Persistent SARS-CoV-2 PCR Positivity Despite Anti-viral Treatment in Immunodeficient Patients.

PURPOSE: COVID-19 infection in immunodeficient individuals can result in chronically poor health, persistent or relapsing SARS-CoV-2 PCR positivity, and long-term infectious potential. While clinical trials have demonstrated promising outcomes using anti-SARS-CoV-2 medicines in immunocompetent hosts, their ability to achieve sustained viral clearance in immunodeficient patients remains unknown. We therefore aimed to study long-term virological outcomes in patients treated at our centre. METHODS: We followed up immunocompromised inpatients treated with casirivimab-imdevimab (Ronapreve) between September and December 2021, and immunocompromised patients who received sotrovimab, molnupiravir, nirmatrelvir/ritonavir (Paxlovid), or no treatment from December 2021 to March 2022. Nasopharyngeal swab and sputum samples were obtained either in hospital or in the community until sustained viral clearance, defined as 3 consecutive negative PCR samples, was achieved. Positive samples were sequenced and analysed for mutations of interest. RESULTS: We observed sustained viral clearance in 71 of 103 patients, none of whom died. Of the 32/103 patients where sustained clearance was not confirmed, 6 died (between 2 and 34 days from treatment). Notably, we observed 25 cases of sputum positivity despite negative nasopharyngeal swab samples, as well as recurrence of SARS-CoV-2 positivity following a negative sample in 12 cases. Patients were then divided into those who cleared within 28 days and those with PCR positivity beyond 28 days. We noted lower B cell counts in the group with persistent PCR positivity (mean (SD) 0.06 (0.10) ×109/L vs 0.22 (0.28) ×109/L, p = 0.015) as well as lower IgA (median (IQR) 0.00 (0.00-0.15) g/L vs 0.40 (0.00-0.95) g/L, p = 0.001) and IgM (median (IQR) 0.05 (0.00-0.28) g/L vs 0.35 (0.10-1.10) g/L, p = 0.005). No differences were seen in CD4+ or CD8+ T cell counts. Antiviral treatment did not impact risk of persistent PCR positivity. CONCLUSION: Persistent SARS-CoV-2 PCR positivity is common among immunodeficient individuals, especially those with antibody deficiencies, regardless of anti-viral treatment. Peripheral B cell count and serum IgA and IgM levels are predictors of viral persistence.

Social Media Use in Psychiatric Graduate Medical Education: Where We Are and the Places We Could Go.

This commentary discusses the use of social media in psychiatric graduate medical education (GME) based on a systematic search of the literature. The authors conclude that research on social media use in psychiatric GME is in its infancy. For the most part, the few articles that have been published on this topic caution against the use of social media in psychiatric training. However, reports from other specialties, in which social media use in medical education has been more extensively studied, suggest that there may be significant benefits to incorporating social media into medical education. Although additional challenges may exist in implementing these tools in psychiatric education, the authors suggest that this is an emerging field of scholarship that merits further investigation.

Outcomes for ulnar collateral ligament reconstruction: a retrospective review using the KJOC assessment score with two-year follow-up in an overhead throwing population.

BACKGROUND: Injury to the ulnar collateral ligament (UCL) often results in valgus elbow instability requiring reconstruction. No standardized and validated outcome measure has compared outcomes between surgical techniques and institutions in the overhead throwing athlete. The aim of this study was to use the Kerlan-Jobe Orthopaedic Clinic shoulder and elbow score (KJOC score) to report functional outcomes in overhead throwing athletes undergoing UCL reconstruction. We predict that the KJOC score in our general throwing population will provide an accurate assessment of postoperative outcomes consistent with previously published reports. METHODS: A retrospective review of 33 patients undergoing UCL reconstruction was carried out during a 5-year period between 2004 and 2009. Minimum follow-up was 2.2 years with an average of 3.7 years. All surgeries were performed by fellowship-trained surgeons using either the docking (n = 12) or modified Jobe technique (n = 21). Age, sport, position, and return to play status were obtained. The KJOC score was administered to assess final functional outcome. RESULTS: A total of 33 athletes underwent UCL reconstruction-30 baseball players and 3 javelin throwers. Of these, 27 (82%) returned to their sport at their previous level in an average of 12.25 months. The overall average KJOC score was 76. Athletes who returned to their previous level of play had a mean KJOC score of 77. Those who were unable to return to play had a mean score of 69. CONCLUSION: Our study demonstrates consistent outcomes for UCL reconstruction using the KJOC shoulder and elbow score compared with previously reported data.

The effect of meniscal tears on cartilage loss of the knee: findings on serial MRIs.

BACKGROUND: The relationship between meniscal tears and progressive loss of hyaline cartilage and osteoarthritis of the knee has been reported in the literature. The current treatment protocols for meniscal tears include conservative treatment, meniscal repair, and meniscectomy. Treatment plans are based on factors such as tear pattern, patient age, and associated pathology. The mechanism, pattern, and treatment of meniscal tears vary with age and activity level. Younger, more active patients often sustain more acute tears, which are more amenable to repair due to increased propensity for healing compared with older patients. It is unclear which patients or types of meniscal tears will go on to sustain cartilage loss or osteoarthritis. OBJECTIVE: In our study, we aimed to determine magnetic resonance imaging (MRI) findings in patients with meniscal tears that may be predictive as a risk factor for future cartilage loss. METHODS: A database was retrospectively searched for patients with ≥ 2 MRIs of the same knee over a 7-year period, with the initial report containing the keyword "meniscal tear." Follow-up examinations were then evaluated for cartilage loss. RESULTS: Seventy-six meniscal tears were evaluated. Initial MRI findings associated with cartilage loss included subchondral bone marrow edema (P < 0.0001), meniscal extrusion (P < 0.001), radial meniscal tear (P = 0.017), and posterior horn meniscal tear (P = 0.031). In patients without meniscectomy, cartilage loss was observed in 38% (15/39) compared with 76% (28/37) in patients with meniscectomy, (P = 0.0001). CONCLUSION: Subchondral bone marrow edema and meniscal extrusion were the strongest MRI predictors for cartilage loss in an untreated knee with a meniscal tear. There was significantly greater cartilage loss in patients post-meniscectomy at follow-up than in those who did not undergo meniscectomy.

Characterization of a murine mixed neuron-glia model and cellular responses to regulatory T cell-derived factors.

One of the unmet clinical needs in demyelinating diseases such as Multiple Sclerosis (MS) is to provide therapies that actively enhance the process of myelin regeneration (remyelination) in the central nervous system (CNS). Oligodendrocytes, the myelinating cells of the CNS, play a central role in remyelination and originate from oligodendrocyte progenitor cells (OPCs). We recently showed that depletion of regulatory T cells (Treg) impairs remyelination in vivo, and that Treg-secreted factors directly enhance oligodendrocyte differentiation. Here we aim to further characterize the dynamics of Treg-enhanced oligodendrocyte differentiation as well as elucidate the cellular components of a murine mixed neuron-glia model. Murine mixed neuron-glia cultures were generated from P2-7 C57BL/6 mice and characterized for percentage of neuronal and glial cell populations prior to treatment at 7 days in vitro (div) as well as after treatment with Treg-conditioned media at multiple timepoints up to 12 div. Mixed neuron-glia cultures consisted of approximately 30% oligodendroglial lineage cells, 20% neurons and 10% microglia. Furthermore, a full layer of astrocytes, that could not be quantified, was present. Treatment with Treg-conditioned media enhanced the proportion of MBP+ oligodendrocytes and decreased the proportion of PDGFRα+ OPCs, but did not affect OPC proliferation or survival. Treg-enhanced oligodendrocyte differentiation was not caused by Treg polarizing factors, was dependent on the number of activation cycles Treg underwent and was robustly achieved by using 5% conditioned media. These studies provide in-depth characterization of a murine mixed neuron-glia model as well as further insights into the dynamics of Treg-enhanced oligodendrocyte differentiation.

Regulatory T cells promote myelin regeneration in the central nervous system.

Regeneration of CNS myelin involves differentiation of oligodendrocytes from oligodendrocyte progenitor cells. In multiple sclerosis, remyelination can fail despite abundant oligodendrocyte progenitor cells, suggesting impairment of oligodendrocyte differentiation. T cells infiltrate the CNS in multiple sclerosis, yet little is known about T cell functions in remyelination. We report that regulatory T cells (Treg) promote oligodendrocyte differentiation and (re)myelination. Treg-deficient mice exhibited substantially impaired remyelination and oligodendrocyte differentiation, which was rescued by adoptive transfer of Treg. In brain slice cultures, Treg accelerated developmental myelination and remyelination, even in the absence of overt inflammation. Treg directly promoted oligodendrocyte progenitor cell differentiation and myelination in vitro. We identified CCN3 as a Treg-derived mediator of oligodendrocyte differentiation and myelination in vitro. These findings reveal a new regenerative function of Treg in the CNS, distinct from immunomodulation. Although the cells were originally named 'Treg' to reflect immunoregulatory roles, this also captures emerging, regenerative Treg functions.

Developing a Curriculum to Promote Professionalism for Medical Students Using Social Media: Pilot of a Workshop and Blog-Based Intervention.

BACKGROUND: As the use of social media (SM) tools becomes increasingly widespread, medical trainees need guidance on applying principles of professionalism to their online behavior. OBJECTIVE: To develop a curriculum to improve knowledge and skills regarding professionalism of SM use by medical students. METHODS: This project was conducted in 3 phases: (1) a needs assessment was performed via a survey of medical students regarding SM use, rationale for and frequency of use, and concerns; (2) a workshop-format curriculum was designed and piloted for preclinical students to gain foundational knowledge of online professionalism; and (3) a complementary longitudinal SM-based curriculum was designed and piloted for clinical students to promote both medical humanism and professionalism. RESULTS: A total of 72 medical students completed the survey (response rate 30%). Among the survey respondents, 71/72 (99%) reported visiting social networking sites, with 55/72 (76%) reporting daily visits. Privacy of personal information (62/72, 86%) and mixing of personal/professional identities (49/72, 68%) were the students' most commonly endorsed concerns regarding SM use. The workshop-format curriculum was evaluated qualitatively via participant feedback. Of the 120 students who participated in the workshop, 91 completed the post workshop evaluation (response rate 76%), with 56 positive comments and 54 suggestions for improvement. The workshop was experienced by students as enjoyable, thought provoking, informative, and relevant. Suggestions for improvement included adjustments to timing, format, and content of the workshop. The SM-based curriculum was evaluated by a small-scale pilot of 11 students, randomized to the intervention group (participation in faculty-moderated blog) or the control group. Outcomes were assessed quantitatively and qualitatively via personal growth scales, participant feedback, and analysis of blog themes. There was a trend toward improvement in total personal growth scores among those students in the blog group from 3.65 (0.47) to 4.11 (0.31) (mean [SD]) with no change observed for the students in the control group (3.89 [0.11] before and after evaluation). Themes relevant to humanism and professionalism were observed in the blog discussion. CONCLUSIONS: Most medical students surveyed reported using SM and identified privacy and personal-professional boundaries as areas of concern. The workshop format and SM-based curricula were well-received by students whose formative feedback will inform the refinement and further development of efforts to promote professionalism among medical students.

Postoperative radiographs after ACL reconstruction are not cost-effective.

Postoperative radiographs have become standard after anterior cruciate ligament (ACL) reconstruction, even though few findings in the literature substantiate their efficacy. The goal of this study was to determine whether routine postoperative radiographs were cost-effective in patients undergoing ACL reconstruction. In addition, the authors sought to determine whether these radiographs provided meaningful clinical information that changed postoperative management. Between January and December 2010, the authors retrospectively reviewed all patients who underwent ACL reconstruction at their institution. The clinical course of all patients was reviewed to determine whether the results of the radiograph at the time of interpretation changed the plan of care. All radiographs were then scrutinized for abnormal findings that could have changed the plan of care if noted at the time of follow-up. Of 624 patients who underwent ACL reconstruction, 340 (54.4%) had a postoperative radiograph within 30 days. No radiograph showed a complication as interpreted by the surgeon at the time the radiograph was obtained, and no changes were made in routine postoperative care. On final review of each radiograph, none showed findings that would have changed management. The cost of performing and interpreting radiographs was $42.62 per patient, with a combined cost of $14,490.80. The findings of the study showed that postoperative radiographs after ACL reconstruction should not be considered "routine" practice. In addition, because these studies provided little clinical information, they are recommended only when symptoms suggest a mechanical complication and in cases of unforeseen postoperative trauma.

Results of ACL reconstruction with tibial Retroscrew fixation: Comparison of clinical outcomes and tibial tunnel widening.

UNLABELLED: ACL reconstruction with the RetroScrew™ shows superior clinical outcomes compared to historical Achilles allograft studies with antegrade screws. Addition of antegrade screw augmentation to retrograde fixation causes an increase in tibial tunnel widening. INTRODUCTION: In traditional antegrade screw fixation of Anterior cruciate ligament (ACL) soft tissue allografts, the screw is secured in the opposite direction of graft tension, potentially altering the appropriate tension on the graft. The RetroScrew (Arthrex) is a bioabsorbable screw placed in a retrograde fashion, potentially improving the tension of the graft by placing the screw in a proximal-to-distal direction. In addition, the RetroScrew theoretically decreases tibial tunnel widening by closing the aperture of the tibial tunnel, which prevents ingress of synovial fluid. Early tunnel expansion has been implicated due to excessive transverse and longitudinal graft motion. The clinical effects of tunnel expansion have yet to be fully understood. The purpose of this study is to assess the clinical results and tunnel width after ACL soft tissue fixation in the tibia with the RetroScrew. METHODS: Fifty-nine patients who underwent ACL reconstruction performed by two surgeons using the RetroScrew device returned for postoperative evaluation at an average of 25 months following surgery with a minimum follow-up of 12 months. Clinical evaluation, SF-36, IKDC and KT-1000 scores were recorded, and knee radiographs were used to measure tibial tunnel widening. Thirty-five patients had backup antegrade screw fixation in conjunction with the RetroScrew, and 24 patients had RetroScrew fixation alone. The results were compared to two previously reported studies on ACL reconstruction with Achilles tendon allograft that used antegrade screws. RESULTS: The average IKDC score was 87 (range: 44-100), with mean KT-1000 side-to-side difference of 1.2 mm (range: 0-5 mm). Tibial tunnel widening was 4.93 mm (SD 3.32) on AP radiographs and 4.40 mm (SD 2.72) on lateral radiographs greater than the native tunnel drilling. Patients with additional backup fixation had significantly more tunnel widening than patients without backup fixation (P < 0.05). There was one failure based on KT-1000 measurements. When compared to previous studies using ACL allografts, RetroScrew patients had statistically superior Lachman exams, KT-1000 side-to-side differences and decreased tibial tunnel widening (P < 0.05) when antegrade fixation was excluded. CONCLUSION: Patients who underwent Achilles allograft ACL reconstruction with the RetroScrew had improved clinical results compared to historical controls using antegrade fixation. Tibial tunnel widening was increased when using additional antegrade screw fixation, suggesting that the amount of bioabsorbable material within the tibial tunnel was related to the degree of tunnel widening.

Comprehensive investigation of the caveolin 2 gene: resequencing and association for kidney transplant outcomes.

Caveolae are plasma membrane structures formed from a complex of the proteins caveolin-1 and caveolin-2. Caveolae interact with pro-inflammatory cytokines and are dysregulated in fibrotic disease. Although caveolae are present infrequently in healthy kidneys, they are abundant during kidney injury. An association has been identified between a CAV1 gene variant and long term kidney transplant survival. Chronic, gradual decline in transplant function is a persistent problem in kidney transplantation. The aetiology of this is diverse but fibrosis within the transplanted organ is the common end point. This study is the first to investigate the association of CAV2 gene variants with kidney transplant outcomes. Genomic DNA from donors and recipients of 575 kidney transplants performed in Belfast was investigated for common variation in CAV2 using a tag SNP approach. The CAV2 SNP rs13221869 was nominally significant for kidney transplant failure. Validation was sought in an independent group of kidney transplant donors and recipients from Dublin, Ireland using a second genotyping technology. Due to the unexpected absence of rs13221869 from this cohort, the CAV2 gene was resequenced. One novel SNP and a novel insertion/deletion in CAV2 were identified; rs13221869 is located in a repetitive region and was not a true variant in resequenced populations. CAV2 is a plausible candidate gene for association with kidney transplant outcomes given its proximity to CAV1 and its role in attenuating fibrosis. This study does not support an association between CAV2 variation and kidney transplant survival. Further analysis of CAV2 should be undertaken with an awareness of the sequence complexities and genetic variants highlighted by this study.

Interactions between oestrogen and the renin angiotensin system - potential mechanisms for gender differences in Alzheimer's disease.

Interactions between oestrogen and the renin angiotensin system (RAS) are reviewed and explored from the perspective where these interactions may modulate risk of developing Alzheimer's disease (AD). AD is more prevalent in women than men, partly attributed to women's increased life expectancy; however underlying vascular differences may also contribute to AD risk. The RAS is a key regulator of blood pressure (BP). Pharmacological inhibition of angiotensin converting enzyme (ACE) and blockade of angiotensin II type 1 receptors (AT1R) are widely used to treat hypertension. Variation in components of the RAS such as ACE, neprilysin (NEP) and AT1R have been reported in AD, some of which may also directly alter AD neuropathology with changes in amyloid beta (Aß) levels, cognitive decline and neuroinflammation. Recently, RAS inhibiting drugs have been shown to attenuate the incidence, progression and pathology of AD. Oestrogen is also thought to prevent hypertension by reducing the vasoconstrictive actions of the RAS. Reduced oestrogen levels in women during the menopausal transition may therefore increase their risk of hypertension and/or RAS-mediated changes to cerebrovascular or AD pathology. Specifically, oestrogen prevents the production and action of angiotensin II (Ang II), thought to exert harmful effects of the RAS in both hypertension and AD, while also potentially facilitating RAS-mediated Aß degradation. These oestrogen-RAS interactions may partly explain current conflicting findings regarding oestrogen depletion and hormone therapy with respect to AD risk. Clinical trials targeting either the RAS or oestrogen systems for AD prevention and treatment should perhaps give closer attention to key biochemical components of these pathways as potential confounders to primary and secondary outcome measures.

A complex injury of the distal ulnar physis: a case report and brief review of the literature.

Physeal fractures of the distal forearm are common injuries in children and adolescents. However, Salter-Harris type III and type IV fractures of the distal ulnar epiphysis are often high-energy injuries that require open reduction for restoration of anatomical alignment. These injuries are uncommon and there are few descriptions of them in the contemporary literature. Here we report the case of a 13-year-old boy with a type IV distal ulna fracture not diagnosed with standard radiography. After closed manipulation, an incompletely reduced physis was suspected on the basis of fluoroscopic imaging and comparison radiographs of the contralateral wrist. Computed tomography showed a large, displaced physeal fragment. The patient underwent open reduction and internal fixation. Thorough radiographic assessment should be conducted when there is a high suspicion for these fracture patterns. Appropriate diagnosis can lead to expedient reduction and expectant management of sequelae associated with these injuries.