BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Reversible expansion of tissue macrophages in response to macrophage colony-stimulating factor (CSF1) transforms systemic lipid and carbohydrate metabolism.

Macrophages regulate metabolic homeostasis in health and disease. Macrophage colony-stimulating factor (CSF1)-dependent macrophages contribute to homeostatic control of the size of the liver. This study aimed to determine the systemic metabolic consequences of elevating circulating CSF1. Acute administration of a CSF1-Fc fusion protein to mice led to monocytosis, increased resident tissue macrophages in the liver and all major organs, and liver growth. These effects were associated with increased hepatic glucose uptake and extensive mobilization of body fat. The impacts of CSF1 on macrophage abundance, liver size, and body composition were rapidly reversed to restore homeostasis. The effects of CSF1 on metabolism were independent of several known endocrine regulators and did not impact the physiological fasting response. Analysis using implantable telemetry in metabolic cages revealed progressively reduced body temperature and physical activity with no change in diurnal food intake. These results demonstrate the existence of a dynamic equilibrium between CSF1, the mononuclear phagocyte system, and control of liver-to-body weight ratio, which in turn controls systemic metabolic homeostasis. This novel macrophage regulatory axis has the potential to promote fat mobilization, without changes in appetence, which may have novel implications for managing metabolic syndrome.NEW & NOTEWORTHY CSF1 administration expands tissue macrophages, which transforms systemic metabolism. CSF1 drives fat mobilization and glucose uptake to support liver growth. The effects of CSF1 are independent of normal hormonal metabolic regulation. The effects of CSF1 are rapidly reversible, restoring homeostatic body composition. CSF1-dependent macrophages and liver size are coupled in a dynamic equilibrium.

A Spiky Silver-Iron Oxide Nanoparticle for Highly Efficient Targeted Photothermal Therapy and Multimodal Imaging of Thrombosis.

Thrombosis and its complications are responsible for 30% of annual deaths. Limitations of methods for diagnosing and treating thrombosis highlight the need for improvements. Agents that provide simultaneous diagnostic and therapeutic activities (theranostics) are paramount for an accurate diagnosis and rapid treatment. In this study, silver-iron oxide nanoparticles (AgIONPs) are developed for highly efficient targeted photothermal therapy and imaging of thrombosis. Small iron oxide nanoparticles are employed as seeding agents for the generation of a new class of spiky silver nanoparticles with strong absorbance in the near-infrared range. The AgIONPs are biofunctionalized with binding ligands for targeting thrombi. Photoacoustic and fluorescence imaging demonstrate the highly specific binding of AgIONPs to the thrombus when functionalized with a single chain antibody targeting activated platelets. Photothermal thrombolysis in vivo shows an increase in the temperature of thrombi and a full restoration of blood flow for targeted group but not in the non-targeted group. Thrombolysis from targeted groups is significantly improved (p < 0.0001) in comparison to the standard thrombolytic used in the clinic. Assays show no apparent side effects of AgIONPs. Altogether, this work suggests that AgIONPs are potential theranostic agents for thrombosis.

Idiopathic Intracranial Hypertension in Female-to-Male Transgender Patients on Exogenous Testosterone Therapy.

PURPOSE: To present four female-to-male (FTM) transgender patients on testosterone therapy diagnosed with idiopathic intracranial hypertension (IIH). METHODS: The authors report 4 consecutive FTM transgender patients on exogenous testosterone diagnosed with IIH at a single institution. RESULTS: Patient 1 presented with progressive blurred vision and a central scotoma 10 weeks after starting testosterone cypionate injections for hormonal gender transition. Bilateral grade 5 papilledema was present; the patient underwent bilateral optic nerve sheath fenestration with improved vision and resolution of edema. Patient 2 presented with transient vision loss, pulsatile tinnitus, and blurred vision 13 months after starting testosterone cypionate injections. The patient had grade 4 and 3 disc edema of the right and left eyes, respectively. Patient 3 presented with headaches and pulsatile tinnitus and was on testosterone injections at an unknown dose. The examination revealed grade 1 and 2 disc edema of the right and left eyes, respectively. Patient 4 presented with decreased vision, transient visual obscurations, and daily migraines while using topical testosterone gel every other day. Color vision was reduced, and lumbar puncture revealed elevated intracranial pressure. All patients had neuroimaging findings consistent with increased intracranial pressure. CONCLUSIONS: Testosterone therapy plays an essential role in FTM hormonal transitioning and may play a role in IIH. Patients undergoing testosterone therapy for gender transition should be informed of the possibility of developing IIH while on treatment, with obesity possibly increasing this risk. Comprehensive eye examinations should be considered in these patients before initiating hormone therapy.

Spontaneous Subperiosteal Orbital Hematoma Associated With Cocaine-Induced Midline Destructive Lesion.

The authors present a case of a non-traumatic, spontaneous subperiosteal orbital hematoma in a woman with a history of chronic pansinusitis and absence of midline nasal cavity structures due to chronic inhalational cocaine use. The patient underwent left orbitotomy and drainage of the lesion, showing mostly blood with a small amount of purulence that grew methicillin-resistant Staphylococcus aureus when cultured. The patient received 4 weeks of intravenous antibiotics in addition to functional endoscopic sinus surgery. At 1 month after surgery, her vision had returned to baseline, and proptosis was resolved. Fewer than 20 cases of subperiosteal orbital hematomas associated with chronic sinusitis have been reported. To the authors' knowledge, this is the first reported case of a subperiosteal orbital hematoma associated with cocaine-induced midline destructive lesions. Patient consent to obtain photographs was obtained and archived. All collection and evaluation of patient health information were compliant with the Health Insurance Portability and Accountability Act, and this report adheres to the Declaration of Helsinki.

Superior Visual Field Testing Using Virtual Reality With and Without Eye Tracking for Functional Upper Eyelid Surgery Evaluation: A Pilot Study.

PURPOSE: To assess the sensitivity and specificity of superior visual field tests administered in virtual reality (VR) with eye tracking (VR-ET) and without eye tracking (VR 0 ) for the fulfillment of insurance coverage criteria for functional upper eyelid surgery as compared with standard automated perimetry (SAP). METHODS: This prospective cross-sectional study included 78 eyes from 41 patients with ptosis, brow ptosis, and dermatochalasis undergoing functional upper eyelid surgery evaluation. Participants underwent serial superior visual field tests using SAP and VR 0 or VR-ET in randomized order. Fulfillment of insurance coverage criteria for blepharoplasty was defined as a 30% increase in the grid seen from the untaped to the taped state. The main outcome measure was the sensitivity and specificity of VR 0 , VR-ET, and overall VR in meeting insurance coverage criteria as compared with SAP. RESULTS: VR had a sensitivity of 84.1% and specificity of 67.6%, with no significant difference between VR 0 and VR-ET. SAP agreed on insurance coverage criteria fulfillment with VR 0 in 28 (71.8%) eyes and with VR-ET in 32 (82.1%) eyes. Insurance coverage criteria fulfillment rates varied significantly by diagnosis on SAP ( p = 0.012) but not VR ( p = 0.059). CONCLUSIONS: VR may be an alternative to SAP for functional upper eyelid surgery evaluation. Future studies are needed to determine differences in patient satisfaction, testing and waiting time, and test-retest reliability between VR and SAP.

Use of Porcine Urinary Bladder Matrix in Socket Reconstruction After Pediatric Orbital Exenteration.

Reconstruction options after orbital exenteration can be challenging, time-consuming, and require intensive postoperative care. Engineered dermal acellular matrices offer a quick and easy option for wound healing that has proven to be successful in various settings. Specifically, the porcine urinary bladder matrix has demonstrated success in periocular and orbital wound healing. This report describes a pediatric patient who underwent repair with porcine urinary bladder matrix after orbital exenteration for recurrent alveolar rhabdomyosarcoma. The patient did not require any additional reconstructive procedures. To our knowledge, this is the youngest patient to receive a porcine urinary bladder matrix after exenteration.

Cemiplimab for Orbital Squamous Cell Carcinoma in 11 Cases.

PURPOSE: To review the demographics, clinical features, and response of orbital squamous cell carcinoma treated with cemiplimab. METHODS: This is a retrospective multi-institutional series. Patient characteristics, drug dosing, duration, and response to treatment were evaluated. RESULTS: The study cohort consisted of 11 patients from 5 institutions. All patients received a regimen of 350 mg q 3 weeks and an average of 11.2 cycles (SD 5.8). No patient experienced significant side effects requiring treatment or cessation of cemiplimab. Complete response was achieved in 9 patients (82%) treated with cemiplimab. CONCLUSIONS: Immune checkpoint inhibitors, such as cemiplimab provide a globe-sparing option for the treatment of orbital squamous cell carcinoma. It is important to consider these agents especially when orbital exenteration is the alternative.

Lateral Tarsal Strip Complications With and Without Conjunctiva Stripping.

PURPOSE: The lateral tarsal strip (LTS) procedure is commonly used to correct eyelid malposition. When performing LTS, some surgeons elect to remove conjunctiva from the tarsal strip, while others do not. It has been hypothesized that without conjunctival stripping, the buried conjunctival tissue can cause complications such as inclusion cysts and granulomas. However, there is limited data comparing LTS cases with and without conjunctiva removal. The authors sought to evaluate whether conjunctival stripping had any impact on complication rates with LTS. METHODS: LTS operations for ectropion correction were retrospectively reviewed and were separated into 2 cohorts, Con (conjunctiva not removed) or Coff (conjunctival removed). Charts were reviewed for outcomes and complications including inclusion cyst formation, granuloma formation, wound dehiscence, infection, and focal rim tenderness. RESULTS: The complication rate was 10% versus 8% for Con versus Coff respectively ( p = 0.54). The common complications of LTS surgery were granuloma (4%), wound dehiscence (3%), focal rim tenderness (3%), and infection requiring antibiotics (<1%). There was no significant difference in these complications between the Con and Coff cohorts. CONCLUSIONS: Complications in both groups were minimal, similar to prior studies, and there was no difference between the 2 cohorts. While it has been suggested that buried conjunctiva may result in increased complication rates, the author's findings suggest that removing the tarsal conjunctiva is a superfluous step in the LTS surgery and does not affect complication rates.

Basal Cell Carcinoma and Eccrine Porocarcinoma of the Eyelid.

An 81-year-old woman presented with a progressively enlarging indurated, firm lesion encompassing one-third of the left upper eyelid. Four years prior, a similar lesion at that same site had been excised and diagnosed as a basal cell carcinoma. The patient underwent a full-thickness excision of the lesion with frozen section, cryotherapy, and reconstruction. A free tarsal graft and hard palate composite graft was used to reconstruct the posterior lamella. A Mustarde myocutaneous rotational flap was used to reconstruct the anterior lamella. Histopathology illustrated nests of pleomorphic basophilic cells with varying mitotic activity and immunohistochemical staining consistent with eccrine porocarcinoma. This case highlights similarities in the presentation and appearance of basal cell carcinoma and periorbital eccrine porocarcinoma. It is possible that there was de novo development of the 2 tumors on the eyelid or recurrence of a misdiagnosed eccrine porocarcinoma. Eccrine porocarcinomas are rare malignant sweat gland tumors associated with a risk of recurrence after excision and metastasis.

Orbital Bony Reconstruction With Presized and Precontoured Porous Polyethylene-Titanium Implants.

PURPOSE: Complex bony orbital defects are reconstructively challenging due to loss of intraoperative anatomical landmarks and adjacent support. Presized and precontoured porous polyethylene-titanium implants (Medpor Titan 3D Orbital Floor Implant) are designed to reestablish normal orbital floor and medial wall anatomy and are modeled after anatomically averaged orbits. This is the first study to report clinical outcomes with this implant. METHODS: This retrospective case series reviewed clinical data and outcomes for patients undergoing orbital reconstruction with a presized and precontoured porous polyethylene-titanium orbital implant from January 2016 to June 2018. RESULTS: A total of 34 orbits of 33 patients were identified (mean age: 43 ± 16 years, 70% men). Most bony defects were a result of trauma and included large orbital floor deformities (100%), medial wall defects (74%), disrupted inferomedial struts (68%), and broken posterior ledges (82%). Symptomatic diplopia (73%) and enophthalmos (89%, mean: 3.7 ± 2.1 mm) were common preoperatively. Many cases were revisions (44%). Mean follow up was 7.8 ± 6.7 months. All patients had improved globe positioning, enophthalmos, and hypoglobus. Seven patients had persistent postoperative diplopia: 6 responded to prism therapy and 1 required strabismus surgery. One patient required retrobulbar hematoma drainage and 1 patient required implant explantation due to chronic infection. CONCLUSIONS: Commercially available presized and precon toured porous polyethylene-titanium implants are useful for complex orbital bony defects and can achieve functional improve ments in diplopia, enophthalmos, and extraocular motility with a low incidence of postoperative complications or revisional surgery.

A High-Fat Diet Increases Influenza A Virus-Associated Cardiovascular Damage.

BACKGROUND: Influenza A virus (IAV) causes a wide range of extrarespiratory complications. However, the role of host factors in these complications of influenza virus infection remains to be defined. METHODS: Here, we sought to use transcriptional profiling, virology, histology, and echocardiograms to investigate the role of a high-fat diet in IAV-associated cardiac damage. RESULTS: Transcriptional profiling showed that, compared to their low-fat counterparts (LF mice), mice fed a high-fat diet (HF mice) had impairments in inflammatory signaling in the lung and heart after IAV infection. This was associated with increased viral titers in the heart, increased left ventricular mass, and thickening of the left ventricular wall in IAV-infected HF mice compared to both IAV-infected LF mice and uninfected HF mice. Retrospective analysis of clinical data revealed that cardiac complications were more common in patients with excess weight, an association which was significant in 2 out of 4 studies. CONCLUSIONS: Together, these data provide the first evidence that a high-fat diet may be a risk factor for the development of IAV-associated cardiovascular damage and emphasizes the need for further clinical research in this area.

Mitochondrial targeted therapy with elamipretide (MTP-131) as an adjunct to tumor necrosis factor inhibition for traumatic optic neuropathy in the acute setting.

Traumatic optic neuropathy (TON) can occur following blunt trauma to the orbit and can lead to permanent vision loss. In this study, we investigated the effectiveness of elamipretide (MTP-131), a small mitochondrially-targeted tetrapeptide, in conjunction with etanercept, a tumor necrosis factor (TNF) inhibitor, as neuroprotective agents of retinal ganglion cells (RGCs) after optic nerve trauma with sonication-induced TON (SI-TON) in mice. Treatment with intravitreal MTP-131 and subcutaneous etanercept and MTP-131 showed a 21% increase (p < 0.01) in RGC survival rate compared to PBS-treated control eyes. Subcutaneous etanercept and MTP-131 had an 11% increase (p < 0.05) in RGC survival compared to controls. Subcutaneous etanercept only group showed 20% increase (p < 0.01) in RGC survival compared to controls, while subcutaneous MTP-131 alone showed a 17% increase (p < 0.01). Surprisingly, we did not observe a synergistic effect between the two drugs in the group receiving both etanercept and MTP-131. One possible explanation for the absence of a synergistic effect is that MTP-131 and etanercept may be acting on different portions of the same pathway.

Rare/cryptic Aspergillus species infections and importance of antifungal susceptibility testing.

BACKGROUND: The number of patients infected with Aspergillus rose dramatically in recent years. However, studies on the clinical spectrum and antifungal susceptibilities of non-classical (non-fumigatus, non-flavus, non-niger and non-terreus) pathogenic Aspergillus species are very limited. OBJECTIVES: We examined the clinical spectrum and antifungal susceptibilities of 34 non-duplicated, non-classical Aspergillus isolates collected from Hong Kong, Shenzhen and Shanghai. METHODS: The Aspergillus isolates were identified by internal transcribed spacer, partial BenA and partial CaM sequencing and phylogenetic analyses. Susceptibility testing against eight antifungals was performed following the European Committee for Antimicrobial Susceptibility Testing's methodology. RESULTS: The 34 Aspergillus isolates were identified as 14 different rare/cryptic species of four sections (Flavi [n = 8], Nidulantes [n = 8], Nigri [n = 17] and Restricti [n = 1]). Except for one patient whose clinical history could not be retrieved, 72.7% of the remaining patients had underlying conditions predisposing them to Aspergillus infections. The most common diseases were pulmonary infections (n = 15), followed by skin/nail infections (n = 6), chronic otitis externa and/or media (n = 5), wound infections (n = 2) and mastoiditis/radionecrosis (n = 1), while three were colonisations. Five patients succumbed due to the infections during the admission, and another two died 5 years later because of chronic pulmonary aspergillosis. Antifungal susceptibility testing showed that they possessed different susceptibility profiles compared to the classical Aspergillus species. The majority of isolates characterised were sensitive or wild-type to amphotericin B. The minimum effective concentrations for all the three echinocandins were also low. CONCLUSION: Susceptibility testing should be performed for infections due to these rare/cryptic Aspergillus species to guide proper patient management.

Challenges and Opportunities of Nontraditional Approaches to Treating Bacterial Infections.

Due to increasing rates of antimicrobial-resistant infections and the current inadequacy of the antibiotic pipeline, there is increasing interest in nontraditional approaches to antibacterial therapies. We define "traditional" agents as small-molecule agents that directly target bacterial components to exert a bacteriostatic or bactericidal effect, and "nontraditional approaches" as antimicrobial therapeutics that work through other means (ie, not a small molecule and/or utilizes a nontraditional target). Due to their atypical features, such therapies may be less susceptible to the emergence of resistance than traditional antibiotics. They include approaches such as monoclonal antibodies, virulence disruptors, immunomodulators, phage therapies, microbiome-based therapies, antibiotic potentiators, and antisense approaches. This article discusses both the developmental and regulatory advantages and challenges associated with each of these technologies. By identifying existing regulatory and developmental gaps, we hope to provide a sense of where focusing resources may provide the greatest impact on successful product development.

Titanium T-Plate as a Platform for Globe Stabilization in Acquired Nystagmus and Oscillopsia Without a Null Zone.

A 49-year-old woman with debilitating nystagmus and oscillopsia failed conservative therapy. A titanium T-plate was anchored to the lateral orbital rim and cantilevered into the orbit where it was secured to the inferior rectus muscle tendon with a suture. After the procedure was performed on both eyes, the patient had significant decreases in the amplitudes of her nystagmus and oscillopsia, thereby improving her daily function. She had sustained duration of effect through 7 years of follow up. This novel surgical technique holds promise in the treatment of acquired nystagmus and debilitating oscillopsia for which conventional therapy may be ineffective. The case report is in compliance with the Health Insurance Portability and Accountability Act.

A matched case-control comparison of hospital costs and outcomes for knee replacement patients admitted postoperatively to acute care versus rehabilitation.

For select total knee arthroplasty (TKA) patients, we have established an alternative pathway to bypass the acute care surgical ward and directly admit patients from the post-anesthesia care unit to on-campus rehabilitation. We retrospectively examined whether this 'fast track' pathway decreased costs and improved patient outcomes. After reviewing records of consecutive primary unilateral TKA patients over a 15-month period, each patient admitted to rehabilitation was matched with a control admitted to the acute care ward. The primary outcome was estimated total hospitalization cost (length of stay in days multiplied by the average cost per day). Secondary outcomes were length of stay, in-hospital pain scores, opioid use, maximum ambulatory distance and 30-day readmission, morbidity, and mortality. Of the 262 TKA patients during the study period, 14 were admitted to rehabilitation and were matched to 14 patients admitted to acute care. Estimated total hospitalization cost [median (10th-90th percentiles)] was US$30,755 (US$23,066-38,444) for ward patients compared to US$17,620 (US$13,215-33,918) for rehabilitation patients (P = 0.006). This difference [mean (95% CI)] was US$10,143 (US$2174-18,112). There were no other differences. For facilities similar to ours, direct postoperative admission of select TKA patients to subacute rehabilitation may be less costly than acute care and may not negatively affect outcomes.

Establishing prostate cancer patient derived xenografts: lessons learned from older studies.

BACKGROUND: Understanding the progression of prostate cancer to androgen-independence/castrate resistance and development of preclinical testing models are important for developing new prostate cancer therapies. This report describes studies performed 30 years ago, which demonstrate utility and shortfalls of xenografting to preclinical modeling. METHODS: We subcutaneously implanted male nude mice with small prostate cancer fragments from transurethral resection of the prostate (TURP) from 29 patients. Successful xenografts were passaged into new host mice. They were characterized using histology, immunohistochemistry for marker expression, flow cytometry for ploidy status, and in some cases by electron microscopy and response to testosterone. Two xenografts were karyotyped by G-banding. RESULTS: Tissues from 3/29 donors (10%) gave rise to xenografts that were successfully serially passaged in vivo. Two, (UCRU-PR-1, which subsequently was replaced by a mouse fibrosarcoma, and UCRU-PR-2, which combined epithelial and neuroendocrine features) have been described. UCRU-PR-4 line was a poorly differentiated prostatic adenocarcinoma derived from a patient who had undergone estrogen therapy and bilateral castration after his cancer relapsed. Histologically, this comprised diffusely infiltrating small acinar cell carcinoma with more solid aggregates of poorly differentiated adenocarcinoma. The xenografted line showed histology consistent with a poorly differentiated adenocarcinoma and stained positively for prostatic acid phosphatase (PAcP), epithelial membrane antigen (EMA) and the cytokeratin cocktail, CAM5.2, with weak staining for prostate specific antigen (PSA). The line failed to grow in female nude mice. Castration of three male nude mice after xenograft establishment resulted in cessation of growth in one, growth regression in another and transient growth in another, suggesting that some cells had retained androgen sensitivity. The karyotype (from passage 1) was 43-46, XY, dic(1;12)(p11;p11), der(3)t(3:?5)(q13;q13), -5, inv(7)(p15q35) x2, +add(7)(p13), add(8)(p22), add(11)(p14), add(13)(p11), add(20)(p12), -22, +r4[cp8]. CONCLUSIONS: Xenografts provide a clinically relevant model of prostate cancer, although establishing serially transplantable prostate cancer patient derived xenografts is challenging and requires rigorous characterization and high quality starting material. Xenografting from advanced prostate cancer is more likely to succeed, as xenografting from well differentiated, localized disease has not been achieved in our experience. Strong translational correlations can be demonstrated between the clinical disease state and the xenograft model.