T-cell lymphoblastic lymphoma involving the ocular adnexa: report of two cases and review of the current literature.

The majority of ocular adnexal lymphomas are B-cell in origin. We report two cases of T-cell lymphoblastic lymphoma (T-LBL) involving the ocular adnexa. One patient presented with a painless pink conjunctival lesion and inferior orbital fullness. The second patient presented with a painless orbital mass. The diagnoses were confirmed by histopathology and immunohistochemistry. Both patients had extensive multifocal lesions during staging. Prompt intensified chemotherapy regimens were initiated. T-LBL is an aggressive disease with poor prognosis. This report emphasizes the importance of timely diagnosis by the ophthalmologist with co-management and treatment with an oncologist.

Impact of Community Health Workers on Use of Healthcare Services in the United States: A Systematic Review.

BACKGROUND: As the US transitions to value-based healthcare, physicians and payers are incentivized to change healthcare delivery to improve quality of care while controlling costs. By assisting with the management of common chronic conditions, community health workers (CHWs) may improve healthcare quality, but physicians and payers who are making choices about care delivery also need to understand their effects on healthcare spending. METHODS: We searched PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, PsycINFO, Embase, and Web of Science from the inception of each database to 22 June 2015. We included US-based studies that evaluated a CHW intervention for patients with at least one chronic health condition and reported cost or healthcare utilization outcomes. We evaluated studies using tools specific to study design. RESULTS: Our search yielded 2,941 studies after removing duplicates. Thirty-four met inclusion and methodological criteria. Sixteen studies (47%) were randomized controlled trials (RCTs). RCTs typically had less positive outcomes than other study designs. Of the 16 RCTs, 12 reported utilization outcomes, of which 5 showed a significant reduction in one or more of ED visits, hospitalizations and/or urgent care visits. Significant reductions reported in ED visits ranged from 23%-51% and in hospitalizations ranged from 21%-50%, and the one significant reduction in urgent care visits was recorded at 60% (p < 0.05 for all). DISCUSSION: Our results suggest that CHW interventions have variable effects, but some may reduce costs and preventable utilization. These findings suggest that it is possible to achieve reductions in care utilization and cost savings by integrating CHWs into chronic care management. However, variations in cost and utilization outcomes suggest that CHWs alone do not make an intervention successful. The paucity of rigorous studies and heterogeneity of study designs limited conclusions about factors associated with reduced utilization.

Dietary Flavonoid Intake Reduces the Risk of Head and Neck but Not Esophageal or Gastric Cancer in US Men and Women.

Background: Flavonoids are bioactive polyphenolic compounds found in fruits, vegetables, and beverages of plant origin. Previous studies have shown that flavonoid intake reduces the risk of certain cancers; however, few studies to date have examined associations of flavonoids with upper gastrointestinal cancers or used prospective cohorts.Objective: Our study examined the association between intake of flavonoids (anthocyanidins, flavan-3-ols, flavanones, flavones, flavonols, and isoflavones) and risk of head and neck, esophageal, and gastric cancers.Methods: The NIH-AARP Diet and Health Study is a prospective cohort study that consists of 469,008 participants. Over a mean 12-y follow-up, 2453 head and neck (including 1078 oral cavity, 424 pharyngeal, and 817 laryngeal), 1165 esophageal (890 adenocarcinoma and 275 squamous cell carcinoma), and 1297 gastric (625 cardia and 672 noncardia) cancer cases were identified. We used Cox proportional hazards regression models to estimate HRs and CIs for the associations between flavonoid intake assessed at study baseline and cancer outcomes. For 56 hypotheses examined, P-trend values were adjusted using the Benjamini-Hochberg (BH) procedure for false discovery rate control.Results: The highest quintile of total flavonoid intake was associated with a 24% lower risk of head and neck cancer (HR: 0.76; 95% CI: 0.66, 0.86; BH-adjusted 95% CI: 0.63, 0.91; P-trend = 0.02) compared with the lowest quintile. Notably, anthocyanidins were associated with a 28% lower risk of head and neck cancer (HR: 0.72; 95% CI: 0.62, 0.82; BH-adjusted 95% CI: 0.59, 0.87; P-trend = 0.0005), and flavanones were associated with a 22% lower risk of head and neck cancer (HR: 0.78; 95% CI: 0.68, 0.89; BH-adjusted 95% CI: 0.64, 0.94; P-trend: 0.02). No associations between flavonoid intake and risk of esophageal or gastric cancers were found.Conclusions: Our results indicate that flavonoid intake is associated with lower head and neck cancer risk. These associations suggest a protective effect of dietary flavonoids on head and neck cancer risk, and thus potential as a risk reduction strategy.

Self-inflicted enucleations: Clinical features of seven cases.

We report the clinical presentation, radiography, and management outcomes of autoenucleations (AE). Charts of 7 patients evaluated at 4 institutions with AE were reviewed. Four males and three females had a mean age of 50 years (range 26-72 years). The etiologies were psychosis secondary to underlying mental illness (6, 88%) and substance use (1, 12%), and the mechanism was largely blunt digital injury (6, 88%). Three (43%) AE patients suffered bilateral enucleations. Common concomitant injuries included eyelid lacerations (5, 71%) and optic nerve avulsion (3, 43%). Radiography was utilized for all of the study patients with computed tomography as the most common (5, 71%), followed by ultrasound (1, 14%), and magnetic resonance imaging with CT angiography (1, 14). Orbital exploration was performed in the management of all patients. Orbital implants were placed in 4 (57%) patients. Patients were followed for a mean of 1.9 months (range 1-4 months). Autoenucleation affects both genders and is commonly associated with eyelid lacerations, optic nerve avulsion, and intracranial hemorrhage. The association with intracranial hemorrhage is consistent with prior reports of internal carotid artery injury following shearing of the optic nerve. Autoenucleation cases were seen secondary to mental or substance induced psychosis, and these patients may be at risk for future injuries such as AE of the contralateral globe. The common causes for psychosis reported our patient group include schizophrenia, depression, schizoaffective disorder, and methamphetamine-induced psychosis, which corroborates with similar cases in the literature. Two of three cases of bilateral AE suffered sequential AE where the contralateral globe was enucleated days apart. All patients suffering AE should have full medical, psychiatric, neurologic, and radiologic evaluation and monitoring while under care. When evaluating patients with obvious ocular injury, accompanying intracranial injuries should be ruled out in a timely fashion before pursuing surgical intervention.

Correlation of X-ray computed tomography with quantitative nuclear magnetic resonance methods for pre-clinical measurement of adipose and lean tissues in living mice.

Numerous obesity studies have coupled murine models with non-invasive methods to quantify body composition in longitudinal experiments, including X-ray computed tomography (CT) or quantitative nuclear magnetic resonance (QMR). Both microCT and QMR have been separately validated with invasive techniques of adipose tissue quantification, like post-mortem fat extraction and measurement. Here we report a head-to-head study of both protocols using oil phantoms and mouse populations to determine the parameters that best align CT data with that from QMR. First, an in vitro analysis of oil/water mixtures was used to calibrate and assess the overall accuracy of microCT vs. QMR data. Next, experiments were conducted with two cohorts of living mice (either homogenous or heterogeneous by sex, age and genetic backgrounds) to assess the microCT imaging technique for adipose tissue segmentation and quantification relative to QMR. Adipose mass values were obtained from microCT data with three different resolutions, after which the data were analyzed with different filter and segmentation settings. Strong linearity was noted between the adipose mass values obtained with microCT and QMR, with optimal parameters and scan conditions reported herein. Lean tissue (muscle, internal organs) was also segmented and quantified using the microCT method relative to the analogous QMR values. Overall, the rigorous calibration and validation of the microCT method for murine body composition, relative to QMR, ensures its validity for segmentation, quantification and visualization of both adipose and lean tissues.

Retrospective Study of Preoperative Laser Peripheral Iridotomy Versus Intraoperative Surgical Peripheral Iridectomy in Descemet Membrane Endothelial Keratoplasty.

PURPOSE: The aim of this study was to examine the outcomes of laser peripheral iridotomy (LPI) and surgical peripheral iridectomy (SPI) for Descemet membrane endothelial keratoplasty (DMEK) and DMEK with cataract extraction (triple DMEK). METHODS: This retrospective interventional study included 135 eyes of 135 patients who underwent DMEK alone or triple DMEK. Primary outcomes were graft detachments necessitating rebubbling, repeat grafts, and pupillary block. The secondary outcomes included rejection, cystoid macular edema, uveitis, intraoperative hyphema, visual disturbances, and surgical time. RESULTS: Thirty-one eyes in the LPI group and 104 eyes in the SPI group were included. Fifty-six eyes had DMEK alone, and 79 had triple DMEK. Visually significant graft detachments occurred in 7 of 31 eyes in the LPI group versus 19 of 104 eyes in the SPI group ( P = 0.61). No statistical significance in DMEK alone versus triple DMEK groups ( P = 0.61 vs. P > 0.99). Two patients in the LPI group and 5 in the SPI group required regraft ( P = 0.66). One (3.2%) experienced pupillary block compared with 5 (4.8%) ( P = 0.99) in the LPI and SPI groups, respectively. Secondary outcomes were similar in both groups ranging from 0% to 3% ( P > 0.99). None had visual disturbances. In DMEK alone, duration of surgery was significantly shorter in the LPI versus SPI group (32.8 vs. 44.1 minutes, P = 0.02). CONCLUSIONS: This study demonstrated similar outcomes between LPI and SPI, although the LPI group had a shorter duration of surgery when DMEK was performed alone. The remainder of the outcomes demonstrated no statistically significant differences.

7-Oxopyrrolopyridine-derived DPP4 inhibitors-mitigation of CYP and hERG liabilities via introduction of polar functionalities in the active site.

Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 µM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 µmol/kg in ob/ob mice.

Eye Protection for Patients With COVID-19 Undergoing Prolonged Prone-Position Ventilation.

Importance: Critically ill patients with coronavirus disease 2019 (COVID-19) who are unresponsive to maximum optimal ventilator settings may be in a prone position for at least 16 hours per day to improve oxygenation. This extended duration of prone positioning puts patients at risk of developing orbital compartment syndrome if direct pressure to the orbit and the globe occurs and concomitant protection of the eyes is not undertaken. Objective: To report 2 cases of orbital compartment syndrome, as well as optic disc edema and retinal hemorrhages, in the setting of prolonged prone positioning of patients in the intensive care unit during the COVID-19 pandemic. Design, Setting, and Participants: The cases took place from April 27, 2020, to May 4, 2020, at a COVID-19 intensive care unit of a tertiary care hospital. Four of 16 patients in the intensive care unit required prolonged prone-position ventilation. A bedside eye examination was performed on 4 selected patients due to the observed presence of substantial periorbital edema. Main Outcomes and Measures: Intraocular pressures and fundus findings of 4 patients with periorbital edema. Results: Two of 4 patients who were in the prone position for extended periods of time had bilateral fundoscopic findings of optic disc edema and retinal hemorrhages, possibly consistent with a papillophlebitis. Additionally, both patients had a substantial increase in intraocular pressure of 2- to 3-fold in the prone position compared with the supine position. Conclusions and Relevance: Prolonged prone positioning of patients with COVID-19 can be associated with elevated intraocular pressure from periorbital edema, direct compression on the eye, and increased orbital venous pressure. Orbital compartment syndrome can be avoided by the use of protective cushioning around the eyes and maintaining the patient's head position above heart level during prone positioning. Patients with COVID-19 may also develop papillophlebitis with optic disc edema and retinal hemorrhages, which may be associated with a hypercoagulable state caused by COVID-19. These observations suggest awareness for the possible presence of these ophthalmic findings while treating severely ill patients with COVID-19.

Surgical Outcomes of Epiretinal Membrane Removal Due to Combined Hamartoma of the Retina and RPE.

BACKGROUND AND OBJECTIVE: To evaluate the surgical outcomes of epiretinal membrane (ERM) associated with combined hamartoma of the retina and retinal pigment epithelium (CHRRPE) after vitrectomy and membrane peel. PATIENTS AND METHODS: A retrospective review of 15 patients who underwent pars plana vitrectomy with membrane peeling. No plasmin enzyme was used. RESULTS: The mean age at surgery was 10 years old, with an average follow-up of 5.7 years. The average preoperative visual acuity (VA) was 20/514. The average postoperative VA was 20/138 (P = .0251) at 1-year follow-up and 20/89 (P = .0025) on the latest exam on final follow-up. VA was improved in 14 patients (93%) and deteriorated in one patient (7%). All 15 patients (100%) had improvement of retinal/macular anatomy postoperatively. CONCLUSION: In the treatment of patients with ERM due to CHRRPE, vitrectomy with membrane peeling without plasmin injection can result in improved VA and retinal structure. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:546-554.].

Experience of mismatch repair/microsatellite instability (MMR/MSI) testing among patients with advanced/metastatic colorectal cancer in the US.

Objective: We assessed knowledge and awareness of MMR/MSI testing among advanced/metastatic CRC patients in the US who had previously taken the test.Methods: A non-interventional, cross-sectional online survey was conducted among 150 US CRC patients invited through a research panel. Eligible patients had to be ≥18 years, with stage III or IV CRC (self-reported), had undergone MMR/MSI testing for CRC in past 12 months and could recall the test, and provided informed consent. Descriptive analyses were performed.Results: 81.3% of patients received MMR/MSI testing information from their doctor. Of 64.7% of patients who were a member of a patient support group, 86.6% received information from their groups. Most patients (82.7%) also searched for information on their own (internet searches). Most patients (93.5 to 96.9%) were satisfied with information received from these sources. Reasons for having testing done included increasing knowledge about their cancer (69.3%), being beneficial to determining treatment options (60.7%), and doctor recommendation (62.7%). Key barriers to testing included personal reservations regarding benefits of the test (29.3%), insurance coverage (27.3%), and out-of-pocket costs (18.7%); 45.3% reported no barriers.Conclusions: Patients were well informed about MMR/MSI testing. Increased education of testing benefits and addressing financial barriers may help to further improve testing rates.

Mismatch Repair/Microsatellite Instability Testing Practices among US Physicians Treating Patients with Advanced/Metastatic Colorectal Cancer.

The study objective was to assess US physicians' Mismatch Repair/Microsatellite Instability (MMR/MSI) testing practices for metastatic colorectal cancer (mCRC) patients. A non-interventional, cross-sectional online survey was conducted among 151 physicians (91 oncologists, 15 surgeons and 45 pathologists) treating mCRC patients in the US. Eligible physicians were US-based with at least 5 years of experience treating CRC patients, had at least one mCRC patient in their routine care in the past 6 months, and had ordered at least one MMR/MSI test for CRC in the past 6 months. Descriptive and logistic regression analyses were performed. Awareness of specific MMR/MSI testing guidelines was high (n = 127, 84.1%). Of those, 93.7% (119/127) physicians had awareness of specific published guidelines with majority 67.2% (80/119) being aware of National Comprehensive Cancer Network (NCCN) guidelines. Universal testing for all CRC patients was performed by 68.9% (104/151) physicians, while 29.8% (45/151) selectively order the test for some CRC patients. Key barriers for testing included insufficient tissue sample (48.3%, 73/151), patient declined to have the test done (35.8%, 54/151) and insurance cost concerns for patients (31.1%, 47/151), while 27.2% (41/151) reported no barriers. The survey demonstrated high awareness and compliance with MMR/MSI testing guidelines although universal testing rates seem to be suboptimal.

Dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)).

A series of dihydropyrazolopyrimidine inhibitors of K(V)1.5 (I(Kur)) have been identified. The synthesis, structure-activity relationships and selectivity against several other ion channels are described.

Design and SAR of selective T-type calcium channel antagonists containing a biaryl sulfonamide core.

T-type calcium channel antagonists were designed using a protocol involving the program SPROUT and constrained by a ComFA-based pharmacophore model. Scaffolds generated by SPROUT were evaluated based on their ability to be translated into structures that were synthetically tractable. From this exercise, a novel series of potent and selective T-type channel antagonists containing a biaryl sulfonamide core were discovered.

Discovery of a Potent Acyclic, Tripeptidic, Acyl Sulfonamide Inhibitor of Hepatitis C Virus NS3 Protease as a Back-up to Asunaprevir with the Potential for Once-Daily Dosing.

The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. The objective of this work was the identification of a drug with antiviral properties and toxicology parameters similar to 2, but with a preclinical pharmacokinetic (PK) profile that was predictive of once-daily dosing. Critical to this discovery process was the employment of an ex vivo cardiovascular (CV) model which served to identify compounds that, like 2, were free of the CV liabilities that resulted in the discontinuation of BMS-605339 (1) from clinical trials. Structure-activity relationships (SARs) at each of the structural subsites in 2 were explored with substantial improvement in PK through modifications at the P1 site, while potency gains were found with small, but rationally designed structural changes to P4. Additional modifications at P3 were required to optimize the CV profile, and these combined SARs led to the discovery of BMS-890068 (29).

The discovery of asunaprevir (BMS-650032), an orally efficacious NS3 protease inhibitor for the treatment of hepatitis C virus infection.

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).

RasGRPs are targets of the anti-cancer agent ingenol-3-angelate.

Ingenol-3-angelate (I3A) is a non-tumor promoting phorbol ester-like compound identified in the sap of Euphoria peplus. Similar to tumor promoting phorbol esters, I3A is a diacylglycerol (DAG) analogue that binds with high affinity to the C1 domains of PKCs, recruits PKCs to cellular membranes and promotes enzyme activation. Numerous anti-cancer activities have been attributed to I3A and ascribed to I3A's effects on PKCs. We show here that I3A also binds to and activates members of the RasGRP family of Ras activators leading to robust elevation of Ras-GTP and engagement of the Raf-Mek-Erk kinase cascade. In response to I3A, recombinant proteins consisting of GFP fused separately to full-length RasGRP1 and RasGRP3 were rapidly recruited to cell membranes, consistent with direct binding of the compound to RasGRP's C1 domain. In the case of RasGRP3, IA3 treatment led to positive regulatory phosphorylation on T133 and activation of the candidate regulatory kinase PKCδ. I3A treatment of select B non-Hodgkin's lymphoma cell lines resulted in quantitative and qualitative changes in Bcl-2 family member proteins and induction of apoptosis, as previously demonstrated with the DAG analogue bryostatin 1 and its synthetic analogue pico. Our results offer further insights into the anticancer properties of I3A, support the idea that RasGRPs represent potential cancer therapeutic targets along with PKC, and expand the known range of ligands for RasGRP regulation.

Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778).

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.

Characterization of two novel N-methyl-D-aspartate antagonists: EAA-090 (2-[8,9-dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride).

Two novel N-methyl-d-aspartate (NMDA) antagonists with unique chemical structures, EAA-090 (2-[8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R-alpha-amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride), were compared with CGS-19755 (Selfotel) in ligand binding, electrophysiology, and neuroprotection assays. CGS-19755, EAA-090 and EAB-318 inhibited [(3)H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding to NMDA receptors with IC(50) values of 55, 28, and 7.9 nM, respectively. All three compounds decreased the duration of spontaneous synaptic currents and inhibited NMDA-activated currents in rat hippocampal neurons. IC(50) values for inhibition of current induced by 10 microM NMDA were 795, 477, and 69 nM for CGS-19755, EAA-090, and EAB-318, respectively. The NMDA antagonists protected chick embryo retina slices and cultured rat hippocampal and cortical neurons from glutamate- and NMDA-induced neurotoxicity. In experiments in which different NMDA receptor splice variants and subtypes were expressed in Xenopus oocytes, all three antagonists preferentially blocked NMDA-elicited currents mediated by N-methyl-d-aspartate receptor (NR)1 splice variants containing the N-terminal insertion. They also favored NR2A-versus NR2B- or NR2C-containing NMDA receptors, with EAA-090 showing the greatest selectivity. EAA-090 was 10 times more potent at blocking NR2A-versus NR2B- or NR2C-containing NMDA receptors. In addition to being the most potent NMDA antagonist, EAB-318 inhibited alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. The combination of NMDA and AMPA/kainate block enabled EAB-318 to protect neurons against ischemia induced cell death.

Expression and characterization of human transient receptor potential melastatin 3 (hTRPM3).

Transient receptor potential (TRP) cation-selective channels are an emerging class of proteins that are involved in a variety of important biological functions including pain transduction, thermosensation, mechanoregulation, and vasorelaxation. Utilizing a bioinformatics approach, we have identified the full-length human TRPM3 (hTRPM3) as a member of the TRP family. The hTRPM3 gene is comprised of 24 exons and maps to human chromosome 9q-21.12. hTRPM3 is composed of 1555 amino acids and possesses the characteristic six-transmembrane domain of the TRP family. hTRPM3 is expressed primarily in kidney and, at lesser levels, in brain, testis, and spinal cord as demonstrated by quantitative RT-PCR and Northern blotting. In situ hybridization in human kidney demonstrated that hTRPM3 mRNA expression is predominantly found in the collecting tubular epithelium. Heterologous expression of hTRPM3 in human embryonic kidney cells (HEK 293) showed that hTRPM3 is localized to the cell membrane. hTRPM3-expressing cells exhibited Ca2+ concentration-dependent Ca2+ entry. Depletion of intracellular Ca2+ stores by lowering extracellular Ca2+ concentration and treatment with the Ca2+-ATPase inhibitor thapsigargin or the muscarinic receptor agonist carbachol further augmented hTRPM3-mediated Ca2+ entry. The nonselective Ca2+ channel blocker, lanthanide gadolinium (Gd3+), partially inhibited hTRPM3-mediated Ca2+ entry. These results are consistent with the hypothesis that hTRPM3 mediates a Ca2+ entry pathway that apparently is distinct from the endogenous Ca2+ entry pathways present in HEK 293 cells.