RT-PCR negative COVID-19.

BACKGROUND: COVID-19 is a multi-system infection with emerging evidence-based antiviral and anti-inflammatory therapies to improve disease prognosis. However, a subset of patients with COVID-19 signs and symptoms have repeatedly negative RT-PCR tests, leading to treatment hesitancy. We used comparative serology early in the COVID-19 pandemic when background seroprevalence was low to estimate the likelihood of COVID-19 infection among RT-PCR negative patients with clinical signs and/or symptoms compatible with COVID-19. METHODS: Between April and October 2020, we conducted serologic testing of patients with (i) signs and symptoms of COVID-19 who were repeatedly negative by RT-PCR ('Probables'; N = 20), (ii) signs and symptoms of COVID-19 but with a potential alternative diagnosis ('Suspects'; N = 15), (iii) no signs and symptoms of COVID-19 ('Non-suspects'; N = 43), (iv) RT-PCR confirmed COVID-19 patients (N = 40), and (v) pre-pandemic samples (N = 55). RESULTS: Probables had similar seropositivity and levels of IgG and IgM antibodies as propensity-score matched RT-PCR confirmed COVID-19 patients (60.0% vs 80.0% for IgG, p-value = 0.13; 50.0% vs 72.5% for IgM, p-value = 0.10), but multi-fold higher seropositivity rates than Suspects and matched Non-suspects (60.0% vs 13.3% and 11.6% for IgG; 50.0% vs 0% and 4.7% for IgM respectively; p-values < 0.01). However, Probables were half as likely to receive COVID-19 treatment than the RT-PCR confirmed COVID-19 patients with similar disease severity. CONCLUSIONS: Findings from this study indicate a high likelihood of acute COVID-19 among RT-PCR negative with typical signs/symptoms, but a common omission of COVID-19 therapies among these patients. Clinically diagnosed COVID-19, independent of RT-PCR positivity, thus has a potential vital role in guiding treatment decisions.

Acute Bilateral Compartment Syndrome of the Forearms.

A 43-year-old woman presented to our emergency department with severe bilateral forearm pain. On examination, both forearms were tense and swollen and the patient had excruciating pain, made much worse on passive extension of the fingers. The pain did not resolve with analgesia. The symptoms and clinical examination were highly suspicious for compartment syndrome. However, there was no history of trauma, strenuous physical activity, or any other obvious factor that might have precipitated the onset of a compartment syndrome. The serum creatinine kinase at presentation was greater than 37,000. The patient, however, did have a history of hypertension and was taking losartan, an angiotensinogen II antagonist that has been associated with rhabdomyolysis. The patient was brought to surgery for emergency fasciotomies and made an excellent recovery after surgery. The etiology of this patient's bilateral compartment syndrome is uncertain but may be a manifestation of drug-induced rhabdomyolysis.

A systematic review of the effects of injectable sedative and anesthetic drugs and inhalant anesthetics on intraocular pressure in the dog.

OBJECTIVE: The purpose of this systematic review was to summarize the results of studies that have determined the effect of injectable and inhalant drugs used in anesthesia on intraocular pressure (IOP) in dogs. DATABASES USED: A comprehensive search of research literature was performed without language restriction. The search utilized the PubMed, CAB Abstracts and the University of Georgia's Galileo electronic databases using a combination of free text terms 'Ophthalmology', 'Intraocular Pressure', 'Anesthetic', 'Anesthesia', 'Canine' or 'Dog'. The time frame searched was from 1970 to October 2018. Any published research paper that dealt with sedatives or anesthetics administered systemically and the canine eye was evaluated. CONCLUSIONS: The effects of many anesthetic drugs in dogs with ocular pathology are largely unknown. Many anesthetic drugs do not induce clinically relevant changes in IOP in dogs with normal eyes, although some studies demonstrated results with statistically significant changes. The dose, route of administration, experimental conditions, drug combinations, timing of measurements, measurement technology and setting or individual animal characteristics may all produce some heterogeneity in results from multiple studies.

Drug Use and Postoperative Mortality Following Valve Surgery for Infective Endocarditis: A Systematic Review and Meta-analysis.

BACKGROUND: Infective endocarditis (IE) often requires surgical intervention. An increasingly common cause of IE is injection drug use (IDU-IE). There is conflicting evidence on whether postoperative mortality differs between people with IDU-IE and people with IE from etiologies other than injection drug use (non-IDU-IE). In this manuscript, we compare short-term postoperative mortality in IDU-IE vs non-IDU-IE through systematic review and meta-analysis. METHODS: The review was conducted according to the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Publication databases were queried for key terms included in articles up to September 2017. Randomized controlled trials, prospective cohorts, or retrospective cohorts that reported on 30-day mortality or in-hospital/operative mortality following valve surgery and that compared outcomes between IDU-IE and non-IDU-IE were included. RESULTS: Thirteen studies with 1593 patients (n = 341 [21.4%] IDU-IE) were included in the meta-analysis. IDU-IE patients more frequently had tricuspid valve infection, Staphylococcus infection, and heart failure before surgery. Meta-analysis revealed no statistically significant difference in 30-day postsurgical mortality or in-hospital mortality between the 2 groups. CONCLUSIONS: Despite differing preoperative clinical characteristics, early postoperative mortality does not differ between IDU-IE and non-IDU-IE patients who undergo valve surgery. Future research on long-term outcomes following valve replacement is needed to identify opportunities for improved healthcare delivery with IDU-IE.

Physical removal of metallic carbon nanotubes from nanotube network devices using a thermal and fluidic process.

Electronic and optoelectronic devices based on thin films of carbon nanotubes are currently limited by the presence of metallic nanotubes. Here we present a novel approach based on nanotube alkyl functionalization to physically remove the metallic nanotubes from such network devices. The process relies on preferential thermal desorption of the alkyls from the semiconducting nanotubes and the subsequent dissolution and selective removal of the metallic nanotubes in chloroform. The approach is versatile and is applied to devices post-fabrication.

Melanoma classification and management in the era of molecular medicine.

Melanoma is the most lethal form of skin cancer although surgery is often curative when combined with early screening and prevention. In recurrent or advanced cancer, the emergence of chemotherapy, targeted therapy, and immune checkpoint inhibitors has demonstrated promising clinical outcomes. Such approaches can remarkably halt the progression of disease for many years, although are limited by the acquisition of resistance. The development and approval of combination therapies has further changed the treatment paradigm for certain melanomas. This review focuses on the current state of melanoma epidemiology and recent advancements in melanoma screening, histopathological classification, staged excision (i.e. wide local excision, sentinel lymph node biopsy, and Mohs micrographic surgery), and systemic treatment.

Mendelian Randomization Analysis reveals Inverse Genetic Risks between Skin Cancers and Vitiligo.

Several observational studies have demonstrated a consistent pattern of decreased melanoma risk among patients with vitiligo. More recently, this finding has been supported by a suggested genetic relationship between the two entities, with certain variants significantly associated with an increased risk of melanoma, basal cell carcinoma, and squamous cell carcinoma but a decreased risk of vitiligo. We compared 48 associated variants from a recently published GWAS and identified three variants-located in the TYR, MC1R-DEF8, and RALY-EIF2S2-ASIP-AHCY-ITCH loci- that correlated with an increased risk for melanoma, basal cell carcinoma, and squamous cell carcinoma and a decreased risk for vitiligo. We then used results of skin cancers and vitiligo GWAS to compare the shared genetic properties between these two traits through an unbiased Mendelian randomization analysis. Our results suggest that the inverse genetic relationship between common skin cancers and vitiligo is broader than previously reported owing to the influence of shared genome-wide significant associations.

Deadly public policy: what the future could hold for the HIV epidemic among injection drug users in Vancouver.

The scope and scale of the HIV outbreak that occurred among injection drug users in Vancouver in the late 1990s was unprecedented and resulted in some 2,000 new HIV infections, with incidence rates reaching 18 per 100 person-years. This outbreak, localized mainly in one neighbourhood, cost the Canadian health care system more than 1 billion dollars to diagnose, care and treat. A number of factors combined to stabilize HIV incidence: 1) HIV prevalence became saturated among those at highest risk; 2) several public health policies focused on drug users were implemented, including increased and additional decentralized needle exchange programs, expanded methadone maintenance services, better addiction treatment services, improved housing, and mental health programs; and 3) increased access and expansion of Highly Active Antiretroviral Therapy. To ensure that a similar outbreak never occurs again in Vancouver and other cities, future health policy must consider the political, psychosocial and socioeconomic factors that contributed to this outbreak. These policies must address the unintended adverse consequences of past policies and their repercussions for marginalized individuals living in this community and beyond.

An unusual case of Lemierre syndrome - One pathogen or two?

Lemierre syndrome, or septic thrombophlebitis of the internal jugular vein, is a rare disease that affects healthy young adults following an episode of pharyngitis or other upper respiratory disease. It most commonly involves the anaerobe Fusobacterium necrophorum, a component of normal oral flora. In this report, we present an unusual case of polymicrobial Lemierre syndrome involving both F. necrophorum and Group C streptococcus following an episode of pharyngitis and streptococcal toxic shock syndrome. Providers should consider the possibility of polymicrobial infection when there are imaging findings suggestive of Lemierre Syndrome and adjust antibiotic regimens accordingly.

The Molecular Context of Vulnerability for CDK9 Suppression in Triple Wild-Type Melanoma.

Approximately half of melanoma tumors lack a druggable target and are unresponsive to current targeted therapeutics. One proposed approach for treating these therapeutically orphaned tumors is by targeting transcriptional dependencies (oncogene starvation), whereby survival factors are depleted through inhibition of transcriptional regulators. A drug screen identified a CDK9 inhibitor (SNS-032) to have therapeutic selectivity against wild-type (wt) BRAFwt/NRASwt melanomas compared with BRAFmut/NRASmut mutated melanomas. We then used two strategies to inhibit CDK9 in vitro-a CDK9 degrader (TS-032) and a selective CDK9 kinase inhibitor (NVP-2). At 500 nM, both TS-032 and NVP-2 demonstrated greater suppression of BRAFwt/NRASwt/NF1wt cutaneous and uveal melanomas than mutant melanomas. RNA sequencing analysis of eight melanoma lines with NVP-2 treatment demonstrated that the context of this vulnerability appears to converge on a cell cycle network that includes many transcriptional regulators, such as the E2F family members. The Cancer Genome Atlas human melanoma tumor data further supported a potential oncogenic role for E2F1 and E2F2 in BRAFwt/NRASwt/NF1wt tumors and a direct link to CDK9. Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing therapeutically orphaned BRAF/NRAS/NF1 wt melanomas.

Collagenase Use and a Trap for the Unwary in Patients With Upper Limb Spasticity.

Collagenase has revolutionized the treatment of Dupuytren's disease. It acts by lysing collagen in Dupuytren's cords. It can also act on collagen in tendons, leading to tendon rupture. In this letter, we highlight caution where bowstringed flexor tendons were masquerading as Dupuytren's cords in a patient with upper limb spasticity. The initial plan was to inject the cords with collagenase; however, we proceeded with an open approach. If we had proceeded with our initial plan to inject the palpable cords with collagenase, tendon rupture would have been the likely outcome. We advise that administrators of collagenase proceed with caution in patients with upper limb neurological disorders, bearing in mind that bow-stringed flexor tendons can mimic Dupuytren's cords.

Classifying Melanoma by TERT Promoter Mutational Status.

Although TERT promoter mutations have been associated with a worsened prognosis in melanoma, the relationship between mutation status and downstream telomerase activity and telomere length remains convoluted. Using Sanger sequencing and techniques based on quantitative reverse transcriptase in real time, we evaluated 60 melanoma cell lines for TERT promoter mutational status, copy number, gene expression, and telomere length to provide a comprehensive analysis of the TERT/telomere pathway and establish a classification system whereby the associations between TERT mutations and their downstream molecular manifestations can more easily be ascertained. Mutations at positions -124/125 and -146 were associated with the highest levels of TERT gene expression but had no appreciable impact on absolute telomere length. In contrast, the common variant rs2853669 (at position -245) was significantly associated with longer telomere length via a recessive model in our cohort (P = 0.003). Our results, which are from assays performed on purified melanoma cell lines, suggest that the TERT promoter harbors a more complex mutational landscape than previously thought. Furthermore, the failure of TERT promoter mutations to consistently correlate with TERT expression and telomere length suggests an alternative method whereby tumor cells escape the critical shortening of telomeres.

Recurrent Ameloblastoma Involving Fibula Neo-mandible: Management with Digital Planning and Reconstruction Using a Contralateral Free Fibula Flap.

Ameloblastoma is a locally aggressive tumor that most commonly arises in the mandible. It has a high rate of recurrence if inadequately excised. We report a case of a patient who developed recurrence of his ameloblastoma in his fibula flap mandibular reconstruction despite clear resection margins 23 years after resection. This is the first reported case of recurrent ameloblastoma in a neo-mandible reconstruction in the setting of negative margins. We discuss its surgical management using digital planning and reconstruction using a contralateral free fibula flap. Ameloblastoma is a locally aggressive entity that requires complete excision. Recurrence can even occur in the reconstruction, which can present a challenge to manage. Consideration should be given to repeat excision and second osseous flap reconstruction.

Selective uveal melanoma inhibition with calcium channel blockade.

Uveal malignant melanoma (UMM), the most common primary adult intraocular tumor with a marked metastatic potential, is genetically unique and has unfortunately had few treatment breakthroughs. In this study, we subjected a UMM cell line to high­throughput library screening with 1,018 FDA­approved compounds to identify potential UMM­selective cytotoxic agents. Amlodipine, a dihydropyridine calcium channel blocker (CCB), ranked no. 2 and no. 8 of the most cytotoxic compounds. Thus, we further characterized the differential effects of calcium blockade on UMM and cutaneous malignant melanoma (CMM) lines in vitro using growth inhibition, cell cycle progression, apoptosis and senescence assays. Amlodipine had a significantly higher growth inhibitory potency in UMM (IC50=13.1 µM) than CMM (IC50=15.9 µM, P<0.05) lines. In 3D spherical cell culture, amlodipine treatment significantly impaired tissue volume growth in two UMM lines, but exerted no significant effects among all 3 CMM lines tested. Treatment with 10 and 20 µM amlodipine induced a significant impairment of cell cycle progression and the apoptosis of UMM lines, implicating both of these processes as mediators of the observed growth inhibition in UMM compared to CMM. On the whole, the findings of this study suggest that calcium channel blockade is a potentially effective strategy for selective uveal melanoma targeting.

Surgical management of an incarcerated uterus in a gynecological patient: A case report.

Uterine incarceration is most often described as occurring in pregnancies. Presenting with severe pelvic pain, urinary retention, and in some cases spontaneous abortion, this complication often arises at 12-15 weeks of gestational age. Although usually considered an obstetrical complication, uterine incarceration can occur in nongravid females. This case report presents a gynecological patient with acute urinary retention secondary to uterine incarceration. The patient chose surgical management, and surgery provided immediate symptomatic relief. Our case highlights an uncommon etiology of acute urinary retention and demonstrates the importance of considering the diagnosis of uterine incarceration in nongravid as well as gravid females.

Bilateral synovial cysts of the temporomandibular joint.

Synovial cysts very rarely affect the temporomandibular joint (TMJ). On review of the literature, there are 29 reported cases of unilateral synovial cysts of the TMJ. We present a case of bilateral synovial cysts occurring at the TMJs.

Use of Targeted Next-Generation Sequencing to Identify Activating Hot Spot Mutations in Cherry Angiomas.

Importance: Shared gene variants in benign-malignant process pairs, such as BRAF mutations common to benign nevi and melanoma, are associated with differing phenotypic manifestations. Study of gene mechanisms underlying cherry angioma may uncover previously unknown disease relationships. Objective: To identify somatic mutations present in cherry angioma specimens by using targeted next-generation sequencing. Design, Setting, and Participants: In a single-center case series, 10 formalin-fixed, paraffin-embedded cherry angioma specimens from biopsies performed at Massachusetts General Hospital in Boston from July 10, 2016, to January 23, 2018, were obtained and underwent sequencing across a panel of 323 genes most relevant to cancer. Somatic mutations were curated by excluding variants that were presumed to be germline or of low mapping quality. Main Outcomes and Measures: Identification of somatic mutations associated with cherry angiomas. Results: In 10 cherry angioma tissue samples originating from 6 female and 4 male patients with a median (range) age of 54 (26-79) years, 5 samples (50%) revealed somatic missense mutations in GNAQ (Q209H, Q209R, and R183G) and GNA11 (Q209H). Individually, these mutational hot spots are known to be involved in entities that include congenital and anastomosing hemangiomas, hepatic small-vessel neoplasms (Q209), port-wine stains, and Sturge-Weber syndrome (R183). Both hot spots are associated with blue nevi, melanoma associated with blue nevus, and uveal melanoma. Conclusions and Relevance: In this case series study, the high prevalence of 5 known genetic drivers within the benign cherry angioma entity appears to support the context-dependent role of gene alterations in both benign and malignant proliferations from various cellular origins.