Discovery of NRG1-VII: the myeloid-derived class of NRG1.

The growth factor Neuregulin-1 (NRG1) has pleiotropic roles in proliferation and differentiation of the stem cell niche in different tissues. It has been implicated in gut, brain and muscle development and repair. Six isoform classes of NRG1 and over 28 protein isoforms have been previously described. Here we report a new class of NRG1, designated NRG1-VII to denote that these NRG1 isoforms arise from a myeloid-specific transcriptional start site (TSS) previously uncharacterized. Long-read sequencing was used to identify eight high-confidence NRG1-VII transcripts. These transcripts presented major structural differences from one another, through the use of cassette exons and alternative stop codons. Expression of NRG1-VII was confirmed in primary human monocytes and tissue resident macrophages and induced pluripotent stem cell-derived macrophages (iPSC-derived macrophages). Isoform switching via cassette exon usage and alternate polyadenylation was apparent during monocyte maturation and macrophage differentiation. NRG1-VII is the major class expressed by the myeloid lineage, including tissue-resident macrophages. Analysis of public gene expression data indicates that monocytes and macrophages are a primary source of NRG1. The size and structure of class VII isoforms suggests that they may be more diffusible through tissues than other NRG1 classes. However, the specific roles of class VII variants in tissue homeostasis and repair have not yet been determined.

Photobiomodulation Treatment with a Home-Use Device for COVID-19: A Randomized Controlled Trial for Efficacy and Safety.

Background: Photobiomodulation therapy (PBMT) using devices to deliver red and/or near-infrared light to tissues has shown promising effects in clinical settings for respiratory diseases, including potential benefits in managing symptoms associated with COVID-19. Objective: To determine if at-home self-administered PBMT for patients with COVID-19 is safe and effective. Methods: This was a randomized controlled trial (RCT) carried out at home during the COVID-19 pandemic (September 2020 to August 2021). The treatment group self-administered the Vielight RX Plus PBMT device (635 nm intranasal and 810 nm chest LEDs) and were monitored remotely. Eligible patients scored 4-7 (out of 7) for severity on the Wisconsin Upper Respiratory Symptom Survey (WURSS-44). Patients were randomized equally to Control group receiving standard-of-care (SOC) only or Treatment group receiving SOC plus PBMT. The device was used for 20 min 2X/day for 5 days and, subsequently, once daily for 30 days. The primary end-point was time-to-recovery (days) based on WURSS-44 question 1, "How sick do you feel today?". Subgroup analysis was performed, and Kaplan-Meier and Cox Proportional Hazards analysis were employed. Results: One hundred and ninety-nine eligible patients (18-65 years old) were divided into two subgroups as follows: 136 patients with 0-7 days of symptoms at baseline and 63 patients with 8-12 days of symptoms. Those with 0-7 days of symptoms at baseline recovered significantly faster with PBMT. The median for Treatment group was 18 days [95% confidence interval (CI), 13-20] versus the Control group 21 days (95% CI, 15-28), p = 0.050. The treatment:control hazard ratio was 1.495 (95% CI, 0.996-2.243), p = 0.054. Patients with symptom duration ≥7 days did not show any significant improvement. No deaths or severe adverse events (SAEs) occurred in the Treatment group, whereas there was 1 death and 3 SAEs requiring hospitalization in the Control group. Conclusions: Patients with ≤7 days of COVID-19 symptoms recovered significantly faster with PBMT compared to SOC. Beyond 7 days, PBMT showed no superiority over SOC. Trial Registration: ClinicalTrials.gov NCT04418505.

Lymphocytic Colitis With Enterocolic Lymphocytic Phlebitis.

Enterocolic lymphocytic phlebitis is a rare lymphocytic vasculitis afflicting the gastrointestinal veins without involving the arterial system. Lymphocytic colitis is a more common pathology described as lymphocytic inflammation of the colonic epithelium. Concurrence of both these pathologies is extremely rare. We describe a 53-year-old man presenting with chronic watery diarrhea, abdominal pain, and weight loss. Colonoscopic examination revealed normal-appearing mucosa, but biopsy findings revealed lymphocytic colitis with coexisting enterocolic lymphocytic phlebitis. The patient was started on oral budesonide and responded to the treatment with symptomatic and histopathological resolution.

Comparing binary & ordinal definitions of urinary & stool continence outcomes: Data from the National Spina Bifida Patient Registry.

INTRODUCTION: The National Spina Bifida Patient Registry (NSBPR) assesses bladder and bowel incontinence using ordinal categories, but prior NSBPR analyses employed binary classification. Our aims were to 1) perform the first NSBPR analysis of bladder and bowel incontinence as ordinal outcomes to compare to the binary definition and subject variables; 2) explore the correlation of incontinence with undergarment usage, and 3) assess incontinence status following continence surgeries. METHODS: Data from NSBPR participants' most recent clinic visit from 2013 to 2020 were analyzed. Ordinal categories of incontinence were compared to previously used binary definitions. Incontinence surgical outcomes were analyzed for those with data at least three months post-operatively. Chi-square tests evaluated associations among categorical variables. Univariate and ordinal logistic regression models were used to test associations of ordinal incontinence status with patient and condition factors. Statistical tests were 2-sided; p values < 0.05 were considered significant. RESULTS: Analysis of 7217 individuals using ordinal incontinence outcomes showed little difference from previously used binary outcomes. The final multivariable logistic regression models with ordinal multinomial outcomes showed that associations of incontinence with age, sex, race/ethnicity, health insurance, level of lesion, and continence management technique were similar to prior studies. Among those reporting never being incontinent of both bladder and bowel, 14% reported using protective undergarments. Of the 500 individuals who had bladder outlet surgery, 38% reported never being incontinent of urine. Of 1416 individuals who had appendicostomy (ACE) bowel surgery, 48% reported never being incontinent of stool. DISCUSSION: Our current analysis showed that ordinal continence outcome classification had similar continence findings as previous studies using the binary definition of continence. Expanding the binary definition of continence to include monthly episodes of incontinence did not greatly increase the proportion of continent individuals and, therefore, would have not likely made meaningful differences in continence outcomes in prior NSBPR analyses. However, it is known that even mild incontinence can affect quality of life, therefore, capturing any level of incontiennce is of clinical importance. Confirmation of the association of continence outcomes with sociodemographic, condition-related, and interventional factors with both approaches further validates previous analyses using the binary definition of continence. CONCLUSION: The previously used binary definition of bladder and bowel continence appears robust. Undergarment choice was a poor surrogate for reported incontinence. After bladder and bowel continence surgeries, 38% and 48%, respectively, reported never being incontinent.

Bilateral retinal vasculitis associated with cold agglutinin disease treated with obinutuzumab and infliximab.

Purpose: To describe the clinical course and management of a patient with bilateral retinal vasculitis associated with cold agglutinin disease (CAD) treated with obinutuzumab and infliximab. Observations: A 69-year-old Hispanic woman was referred to a tertiary Uveitis Clinic with progressively worsening blurry vision, right eye (OD) worse than left eye (OS). Past ocular history was significant for epiretinal membranes in both eyes (OU). Past medical history was notable for non-specific joint disease, primarily affecting her knees bilaterally, and pulmonary symptoms (e.g., dyspnea, productive cough) of unclear etiologies one year before presentation. She had been evaluated by rheumatologists and pulmonologists and was placed on low doses of prednisone and methotrexate. Upon examination, her visual acuity was 20/40 in OD and 20/25 in OS. Anterior segment exam was unremarkable with no cell or flare in OU. Dilated fundus examination was notable for 0.5+ vitreous haze in OU and mild vessel attenuation in OU. Wide-angle fluorescein angiography (FA) revealed mild bilateral periphery peri-vasculature leakage in OU. Initial blood evaluations revealed decreased hematocrit, and positive anti-nuclear antibody. Her peripheral smear disclosed 3+ agglutination. She was initially treated with mycophenolate mofetil 1000 mg twice daily and prednisone 20 mg then referred to hematology. Further work up revealed high-titer cold agglutinin and positive thermal amplitude screen at 30 °C. Bone marrow examination demonstrated a chronic lymphocytic leukemia (CLL)-like monoclonal B-cell lymphocytosis. Anti-CD20 monoclonal antibody therapy with obinutuzumab was started in an effort to treat the underlying CLL clone and address the associated ocular vasculitis related to CAD. Three months later, after eight cycles of obinutuzumab, the patient's best- corrected visual acuity (BCVA) continued to be stable at 20/30 in OD and 20/20 in OS. However, FA showed persistent diffuse perivascular leakage. Intravenous infliximab with concurrent intravenous methylprednisolone infusions were started. After two cycles of treatment, FA showed significantly improved perivascular leakage. Visual acuity remained stable at 20/25 in OU. Conclusions and importance: Ocular involvement in CAD is rare. The index case is the first report of retinal vasculitis in a patient with CAD. Our report not only describes the unique course of CAD-related retinal vasculitis, but also introduces and underscores a successful therapeutic plan.

Atovaquone attenuates experimental colitis by reducing neutrophil infiltration of colonic mucosa.

Ulcerative colitis (UC) is a chronic relapsing disease featuring aberrant accumulation of neutrophils in colonic mucosa and the luminal space. Although significant advances in UC therapy have been made with the development of novel biologics and small molecules targeting immune responses, success of most current therapies is still limited, with significant safety concerns. Thus, there is a need to develop additional safe and effective therapies for the treatment of UC. Antimalarial drugs have been safely used for many years to resolve tissue inflammation and the associated pathologies. Atovaquone is a recent FDA-approved antimalarial drug that has shown anti-viral and tumor-suppressive properties in vitro however, its role in mucosal inflammation has not been evaluated. Using pre-clinical murine DSS-induced colitis model combined with complementary in vivo peritonitis and ex vivo human neutrophil activation and chemotaxis assays we investigated functional and mechanistic impacts of atovaquone on disease resolution and neutrophil trafficking. We demonstrate that atovaquone promotes resolution of DSS-induced murine colitis by reducing neutrophil accumulation in the inflamed colonic mucosa. Mechanistically, we show that atovaquone suppressed induction of CD11b expression in neutrophils, reducing their polarization and migratory ability. Thus, our findings identify a new role of atovaquone in promoting resolution of mucosal inflammation, supporting the idea of potential repurposing of this FDA-approved drug as UC therapeutic.

Racial Disparities in Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVE: There are significant racial disparities in stroke in the United States, with Black individuals having a higher risk of incident stroke even when adjusted for traditional stroke risk factors. It is unknown whether Black individuals are also at a higher risk of recurrent stroke. METHODS: Over an 18-month period spanning 2014-2015, we ascertained index stroke cases within the Greater Cincinnati/Northern Kentucky population of 1.3 million. We then followed up all patients for 3 years and determined the risk of recurrence. Multivariable survival analysis was performed to determine the effect of Black race on recurrence. RESULTS: There were 3,816 patients with index stroke/TIA events in our study period, and 476 patients had a recurrent event within 3 years. The Kaplan-Meier estimate of 3-year recurrence rate was 15.4%. Age-adjusted and sex-adjusted stroke recurrence rate was higher in Black individuals (HR 1.34, 95% CI 1.1-1.6; p = 0.003); however, when adjusted for traditional stroke risk factors including hypertension, diabetes, smoking status, age, and left ventricular hypertrophy, the association between Black race and recurrence was significantly attenuated and became nonsignificant (HR 1.1, 95% CI 0.9-1.36, p = 0.32). At younger ages, Black race was more strongly associated with recurrence, and this effect may not be fully attenuated by traditional stroke risk factors. DISCUSSION: Recurrent stroke was more common among Black individuals, but the magnitude of the racial difference was substantially attenuated and became nonsignificant when adjusted for traditional stroke risk factors. Interventions targeting these risk factors could reduce disparities in stroke recurrence.

The Possible Pathogenic Role of IgG4-Producing Plasmablasts in Stricturing Crohn's Disease.

BACKGROUND: Crohn's disease (CD) is a condition on the spectrum of inflammatory bowel disease that affects up to 20 people per 100,000 in the US annually, and with incidence increasing. One of the most significant sources of morbidity in CD is the formation of strictures, with resultant intestinal blockage a common indication for hospitalization and surgical intervention in these patients. The pathophysiology of stricture formation is not fully understood. However, the fibroplasia that leads to fibrostenotic stricture formation may have shared pathophysiology with IgG4-related fibrosis. SUMMARY: Initial intestinal inflammation recruits innate immune cells, such as neutrophils, that secrete IL-1ß and IL-23, which induces a type 17 CD4+ T-helper T-cell (Th17)-mediated adaptive immune response. These CD4+ Th17 T cells also contribute to inflammation by secreting proinflammatory cytokines such as IL-17 and IL-21. IL-21 recruits and stimulates CD4+ T follicular helper (Tfh) cells, which secrete more IL-21. This causes ectopic germinal center formation, recruiting and stimulating naïve B cells. The IL-17 and IL-21 produced by Th17 cells and Tfh cells also induce IgG4 plasmablast differentiation. Finally, these IgG4-producing plasmablasts secrete platelet-derived growth factor (PDGF), which activates local PDGF-receptor expressing fibroblasts and myofibroblasts, resulting in uncontrolled fibroplasia.

The Effectiveness of Self-Guided Virtual-Reality Exposure Therapy for Public-Speaking Anxiety.

Objectives: Self-guided virtual-reality exposure therapy (VRET) is a psychological intervention that enables a person to increase their own exposure to perceived threat. Public-speaking anxiety (PSA) is an anxiety-provoking social situation that is characterized by fear of negative evaluation from an audience. This pilot study aimed to determine whether self-guided VRET (1) increases exposure to PSA-specific virtual social threats, and (2) reduces anxiety, arousal, heartrate and PSA over repeated exposure. Methods: Thirty-two University students (27 completers) with high self-reported public-speaking anxiety attended 2 weekly self-guided VRET sessions. Each session involved the participant delivering a 20-min speech in a virtual classroom. Participants were able to increase their exposure to virtual social threat through the audience size, audience reaction, number of speech prompts, and their own salience in the virtual classroom at 4-min intervals. Participants' heartrates and self-reported anxiety and arousal were monitored during these intervals. Participants completed psychometric assessments after each session and 1 month later. Results: Participants increased their exposure to virtual social threat during each VRET session, which coincided with a reduction in heartrate and self-reported anxiety and arousal. Improvement in PSA occurred post-treatment and 1 month later. The in-session improvement in anxiety correlated with reductions in fear of negative evaluation post-treatment and 1 month later. Conclusions: Increased self-exposure to virtual social threat from self-guided VRET relieves anxiety and shows immediate reductions in subjective and physiological arousal during application, but also yields sustained improvement in PSA.

Treatment-resistant hypertension in a post-transplant patient with cystic fibrosis: a rare case of phaeochromocytoma.

SUMMARY: Phaeochromocytoma is a rare catecholamine-producing tumour. We present the case of phaeochromocytoma in a young man with a background history of a double-lung transplant for cystic fibrosis (CF). Clinical case: A 25-year-old man, with a background history of CF, CF-related diabetes (CFRD) and a double-lung transplant in 2012 was presented to the emergency department with crampy abdominal pain, nausea and vomiting. He was diagnosed with distal intestinal obstructions syndrome (DIOS). Contrast-enhanced CT imaging of the abdomen and pelvis showed a 3.4 cm right adrenal lesion. This was confirmed by a subsequent MRI of adrenal glands that demonstrated moderate FDG uptake, suggestive of a diagnosis of phaeochromocytoma. The patient was noted to be hypertensive with a blood pressure averaging 170/90 mm/Hg despite treatment with three different anti-hypertensive medications - amlodipine, telmisartan and doxazosin. He had hypertension for the last 3 years and had noted increasingly frequent sweating episodes recently, without palpitations or headache. Laboratory analysis showed elevated plasma normetanephrines (NMN) of 3167 pmol/L (182-867) as well as elevated metanephrines (MN) of 793 pmol/L (61-377) and a high 3-MT of 257 pmol/L (<185). Once cathecholamine excess was identified biochemically, we proceeded to functional imaging to further investigate. MIBG scan showed a mild increase in the uptake of tracer to the right adrenal gland compared to the left. The case was discussed at a multidisciplinary (MDT) meeting at which the diagnosis of phaeochromocytoma was made. Following a challenging period of 4 weeks to control the patient's blood pressure with an alpha-blocker and beta-blocker, the patient had an elective right adrenalectomy, with normalisation of his blood pressure post-surgery. The histopathology of the excised adrenal gland was consistent with a 3 cm phaeochromocytoma with no adverse features associated with malignant potential. LEARNING POINTS: Five to ten per cent of patients have a secondary cause for hypertension. Phaeochromocytomas are rare tumours, originating in chromaffin cells and they represent 0.1-1.0% of all secondary hypertension cases. Secondary causes should be investigated in cases where: Patient is presenting <20 years of age or >50 years of age, There is refractory hypertension, or There is serious end-organ damage present. Patients may present with the triad of headache, sweating and palpitations or more vague, non-specific symptoms. Patients with suspected phaeochromocytoma should have 24-h urinary catecholamines measured and if available, plasma metanephrines measured. Those with abnormal biochemical tests should be further investigated with imaging to locate the tumour. Medical treatment involves alpha- and beta-blockade for at least 2 to 3 weeks before surgery as well as rehydration. There is a possibility of relapse so high-risk patients require life-long follow-up.

The Burden of Radiation Exposure During Transcatheter Closure of Atrial Septal Defect.

Radiation reduction in the pediatric cardiac catheterization laboratory is well-suited for targeted quality improvement (QI) interventions. Transcatheter atrial septal defect (ASD) closure was chosen for this QI project based on a homogenous procedural population and inter-operator variability in radiation usage, with the aim to reduce radiation exposure during ASD device closure by 50% over 1 year. The aim for this project was defined and a Key Driver Diagram (KDD) was created with three domains for change: modification of procedural practice, reporting and monitoring/feedback, and team engagement. All patients undergoing attempted transcatheter ASD closure were considered for inclusion. The primary outcome, % reduction in median radiation dose (DAP/Kg), was determined through comparison with a historical cohort. Additional radiation metrics, procedural characteristics, and adverse events (AE) were compared to the historical cohort. Radiation exposure (DAP/kg) was reduced by 55% with a median dose reduction from 26 (15, 61) in a historical cohort to 12 (6, 22) in the intervention population (p <0.001). Fluoroscopy time and cine acquisition utilization significantly decreased. Procedure time, procedural success (defined as successful delivery of the device) and AE did not increase in the QI cohort. Successful practice changes included standardized procedural strategies to limit fluoroscopy and cine acquisition, improved fluoroscopic practice, engagement of the multidisciplinary team, and feedback with data reporting by electronic and in-person reminders. In conclusion, application of QI methodologies such as KDD with engagement of a multidisciplinary team can effectively reduce radiation in the pediatric catheterization laboratory.

Losartan Rescues Inflammation-related Mucociliary Dysfunction in Relevant Models of Cystic Fibrosis.

Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction.Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-ß1 (transforming growth factor ß1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-ß1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-ß1.Conclusions: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.

A Call to Follow-Up: Results Regarding Trauma Clinic Follow-Up Patterns.

The objective of this study was to assess the current practice pattern regarding posthospitalization follow-up of trauma patients among the members of the Eastern Association for the Surgery of Trauma (EAST). An anonymous online multiple-choice survey of EAST members in 2016 was conducted. Ten questions relating to the follow-up care of injured patients were presented to the Active, Senior, and Associate members of EAST. Data were screened for quantitative concerns prior to analysis. Of the 1,610 members surveyed, 289 responded (18%). Approximately 52% of respondents stated that their institution has a dedicated trauma follow-up clinic where most injured patients are seen after discharge. Less than 20% reported that nontrauma multidisciplinary providers are present in clinics. Most (89.5%) reported that follow-up is a single visit, unless a patient has long-standing issues. Only 3 respondents stated that patients are regularly seen 3+ months out from injury, and a significant minority (17.7%) acknowledged no set follow-up timeline. Only 3.6% of participants indicated that they have a psychologist embedded in the trauma team, and 11.5% reported that no system is currently in place to manage mental health. Despite more than 20 years of literature highlighting the long-term physical and mental health sequelae after trauma, these survey results demonstrate that there is a lack of standardized and multidisciplinary follow-up. Given the improvement in outcomes with the identification and treatment of these sequelae, greater attention should be paid to functional recovery, social and psychological well-being, and chronic pain.

Clinical approach to the diagnosis and successful management of anti-NMDA receptor encephalitis when antibody testing is not possible.

Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a multistage illness that progresses from psychosis, memory deficits, seizures and language disintegration to a state of unresponsiveness with catatonic features often associated with abnormal movements, and autonomic and breathing instability. While the disorder predominantly affects children and young adults, and occurs with or without tumour association, the presence of a tumour (usually an ovarian teratoma) is dependent on the age, sex and ethnicity.Teratomas present more frequently in women older than 18 years, and are more predominant in black women than Caucasians. Here we present the case of a patient with probable anti-NMDA receptor encephalitis. She was subsequently found to have a mature teratoma of the ovary (dermoid cyst). Despite immune-modulated therapy, surgery was eventually performed to remove the cyst. This was met with a good clinical recovery.

Piecing Together How Peroxiredoxins Maintain Genomic Stability.

Peroxiredoxins, a highly conserved family of thiol oxidoreductases, play a key role in oxidant detoxification by partnering with the thioredoxin system to protect against oxidative stress. In addition to their peroxidase activity, certain types of peroxiredoxins possess other biochemical activities, including assistance in preventing protein aggregation upon exposure to high levels of oxidants (molecular chaperone activity), and the transduction of redox signals to downstream proteins (redox switch activity). Mice lacking the peroxiredoxin Prdx1 exhibit an increased incidence of tumor formation, whereas baker's yeast (Saccharomyces cerevisiae) lacking the orthologous peroxiredoxin Tsa1 exhibit a mutator phenotype. Collectively, these findings suggest a potential link between peroxiredoxins, control of genomic stability, and cancer etiology. Here, we examine the potential mechanisms through which Tsa1 lowers mutation rates, taking into account its diverse biochemical roles in oxidant defense, protein homeostasis, and redox signaling as well as its interplay with thioredoxin and thioredoxin substrates, including ribonucleotide reductase. More work is needed to clarify the nuanced mechanism(s) through which this highly conserved peroxidase influences genome stability, and to determine if this mechanism is similar across a range of species.

Increased Mortality and Reoperation Rates After Treatment for Septic Arthritis of the Knee in People Who Inject Drugs: Nationwide Inpatient Sample, 2000-2013.

BACKGROUND: The United States has a growing opioid epidemic impacting all aspects of health care including orthopaedic surgery. Septic arthritis of the knee is a condition commonly encountered by orthopaedic surgeons related to opioid and injection drug use (IDU). Changes in the frequency of hospitalizations for IDU-related septic arthritis and differences in septic arthritis patient outcomes according to IDU status in the setting of the burgeoning opioid epidemic are unknown. QUESTIONS/PURPOSES: (1) What proportion of patients with septic arthritis of the knee use injection drugs? (2) Are there any differences in complications, reoperations, length of stay, and leaving against medical advice among patients with septic arthritis of the knee with and without IDU? (3) What are the age and racial trends in IDU-related septic arthritis of the knee from 2000 to 2013? METHODS: The Healthcare Cost and Utilization Project, Nationwide Inpatient Sample database of years 2000 to 2013 was utilized for patients between ages 15 and 64 years with a principal discharge diagnosis of native septic arthritis of the lower leg, the vast majority of which represents the knee. The Nationwide Inpatient Sample is the largest publicly available healthcare database in the United States that can show nationally representative clinical trends and outcomes. Septic arthritis was classified as related or unrelated to IDU based on previously published algorithms using billing codes. Patients with IDU-related septic arthritis were more likely to be black or Hispanic, younger, and use Medicare, Medicaid, or self-payment as their primary payment method. The yearly proportion of patients with septic arthritis who used injection drugs was determined. Hospitalization outcomes including length of stay, leaving against medical advice, number of procedures, and mortality rates were compared after adjusting for age, gender, and race in multivariable regression analyses. The yearly change in proportion of IDU-related septic arthritis in each age, race, and gender group was compared over the study period. RESULTS: The proportion of patients with IDU-related septic arthritis increased from 5% in 2000 to 11% in 2013. After adjusting for age, gender, and race, patients with IDU-related septic arthritis were more likely to die during hospitalization (adjusted odds ratio [AOR], 2.86; 95% confidence interval [CI], 1.51-5.39; p < 0.001) and undergo repeat arthroscopic (AOR, 1.24; 95% CI, 1.06-1.45; p = 0.007) or open irrigation and débridement (AOR, 1.68; 95% CI, 1.28-2.19; p < 0.001). Patients with IDU-related septic arthritis were more likely to leave against medical advice (AOR, 7.13; 95% CI, 5.56-9.15; p < 0.001) and also had an additional 5 days in length of stay (95% CI, 4.1-5.5; p < 0.001) on average compared with patients with septic arthritis unrelated to IDU. There was an increasing proportion of patients with IDU-related septic arthritis who were aged 15 to 34 years and 55 to 64 years from 2000 to 2013. CONCLUSIONS: IDU is increasingly the cause of septic knee admissions and is associated with higher rates of mortality, reoperations, resource utilization, and leaving against medical advice. Orthopaedic surgeons must adequately screen for IDU among patients with septic arthritis and monitor them closely for reoperation with a low threshold to reaspirate a knee in the postoperative period. Future studies should determine the current use and potential benefits of a multidisciplinary approach, including addiction specialists, to aid in the management of the increasing number of these patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker.

A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF. Several proteins screened, including multiple oxidant defense proteins, underwent intermolecular and/or intramolecular cross-linking in response to DVSF. Specific redox-active cysteines within a subset of DVSF targets were found to influence cross-linking; in addition, DVSF-mediated cross-linking of its targets was impaired in cells first exposed to oxidants. Since cross-linking appeared to involve redox-active cysteines in these proteins, we examined whether potential redox partners became cross-linked to them upon DVSF treatment. Specifically, we found that several substrates of thioredoxins were cross-linked to the cytosolic thioredoxin Trx2 in cells treated with DVSF. However, other DVSF targets, like the peroxiredoxin Ahp1, principally formed intra-protein cross-links upon DVSF treatment. Moreover, additional protein targets, including several known to undergo S-glutathionylation, were conjugated via DVSF to glutathione. Our results indicate that DVSF is of potential use as a chemical tool for irreversibly trapping and discovering thiol-based redox partnerships within cells.

Real-time localization of articulated surgical instruments in retinal microsurgery.

Real-time visual tracking of a surgical instrument holds great potential for improving the outcome of retinal microsurgery by enabling new possibilities for computer-aided techniques such as augmented reality and automatic assessment of instrument manipulation. Due to high magnification and illumination variations, retinal microsurgery images usually entail a high level of noise and appearance changes. As a result, real-time tracking of the surgical instrument remains challenging in in-vivo sequences. To overcome these problems, we present a method that builds on random forests and addresses the task by modelling the instrument as an articulated object. A multi-template tracker reduces the region of interest to a rectangular area around the instrument tip by relating the movement of the instrument to the induced changes on the image intensities. Within this bounding box, a gradient-based pose estimation infers the location of the instrument parts from image features. In this way, the algorithm does not only provide the location of instrument, but also the positions of the tool tips in real-time. Various experiments on a novel dataset comprising 18 in-vivo retinal microsurgery sequences demonstrate the robustness and generalizability of our method. The comparison on two publicly available datasets indicates that the algorithm can outperform current state-of-the art.

Laparoscopic approach to a planned two-stage hepatectomy for bilobar colorectal liver metastases.

BACKGROUND: This report describes the technical aspects and outcomes of a laparoscopic approach in planned two-stage liver resections for patients with bilobar colorectal cancer (CRC) liver-only metastases. METHODS: This is a retrospective review of our database examining consecutive patients who underwent an initial first-stage laparoscopic liver resection for CRC metastases, with a planned second-stage resection from 2007 to 2013. RESULTS: Seven patients underwent an initial laparoscopic first stage with concurrent right portal vein ligation (RPVL) in two patients. Median operating time was 100 (60-170) min with a median blood loss of 100 (50-400) mL. Median length of stay was 3 (2-5) days. The remaining five patients required post-operative right portal vein embolization (RPVE). All patients had significant hypertrophy of the future liver remnant (FLR) (future liver remnant volume (FLRV) >25%) and six patients subsequently had a successful open right hepatectomy with one attempted laparoscopically converted to open. Two patients had prolonged bile leaks after the second procedure. Three patients remained disease free, with median follow-up of 34 (13-80) months. One patient had disease progression following RPVE precluding performance of second stage. CONCLUSION: Laparoscopic first-stage resection of tumours in the left liver can be safely combined with RPVL/RPVE to achieve adequate hypertrophy of the FLR, allowing subsequent right hepatectomy.