Effect of monoclonal antibody therapy on the endogenous SARS-CoV-2 antibody response.

Monoclonal antibody treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection has been widely implemented. Effects of treatment on the endogenous primary humoral response to the virus are unknown. A retrospective cohort study performed at a Veterans Health Administration medical center compared serologic responses of treated and untreated COVID-19 patients at high risk for severe outcomes. Three anti-viral spike protein IgG monoclonal treatments were used during the study period, 1) bamlanivimab, 2) casirivimab with imdevimab, and 3) bamlanivimab with etesevimab. Data were analyzed at acute (0-9 days), seroconversion (10-19 days), and maximum antibody (20-39 days) stages. SARS-Cov-2 infection induced a dynamic primary humoral response with anti-spike IgM and anti-nucleocapsid IgG seroconversion occurring after 9 days with maximum serologic indices achieved by 20-39 days. All monoclonal antibody treatments suppressed the endogenous anti-spike IgM response by 85-90% with minor effect on the anti-nucleocapsid response. Thus, passive immunization therapy may cause immunologic interference.

Intratendinous Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Rotator Cuff Disease: A First-In-Human Trial.

Despite relatively good results of current symptomatic treatments for rotator cuff disease, there has been an unmet need for fundamental treatments to halt or reverse the progress of disease. The purpose of this study was to assess the safety and efficacy of intratendinous injection of autologous adipose tissue-derived mesenchymal stem cells (AD MSCs) in patients with rotator cuff disease. The first part of the study consists of three dose-escalation cohorts; the low- (1.0 × 107 cells), mid- (5.0 × 107 ), and high-dose (1.0 × 108 ) groups with three patients each for the evaluation of the safety and tolerability. The second part included nine patients receiving the high-dose for the evaluation of the exploratory efficacy. The primary outcomes were the safety and the shoulder pain and disability index (SPADI). Secondary outcomes included clinical, radiological, and arthroscopic evaluations. Twenty patients were enrolled in the study, and two patients were excluded. Intratendinous injection of AD MSCs was not associated with adverse events. It significantly decreased the SPADI scores by 80% and 77% in the mid- and high-dose groups, respectively. Shoulder pain was significantly alleviated by 71% in the high-dose group. Magnetic resonance imaging examination showed that volume of the bursal-side defect significantly decreased by 90% in the high-dose group. Arthroscopic examination demonstrated that volume of the articular- and bursal-side defects decreased by 83% and 90% in the mid- and high-dose groups, respectively. Intratendinous injection of autologous AD MSCs in patient with a partial-thickness rotator cuff tear did not cause adverse events, but improved shoulder function, and relieved pain through regeneration of rotator cuff tendon. Stem Cells 2018;36:1441-1450.

The Application of Virtual Reality in Shoulder Surgery Rehabilitation.

To achieve a positive functional prognosis in orthopedic surgery, particularly in shoulder surgeries, effective rehabilitation is essential. Recently, there has been growing interest in the use of virtual reality (VR) in the field of orthopedics, particularly for preoperative education and training, as well as clinical and home-based rehabilitation. This report describes the process of developing an application utilizing Meta Quest 2 VR technology (Meta, CA, USA) for rehabilitation after shoulder surgery. This application assists patients in performing postoperative exercises at home by wearing VR equipment tailored to their postoperative weeks. The advantages of VR rehabilitation lie in overcoming the limitations of traditional rehabilitation methods and providing patients with a better rehabilitation experience. Moreover, automating the rehabilitation process and reducing patients' visits to clinics can lead to cost savings. This report raises expectations for the potential and scalability of VR utilization, extending beyond orthopedics to other fields. In addition, it anticipates that with better feedback and motivation, the rehabilitation effects for patients can be further enhanced.

Standard nurse phone triage versus tele-emergency care pilot on Veteran use of in-person acute care: An instrumental variable analysis.

OBJECTIVES: Use of acute care telemedicine is growing, but data on quality, utilization, and cost are limited. We evaluated a Veterans Affairs (VA) tele-emergency care (tele-EC) pilot aimed at reducing reliance on out-of-network (OON) emergency department (ED) care, a growing portion of VA spending. With this service, an emergency physician virtually evaluated selected Veterans calling a nurse triage line. METHODS: Calls to the triage line occurring January-December 2021 and advised to seek care acutely within 24 h were included. We described tele-EC user characteristics, common triage complaints, and patterns in referral to and management by tele-EC. The primary outcome was acute care visits (ED, urgent care, and hospitalizations at VA and OON sites) within 7 days of the index call. Secondary outcomes included mortality, OON acute care spending, and the effect of tele-EC visit modality (phone vs. video). We used both standard regression and instrumental variable (IV) analysis, using the tele-EC physician schedule as the instrument. RESULTS: Of 7845 eligible calls, 15.5% had a tele-EC visit, with case resolution documented in 57%. Compared to standard nurse triage, tele-EC users were less likely to be Black, had more prior ED visits, and were triaged as higher acuity. Calls concerning dizziness/syncope, blood in stool, and chest pain were most likely to have a tele-EC visit. Tele-EC was associated with fewer ED visits than standard nurse triage in both regression (average marginal effect [AME] -16.8%, 95% confidence interval [CI] -19.2 to -14.4) and IV analyses (AME -17.5%, 95% CI -25.1 to -9.8), lower hospitalization rate (AME -3.1%, 95% CI -6.2 to -0.0), and lower OON spending (AME -$248, 95% CI -$458 to -$38). CONCLUSIONS: Among Veterans initially advised to seek care within 24 h, use of tele-EC compared to standard phone triage led to decreased ED visits, hospitalizations, and OON spending within 7 days.

Effect of surface matching mismatch of focal knee articular prosthetic on tibiofemoral contact stress using finite element analysis.

Aims: Focal knee arthroplasty is an attractive alternative to knee arthroplasty for young patients because it allows preservation of a large amount of bone for potential revisions. However, the mechanical behaviour of cartilage has not yet been investigated because it is challenging to evaluate in vivo contact areas, pressure, and deformations from metal implants. Therefore, this study aimed to determine the contact pressure in the tibiofemoral joint with a focal knee arthroplasty using a finite element model. Methods: The mechanical behaviour of the cartilage surrounding a metal implant was evaluated using finite element analysis. We modelled focal knee arthroplasty with placement flush, 0.5 mm deep, or protruding 0.5 mm with regard to the level of the surrounding cartilage. We compared contact stress and pressure for bone, implant, and cartilage under static loading conditions. Results: Contact stress on medial and lateral femoral and tibial cartilages increased and decreased, respectively, the most and the least in the protruding model compared to the intact model. The deep model exhibited the closest tibiofemoral contact stress to the intact model. In addition, the deep model demonstrated load sharing between the bone and the implant, while the protruding and flush model showed stress shielding. The data revealed that resurfacing with a focal knee arthroplasty does not cause increased contact pressure with deep implantation. However, protruding implantation leads to increased contact pressure, decreased bone stress, and biomechanical disadvantage in an in vivo application. Conclusion: These results show that it is preferable to leave an edge slightly deep rather than flush and protruding.

The role of emotion dysregulation and intolerance of uncertainty in autism: Transdiagnostic factors influencing co-occurring conditions.

BACKGROUND: Individuals with autism spectrum disorders (ASD) are more likely to have co-occurring psychiatric conditions such as depression and anxiety. Transdiagnostic constructs such as intolerance of uncertainty (IU) and emotion dysregulation (ED) have both been shown to be individually associated with depression and anxiety in those with ASD. AIMS: The current study examined the relationship between IU and ED, depression, and anxiety in an ED treatment-seeking sample and examined whether ED acts as a mediator between IU-depression and IU-anxiety. METHODS AND PROCEDURES: We examined baseline scores for 78 adolescents and young adults (12-21 years old) who were participating in an ED treatment. We assessed for correlations between IU, Reactivity and Dysphoria, anxiety, and depression symptoms, and then conducted mediation analyses to determine whether Reactivity and Dysphoria functioned as a mediator in IU- anxiety and IU- depression relationships. OUTCOMES AND RESULTS: Concordant with prior research, ED, IU, anxiety, and depression scores were correlated. Both Reactivity and Dysphoria were found to mediate both IU-depression and IU-anxiety. CONCLUSIONS AND IMPLICATIONS: Findings suggest that ED contributes to how IU affects psychopathology. Furthermore, both IU and ED may be pertinent treatment targets for individuals with depression or anxiety and ASD.

Vaccine breakthrough infections in veterans hospitalized with coronavirus infectious disease-2019: A case series.

BACKGROUND: While Severe Acute Respiratory Syndrome Coronavirus-2 vaccine breakthrough infections are expected, reporting on breakthrough infections requiring hospitalization remains limited. This observational case series report reviewed 10 individuals hospitalized with vaccine breakthrough infections to identify patient risk factors and serologic responses upon admission. METHODS: Electronic medical records of BNT162b2 (Pfizer-BioNTech) or mRNA-1732 (Moderna) vaccinated patients admitted to Veterans Affairs Ann Arbor Healthcare System with newly diagnosed Coronavirus Infectious Disease 2019 (COVID-19) between March 15, 2021 and April 15, 2021 were reviewed. Patient variables, COVID-19 lab testing including anti-S IgM, anti-N IgG antibodies, and hospital course were recorded. Based on lab testing, infections were defined as acute infection or resolving/resolved infection. RESULTS: Of the 10 patients admitted with breakthrough infections, all were >70 years of age with multiple comorbidities. Mean time between second vaccine dose and COVID-19 diagnosis was 49 days. In the 7 individuals with acute infection, none had observed serologic response to mRNA vaccination, 5 developed severe disease, and 1 died. Three individuals had anti-N IgG antibodies and a high polymerase chain reaction cycle threshold value, suggesting resolving/resolved infection. CONCLUSIONS: Given the variability of vaccine breakthrough infections requiring hospitalization, serologic testing may impart clarity on timing of infection and disease prognosis. Individuals at risk of diminished response to vaccines and severe COVID-19 may also benefit from selective serologic testing after vaccination to guide risk mitigation strategies in a post-pandemic environment.

SARS-CoV-2 Anti-Spike IgG Antibody and ACE2 Receptor Binding Inhibition Levels among Breakthrough Stage Veteran Patients.

SARS-CoV-2 mRNA vaccines have been critical to curbing pandemic COVID-19; however, a major shortcoming has been the inability to assess levels of protection after vaccination. This study assessed serologic status of breakthrough infections in vaccinated patients at a Veterans Administration medical center from June through December 2021 during a SARS-CoV-2 delta variant wave. Breakthrough occurred mostly beyond 150 days after two-dose vaccination with a mean of 239 days. Anti-SARS-CoV-2 spike (S) IgG levels were low at 0 to 2 days postsymptoms but increased in subjects presenting thereafter. Population measurements of anti-S IgG and angiotensin converting enzyme-2 receptor (ACE2-R) binding inhibition among uninfected, vaccinated patients suggested immune decay occurred after 150 days with 62% having anti-S IgG levels at or below 1,000 AU comparable with breakthrough patients at 0 to 2 days postsymptom onset. In contrast, vaccination after resolved infection conferred robust enduring anti-S IgG levels (5,000 to >50,000 AU) with >90% ACE2-R binding inhibition. However, monoclonal antibody (MAb)-treated patients did not benefit from their prior infection suggesting impaired establishment of B cell memory. Analysis of boosted patients confirmed the benefit of a third vaccine dose with most having anti-S IgG levels above 5,000 AU with >90% ACE2-R binding inhibition, but a subset had levels <5,000 AU. Anti-S IgG levels >5,000 AU were associated with >90% ACE2-R binding inhibition and no documented breakthrough infections, whereas levels falling below 5,000 AU and approaching 1,000 AU were associated with breakthrough infections. Thus, quantitative antibody measurements may provide a means to guide vaccination intervals for the individual. IMPORTANCE Currently, clinicians have no guidance for the serologic assessment of SARS-Cov-2 postvaccination status regarding protection and risk of infection. Vaccination and boosters are administered blindly without evaluation of need or outcome at the individual level. The recent development of automated quantitative assays for anti-SARS-CoV-2 spike protein IgG antibodies permits accurate measurement of humoral immunity in standardized units. Clinical studies, such as reported here, will help establish protective antibody levels allowing identification and targeted management of poor vaccine responders and vaccinated subjects undergoing immune decay.

Novel nanotechnology approaches to diagnosis and therapy of ovarian cancer.

OBJECTIVE: Ovarian carcinoma is the leading cause of death from gynecologic malignancies, which is a direct outcome of missing its diagnosis at an early stage. Approximately 75% of ovarian cancer patients are initially diagnosed with disseminated intra-abdominal disease (stages III-IV) when ~30% of patients have a 5-year survival rate. In addition to the challenge of early detection of ovarian cancer, its therapy presents several challenges including the route of therapy, resistance to therapy with recurrence of cancer, and specific targeting of ovarian cancer to reduce cytotoxic side effects. METHODS: We reviewed recent literature employing nanotechnology approaches to diagnosis and therapy of ovarian cancer. RESULTS: Recent innovations in nanotechnology with applications in cancer diagnostics and therapy help circumvent many pre-existing problems with conventional chemotherapy and present new ways of diagnosis and therapy. CONCLUSIONS: Nanotechnology has promising potential in enhancing early detection of ovarian cancer and treatment of recurrent disease.

Defective protein folding and intracellular retention of thyroglobulin-R19K mutant as a cause of human congenital goiter.

It has been suggested that a thyroglobulin (Tg)-R19K missense mutation may be a newly identified cause of human congenital goiter, which is surprising for this seemingly conservative substitution. Here, we have examined the intracellular fate of recombinant mutant Tg expressed in COS-7 cells. Incorporation of the R19K mutation largely blocked Tg secretion, and this mutant was approximately 90% degraded intracellularly over a 24-h period after synthesis. Before its degradation, the Tg-R19K mutant exhibited abnormally increased association with molecular chaperones BiP, calnexin, and protein disulfide isomerase, and was unable to undergo anterograde advance from the endoplasmic reticulum (ER) through the Golgi complex. Inhibitors of proteasomal proteolysis and ER mannosidase-I both prevented ER-associated degradation of the Tg-R19K mutant and increased its association with ER molecular chaperones. ER quality control around Tg residue 19 is not dependent upon charge but upon side-chain packing, because Tg-R19Q was efficiently secreted. Whereas a Tg mutant truncated after residue 174 folds sufficiently well to escape ER quality control, introduction of the R19K point mutation blocked its secretion. The data indicate that the R19K mutation induces local misfolding in the amino-terminal domain of Tg that has global effects on Tg transport and thyroid hormonogenesis.

Timing of peak bone mass: discrepancies between CT and DXA.

CONTEXT: The time of life in which peak bone mass in the axial skeleton is attained has been the subject of considerable controversy, with estimates ranging from the time of sexual and skeletal maturity to the fifth decade of life. OBJECTIVE: The objective was to examine whether dual energy x-ray absorptiometry (DXA) and computed tomography (CT) values for bone mass and bone density (BD) in the axial skeleton increase after sexual and skeletal maturity. DESIGN/PARTICIPANTS: Measurements of vertebral bone mineral density and bone mineral content (BMC) by DXA and vertebral BD and BMC by CT were obtained in 50 sexually and skeletally mature white females at baseline and 3 yr later. CT BMC values were calculated through analysis of vertebral volume in relation to density (BMC = vertebral volume x BD). RESULTS: Although neither CT BD nor BMC measures changed with time, DXA bone mineral density and BMC values were significantly higher at follow-up (P < 0.0001). Despite strong correlations between DXA and CT bone measures, DXA yielded greater changes in bone values in 47 of 50 subjects. CONCLUSIONS: Bone acquisition in the lumbar spine as measured by CT reaches its peak by sexual and skeletal maturity. In contrast, bone values by DXA continue to increase after puberty and cessation of longitudinal growth. Increases in DXA measures are likely a reflection of inhomogeneous changes in soft tissues around the spine or of disproportionate increases in the posterior elements of the vertebrae rather than of changes within the vertebral body.

Fat mass is not beneficial to bone in adolescents and young adults.

CONTEXT: Although muscle mass is beneficial to bone, studies on the effect of fat mass on bone have yielded conflicting results. OBJECTIVE: The aim of this study was to assess the relations between lean and fat mass and bone structure. DESIGN: This study was cross-sectional. SETTING: The study was conducted in a general community. SUBJECTS: Subjects included 300 healthy sexually mature adolescents and young adults (150 males and 150 females) between the ages of 13 and 21 yr. MAIN OUTCOME MEASURE: We investigated the relation between dual-energy x-ray absorptiometry (DXA) measures of total body fat and lean mass and bone values obtained with DXA (legs and lumbar spine bone mineral density and bone mineral content) and computed tomography (CT) (cross-sectional and cortical bone areas of the femurs and cross-sectional area and cancellous bone density of the vertebrae). RESULTS: Simple and multiple linear regression analyses showed significant positive relations between DXA lean mass and all CT and DXA measures of bone in the axial and appendicular skeletons (all P < 0.005). In contrast, whereas Pearson correlations between DXA measures of fat mass and bone parameters were generally positive, multiple regression analyses showed that fat mass, after accounting for lean mass, trunk height/leg length, had a negative, or no, correlation with CT and DXA values for bone. CONCLUSIONS: Our findings provide compelling evidence that, despite increased mechanical loading and independent of lean mass, adipose tissue is not beneficial to bone structure.

PfClpC Is an Essential Clp Chaperone Required for Plastid Integrity and Clp Protease Stability in Plasmodium falciparum.

The deadly malaria parasite Plasmodium falciparum contains a nonphotosynthetic plastid, known as the apicoplast, that functions to produce essential metabolites, and drugs that target the apicoplast are clinically effective. Several prokaryotic caseinolytic protease (Clp) genes have been identified in the Plasmodium genome. Using phylogenetic analysis, we focused on the Clp members that may form a regulated proteolytic complex in the apicoplast. We genetically targeted members of this complex and generated conditional mutants of the apicoplast-localized PfClpC chaperone and PfClpP protease. Conditional inhibition of the PfClpC chaperone resulted in growth arrest and apicoplast loss and was rescued by addition of the essential apicoplast-derived metabolite IPP. Using a double-conditional mutant parasite line, we discovered that the chaperone activity is required to stabilize the mature protease, revealing functional interactions. These data demonstrate the essential function of PfClpC in maintaining apicoplast integrity and its role in regulating the proteolytic activity of the Clp complex.

Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry.

BACKGROUND: Systemic thrombolysis for acute pulmonary embolism (PE) carries up to a 20% risk of major bleeding, including a 2% to 5% risk of hemorrhagic stroke. We evaluated the safety and effectiveness of catheter-directed therapy (CDT) as an alternative treatment of acute PE. METHODS: One hundred one consecutive patients receiving CDT for acute PE were prospectively enrolled in a multicenter registry. Massive PE (n = 28) and submassive PE (n = 73) were treated with immediate catheter-directed mechanical or pharmacomechanical thrombectomy and/or catheter-directed thrombolysis through low-dose hourly drug infusion with tissue plasminogen activator (tPA) or urokinase. Clinical success was defined as meeting all the following criteria: stabilization of hemodynamics; improvement in pulmonary hypertension, right-sided heart strain, or both; and survival to hospital discharge. Primary safety outcomes were major procedure-related complications and major bleeding events. RESULTS: Fifty-three men and 48 women (average age, 60 years [range, 22-86 years]; mean BMI, 31.03 ± 7.20 kg/m2) were included in the study. The average thrombolytic doses were 28.0 ± 11 mg tPA (n = 76) and 2,697,101 ± 936,287 International Units for urokinase (n = 23). Clinical success was achieved in 24 of 28 patients with massive PE (85.7%; 95% CI, 67.3%-96.0%) and 71 of 73 patients with submassive PE (97.3%; 95% CI, 90.5%-99.7%). The mean pulmonary artery pressure improved from 51.17 ± 14.06 to 37.23 ± 15.81 mm Hg (n = 92) (P < .0001). Among patients monitored with follow-up echocardiography, 57 of 64 (89.1%; 95% CI, 78.8%-95.5%; P < .0001) showed improvement in right-sided heart strain. There were no major procedure-related complications, major hemorrhages, or hemorrhagic strokes. CONCLUSIONS: CDT improves clinical outcomes in patients with acute PE while minimizing the risk of major bleeding. At experienced centers, CDT is a safe and effective treatment of both acute massive and submassive PE. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01097928; URL: www.clinicaltrials.gov.

Safety and efficacy of abatacept in eight rheumatoid arthritis patients with chronic hepatitis B.

OBJECTIVE: There are no previous studies on the use of abatacept in patients with chronic hepatitis B. This medical record review assessed the safety and efficacy of abatacept in 8 patients with rheumatoid arthritis (RA) and chronic hepatitis B. METHODS: A retrospective analysis of patients with RA and chronic hepatitis B treated with abatacept was conducted. The primary outcome was the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) at each followup visit along with markers of hepatitis B reactivation, including aspartate aminotransferase, alanine aminotransferase, and hepatitis B viral load. RESULTS: A total of 47 visit data points were recorded. The mean ± SD duration of followup of patients receiving abatacept was 19.1 ± 12.7 months (range 3-33 months). Analysis was limited to 18 months of followup (included 77% of all visits [36 of 47]). Four patients were started on antiviral prophylaxis for hepatitis B with the initiation of abatacept, while 4 patients were not. Among the 4 patients who received antiviral prophylaxis, RA improved as evidenced by a statistically significant decrease in DAS28-ESR scores, and none had reactivation of hepatitis B. In the 4 patients without antiviral prophylaxis, there was no significant decrease in the DAS28-ESR scores and all 4 experienced reactivation of hepatitis B. There were no adverse events other than the hepatitis B reactivation. CONCLUSION: Use of abatacept in patients with RA and chronic hepatitis B appears feasible if antiviral prophylaxis for hepatitis B is given concurrently. In these patients there were no non-hepatitis-related adverse effects. These data are encouraging and should lead to initiation of controlled trials of abatacept in hepatitis B.

Reactive arthritis: a review.

This review article summarizes the available literature on adolescent reactive arthritis. A review of the pathophysiology, diagnosis, and treatment guidelines will be helpful to better diagnose and treat reactive arthritis.

Oxidoreductase interactions include a role for ERp72 engagement with mutant thyroglobulin from the rdw/rdw rat dwarf.

Newly synthesized thyroglobulin (Tg), the secretory glycoprotein that serves as precursor in thyroid hormone synthesis, normally forms transient covalent protein complexes with oxidoreductases of the endoplasmic reticulum (ER). The Tg-G2320R mutation is responsible for congenital hypothyroidism in rdw/rdw rats, in which a lack of secondary thyroid enlargement (goiter) implicates death of thyrocytes as part of disease pathogenesis. We found that mutant Tg-G2320R was retained within the ER with no detectable synthesis of thyroxine, had persistent exposure of free cysteine thiols, and was associated with activated ER stress response but incomplete ER-associated degradation (ERAD). Tg-G2320R associated with multiple ER resident proteins, most notably ERp72, including covalent Tg-ERp72 interactions. In PC Cl3 thyrocytes, inducible overexpression of ERp72 increased the ability of cells to maintain Tg cysteines in a reduced state. Noncovalent interactions of several ER chaperones with newly synthesized Tg-G2320R diminished over time in parallel with ERAD of the mutant protein, yet a small ERAD-resistant Tg fraction remained engaged in covalent association with ERp72 even 2 days post-synthesis. Such covalent protein aggregates may set the stage for apoptotic thyrocyte cell death, preventing thyroid goiter formation in rdw/rdw rats.