purpose of this study was to compare dorsal and lateral plate fixation of finger proximal phalangeal fractures with regard to factors that influence the outcome. MATERIALS AND METHODS: A retrospective chart review of proximal phalanx fractures treated with dorsal and lateral plating over a 6-year study interval was performed. Demographic data and injury-specific factors were obtained from review of clinic and therapy notes of 42 patients. Fractures were classified based on the OTA classification using preoperative radiographs. Outcomes investigated included final range of motion (ROM) and total active motion (TAM) of all finger joints. Complications and revision surgeries were also analyzed. RESULTS: Fracture comminution, dorsal and a lateral plate position, occupational therapy, and demographic factors did not significantly influence the outcome, complication, and revision rate after plate fixation of finger proximal phalangeal fractures. CONCLUSIONS: Based on the results of this study, no differences in the outcome of finger proximal phalangeal fractures treated by both dorsal and lateral plate fixation were observed. LEVEL OF EVIDENCE: Therapeutic, retrospective comparative, level III.

Borrelia miyamotoi Meningoencephalitis in an Immunocompetent Patient.

Borrelia miyamotoi is an underdiagnosed cause of tick-borne illness in endemic regions and, in rare cases, causes neurological disease in immunocompetent patients. Here, we present a case of serologically confirmed Borrelia miyamotoi meningoencephalitis in an otherwise healthy patient who rapidly improved following initiation of antibiotic therapy.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ~6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report.

SARS-CoV-2 remdesivir resistance mutations have been generated in vitro but have not been reported in patients receiving treatment with the antiviral agent. We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding. Whole genome sequencing identified a mutation, E802D, in the nsp12 RNA-dependent RNA polymerase, which was not present in pre-treatment specimens. In vitro experiments demonstrated that the mutation conferred a ∼6-fold increase in remdesivir IC50 but resulted in a fitness cost in the absence of remdesivir. Sustained clinical and virologic response was achieved after treatment with casirivimab-imdevimab. Although the fitness cost observed in vitro may limit the risk posed by E802D, this case illustrates the importance of monitoring for remdesivir resistance and the potential benefit of combinatorial therapies in immunocompromised patients with SARS-CoV-2 infection.

Possible GoLytely-Associated Cardiac Arrest: A Case Report and Literature Review.

PURPOSE: To report a case of sudden cardiac arrest possibly associated with the administration of GoLytely® (polyethylene glycol 3350 and electrolytes). SUMMARY: A 60-year-old male with a history of hypertension, hyperlipidemia, type 2 diabetes, and coronary artery disease presented to the emergency department with complaints of constipation and lower abdominal pain over the past week, and the inability to urinate over the past day. The patient had received GoLytely as treatment to alleviate symptoms of constipation and abdominal pain. However, several hours after administration of the bowel prep solution, the patient suffered an episode of cardiac arrest. After ruling out other possible etiologies, GoLytely was suspected as a possible cause of cardiac arrest. The patient had suffered an anoxic brain injury and remained intubated and unconscious until he eventually expired, 20 days after the event. CONCLUSION: Although GoLytely appears to be a safe agent with fewer side effects, clinicians need to be mindful of potential life-threatening adverse events following GoLytely administration and monitor patients closely during and after administration.

Designed Parasite-Selective Rhomboid Inhibitors Block Invasion and Clear Blood-Stage Malaria.

Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites.

Role of APOBEC3G/F-mediated hypermutation in the control of human immunodeficiency virus type 1 in elite suppressors.

While many studies show that the APOBEC3 family of cytidine deaminases can inhibit human immunodeficiency virus type 1 (HIV-1) replication, the clinical significance of this host defense mechanism is unclear. Elite suppressors are HIV-1-infected individuals who maintain viral loads below 50 copies/ml without antiretroviral therapy. To determine the role of APOBEC3G/F proteins in the control of viremia in these patients, we used a novel assay to measure the frequency of hypermutated proviral genomes. In most elite suppressors, the frequency was not significantly different than that observed in patients on highly active antiretroviral therapy. Thus, enhanced APOBEC3 activity alone cannot explain the ability of elite suppressors to control viremia.

Dual Antegrade Intramedullary Headless Screw Fixation for Treatment of Unstable Proximal Phalanx Fractures.

Background: Although intramedullary headless screw (IMHS) fixation is a promising minimally invasive surgical treatment option for unstable proximal phalanx fractures, a single IMHS may provide inadequate fixation for certain fracture patterns. The purpose of this study was to evaluate the short-term clinical outcomes in a pilot series of patients with proximal phalanx fractures treated with dual antegrade IMHS fixation. Methods: We performed a retrospective chart review of proximal phalanx fractures treated with dual antegrade IMHS fixation with a minimum 1 year of follow-up. Demographic information including patient age, sex, occupation, workers' compensation status, mechanism of injury, hand dominance, and injured digit were obtained. Postoperative outcomes measured included range of motion, grip strength, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) outcome scores, return to full-duty work interval, and complications. Results: Ten fractures in 10 patients (4 male, 6 female) satisfied study inclusion. The mean age of patients was 39 years (range, 20-62), and average follow-up duration was 84 weeks (range, 61-106). Final postoperative total active motion was 258° (range, 245°-270°), mean grip strength was 97% (range, 84%-104%) of the uninjured side, and QuickDASH score was 3.9 (range, 0-13.6). No complications occurred, and no patients required additional intervention. Conclusions: Dual antegrade IMHS fixation of proximal phalanx fractures resulted in excellent postoperative motion, near-normal grip strength, positive self-reported patient outcomes, and no complications with follow-up of at least 1 year. Further study in a larger number of patients is warranted to determine if this promising technique is superior to other modes of fixation.

Predictors of abnormal electrocardiograms in the pediatric emergency department.

BACKGROUND: Electrocardiograms (ECGs) are ordered in the pediatric emergency room for a wide variety of chief complaints. OBJECTIVES: Criteria are lacking as to when physicians should obtain ECGs. This study uses a large retrospective cohort of 880 pediatric emergency department (ED) patients to highlight objective criteria including significant medical history and specific vital sign abnormalities to guide clinicians as to which patients might have an abnormal ECG. METHODS: Retrospective review of Pediatric ED charts in all patients aged < 18 years who had ECG performed during ED stay. Pediatric ED physician interpretation of the ECG, clinical data on vital signs and past medical history was collected from the medical record for analysis. RESULTS: Of 880 ECGs performed in the ED, 17.4% were abnormal. When controlled for medical history and demographic differences, abnormal ECGs were associated with age-adjusted abnormal ED vital signs including increased heart rate (odds ratio [OR] 1.85, 95% confidence interval [CI] 1.1-3.09) and increased respiratory rate (OR 1.74, CI 1.42-2.62). In a logistic regression analysis, certain chief complaints and history components were less likely to have abnormal ECGs including complaints of chest pain (OR 0.38, CI 0.18-0.80) and known history of gastrointestinal or respiratory condition (i.e., asthma) (OR 0.48, CI 0.29-0.79). CONCLUSIONS: In this cohort of patients, those with a chief complaint of chest pain or known respiratory conditions and normal age-adjusted vital signs in the ED have low likelihood of an abnormal ECG.

Natural History of New-onset Inflammatory Bowel Disease Among Patients With Multiple Sclerosis.

Patients with MS and IBD were as likely to have stricturing, fistulizing, and extensive IBD as IBD controls. Although MS-IBD patients were less likely to initiate anti-TNF therapy, they did not have worsened risk of progression to surgery on follow-up.

An Aminopeptidase in the Drosophila Testicular Niche Acts in Germline Stem Cell Maintenance and Spermatogonial Dedifferentiation.

Extrinsic cues from the niche are known to regulate adult stem cell self-renewal versus differentiation. Here, we report that an aminopeptidase Slamdance (Sda) acts in the Drosophila testicular niche to maintain germline stem cells (GSCs) and regulate progenitor germ cell dedifferentiation. Mutations in sda lead to dramatic testicular niche deterioration and stem cell loss. Recombinant Sda has specific aminopeptidase activity in vitro, and the in vivo function of Sda requires an intact aminopeptidase domain. Sda is required for accumulation of mature DE-cadherin, and overexpression of DE-cadherin rescues most sda mutant phenotypes, suggesting that DE-cadherin is an important target of Sda. Finally, Sda is both necessary and sufficient to promote dedifferentiation during aging and recovery from genetically manipulated depletion of GSCs. Together, our results suggest that a niche factor promotes both stem cell maintenance and progenitor cell dedifferentiation.

Evolution of an attenuated HIV-1 isolate in an elite suppressor.

Elite controllers or suppressors (ES) control viral replication without antiretroviral therapy. While many ES are infected with replication-competent virus, others have evidence of infection with attenuated isolates. Here we report a case of an ES infected with an HIV-1 isolate that contained a 38-base pair deletion in nef that led to a reading frame shift and a premature stop codon. Interestingly, clones amplified from plasma or cultured from CD4(+) T cells between 2006 and 2008 contained one of two separate compensatory deletions that restored the reading frame. A new insertion generated by duplication of adjacent sequences was found in isolates obtained in 2010 and this evolution was accompanied by the development of low level viremia. This article provides evidence of the evolution of an attenuated HIV-1 isolate toward greater virulence in an elite suppressor.

Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors.

Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who control viremia to levels below the limit of detection of current assays. The mechanisms involved in this control have not been fully elucidated. Several studies have demonstrated that some ES are infected with defective viruses, but it remains unclear whether others are infected with replication-competent HIV-1. To answer this question, we used a sensitive coculture assay in an attempt to isolate replication-competent virus from a cohort of 10 ES. We successfully cultured six replication-competent isolates from 4 of the 10 ES. The frequency of latently infected cells in these patients was more than a log lower than that seen in patients on highly active antiretroviral therapy with undetectable viral loads. Full-length sequencing of all six isolates revealed no large deletions in any of the genes. A few mutations and small insertions and deletions were found in some isolates, but phenotypic analysis of the affected genes suggested that their function remained intact. Furthermore, all six isolates replicated as well as standard laboratory strains in vitro. The results suggest that some ES are infected with HIV-1 isolates that are fully replication competent and that long-term immunologic control of replication-competent HIV-1 is possible.