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Supplementary Figures S1-S2.

Toxoplasma gondii is a ubiquitous parasitic protozoan that poses a health threat to wildlife and human health worldwide. Oocysts shed into the environment in felid host feces may persist for several years. Runoff from rainfall and snowmelt may carry the oocysts into waterways. Semiaquatic mammals such as the Northern American river otter (Lontra canadensis) are particularly at risk of exposure, as they may encounter infective stages in both terrestrial and aquatic environments. Despite this risk, only a small number of studies have examined the prevalence of T. gondii in US river otter populations. Tongue tissue was sampled from 124 otters from the Upper Peninsula of Michigan submitted by trappers to the Michigan Department of Natural Resources in the 2018-19 harvest season. Following DNA extraction, a portion of the B1 T. gondii gene was amplified with PCR. A subset of positive samples was genotyped for comparison with known T. gondii sequences. Of the 124 tongue samples, 35 (28%) were positive for T. gondii. Prevalence did not differ significantly between sexes or age classes across the entire study area. Most (53.8%) of the genotyped samples were type 4 (type 12), a genotype commonly found in North American wildlife. Genotypes 127 and 197 were also found. Three clusters of T. gondii prevalence were identified through SaTScan analysis, although they were not significant. When modeling prevalence of T. gondii with covariates at individual otter locations, the top three models included the presence of Sarcocystis, area of exotic plants, area of agriculture, and sex of the otter. Our results suggest that T. gondii is widespread in otter populations in the Upper Peninsula of Michigan.

Background: Evidence suggests that poor sleep increases risk of delirium. Because delirium is associated with poor outcomes, institutions have developed protocols to improve sleep in critically ill patients. Objective: To assess the impact of implementing a multicomponent sleep protocol. Methods: In this prospective, preimplementation and postimplementation evaluation, adult patients admitted to the medical intensive care unit (ICU) over 42 days were included. Outcomes evaluated included median delirium-free days, median Richards-Campbell Sleep Questionnaire (RCSQ) score, median optimal sleep nights, duration of mechanical ventilation (MV), ICU and hospital length of stay (LOS), and in-hospital mortality. Results: The preimplementation group included 78 patients and postimplementation group, 84 patients. There was no difference in median delirium-free days (1 day [interquartile range, IQR, = 0-2.5] vs 1 day [IQR = 0-2]; P = 0.48), median RCSQ score (59.4 [IQR = 43.2-71.6] vs 61.2 [IQR = 49.9-75.5]; P = 0.20), median optimal sleep nights (1 night [IQR = 0-2] vs 1 night [IQR = 0-2]; P = 0.95), and in-hospital mortality (16.7% vs 17.9%, P = 1.00). Duration of MV (8 days [IQR = 4-10] vs 4 days [IQR = 2-7]; P = 0.03) and hospital LOS (13 days [IQR = 7-22.3] vs 8 days [IQR = 6-17]; P = 0.05) were shorter in the postimplementation group, but both were similar between groups after adjusting for age and severity of illness. Conclusions and Relevance: This report demonstrates that implementation of a multicomponent sleep protocol in everyday ICU care is feasible, but limitations exist when evaluating impact on measurable outcomes. Additional evaluations are needed to identify the most meaningful interventions and best practices for quantifying impact on patient outcomes.

Viral and host factors can shape SARS-CoV-2 within-host viral diversity and virus evolution. However, little is known about lineage-specific and vaccination-specific mutations that occur within individuals. Here we analysed deep sequencing data from 2,146 SARS-CoV-2 samples with different viral lineages to describe the patterns of within-host diversity in different conditions, including vaccine-breakthrough infections. Variant of Concern (VOC) Alpha, Delta, and Omicron samples were found to have higher within-host nucleotide diversity while being under weaker purifying selection at full genome level compared to non-VOC SARS-CoV-2 viruses. Breakthrough Delta and Omicron infections in Comirnaty and CoronaVac vaccinated individuals appeared to have higher within-host purifying selection at the full-genome and/or Spike gene levels. Vaccine-induced antibody or T cell responses did not appear to have significant impact on within-host SARS-CoV-2 evolution. Our findings suggest that vaccination does not increase SARS-CoV-2 protein sequence space and may not facilitate emergence of more viral variants.

Practice guidelines recommend palliative care for patients with advanced cancer, but gaps in access and quality of care persist.To increase goals-of-care (GOC) communication for hospitalized patients with Stage IV cancer.An interdisciplinary team designed a quality improvement intervention to enhance oncology palliative care, including training in communication skills and triggers for palliative care consults.All adult inpatients with Stage IV cancer and unplanned admission at an 804-bed hospital affiliated with a National Cancer Institute (NCI) Comprehensive Cancer Center.The primary quality measure was the percentage of patients with Stage IV cancer who had a GOC discussion during hospitalization; secondary measures included screening for pain, dyspnea, spiritual needs, and outcomes of intensive care, hospice, and 30-day readmission.In the 11-month study period, n = 330, Stage IV cancer patients were hospitalized. Comparing the first three months with the final three months, rates of GOC discussion increased from 29% to 48% (p = 0.013), and specialty palliative care consultation increased from 18% to 33%, (p = 0.026). Rates of symptom screening, intensive care unit transfer, hospice, and 30-day re-admission did not change overall. However, patients with specialty palliative care more frequently had pain screening (91% vs. 81%, p = 0.020), spiritual assessment (48% vs. 10%, p 0.001), and hospice referral (39% vs. 9%, p 0.001), and they were less likely to be re-admitted within 30 days (12% vs. 21%, p = 0.059).Interdisciplinary quality improvement was effective to increase GOC discussions and palliative care consults for patients with Stage IV cancer.

Purpose: Intermediate care units (IMCUs) represent an alternative care setting with nurse staffing levels between those of the general ward and the intensive care unit (ICU). Despite rising prevalence, little is known about IMCU practices across US hospitals. The purpose of this study is to characterize utilization patterns and assess for variation. Materials and Methods: A 14-item survey was distributed to a random nationwide sample of pulmonary and critical care physicians between January and April 2017. Results: A total of 51 physicians from 24 different states completed the survey. Each response represented a unique institution, the majority of which were public (59%), academic (73%), and contained at least 1 IMCU (65%). Of the IMCUs surveyed, 58% operated as 1 mixed unit that admitted medical, cardiac, and surgical patients as opposed to having separate subspecialty units. Ninety-one percent of units admitted step-down patients from the ICU, but 39% of units accepted a mix of step-up patients, step-down patients, postoperative patients, and patients from the emergency department. Intensivists managed care in 21% of units whereas 36% had no intensivist involvement. Conclusion: Organization practices vary considerably between IMCUs across institutions. The impact of different organization practices on patient outcomes should be assessed.

In the Fluid and Catheter Treatment Trial (FACTT) of the National Institutes of Health Acute Respiratory Distress Syndrome Network, a conservative fluid protocol (FACTT Conservative) resulted in a lower cumulative fluid balance and better outcomes than a liberal fluid protocol (FACTT Liberal). Subsequent Acute Respiratory Distress Syndrome Network studies used a simplified conservative fluid protocol (FACTT Lite). The objective of this study was to compare the performance of FACTT Lite, FACTT Conservative, and FACTT Liberal protocols.Retrospective comparison of FACTT Lite, FACTT Conservative, and FACTT Liberal. Primary outcome was cumulative fluid balance over 7 days. Secondary outcomes were 60-day adjusted mortality and ventilator-free days through day 28. Safety outcomes were prevalence of acute kidney injury and new shock.ICUs of Acute Respiratory Distress Syndrome Network participating hospitals.Five hundred three subjects managed with FACTT Conservative, 497 subjects managed with FACTT Liberal, and 1,124 subjects managed with FACTT Lite.Fluid management by protocol.Cumulative fluid balance was 1,918 ± 323 mL in FACTT Lite, -136 ± 491 mL in FACTT Conservative, and 6,992 ± 502 mL in FACTT Liberal (p0.001). Mortality was not different between groups (24% in FACTT Lite, 25% in FACTT Conservative and Liberal, p = 0.84). Ventilator-free days in FACTT Lite (14.9 ± 0.3) were equivalent to FACTT Conservative (14.6 ± 0.5) (p = 0.61) and greater than in FACTT Liberal (12.1 ± 0.5, p0.001 vs Lite). Acute kidney injury prevalence was 58% in FACTT Lite and 57% in FACTT Conservative (p = 0.72). Prevalence of new shock in FACTT Lite (9%) was lower than in FACTT Conservative (13%) (p = 0.007 vs Lite) and similar to FACTT Liberal (11%) (p = 0.18 vs Lite).FACTT Lite had a greater cumulative fluid balance than FACTT Conservative but had equivalent clinical and safety outcomes. FACTT Lite is an alternative to FACTT Conservative for fluid management in Acute Respiratory Distress Syndrome.

Context Patients triggering rapid response team (RRT) intervention are at high risk for adverse outcomes. Data on symptom burden of these patients do not currently exist, and current symptom management and communication practices of RRT clinicians are unknown. Objectives We sought to identify the symptom experience of RRT patients and observe how RRT clinicians communicate with patients and their families. Methods We conducted a prospective observational study from August to December 2015. Investigators attending RRT events measured frequencies of symptom assessment, communication, and supportive behaviors by RRT clinicians. As the rapid response event concluded, investigators measured patient-reported pain, dyspnea, and anxiety using a numeric rating scale of 0 (none) to 10 (most severe), with uncontrolled symptoms defined as numeric rating scale score of ≥4. Results We observed a total of 52 RRT events. RRT clinicians assessed for pain during the event in 62% of alert patients, dyspnea in 38%, and anxiety in 21%. Goals of care were discussed during 3% of events and within 24 hours in 13%. For the primary outcome measure, at the RRT event conclusion, 44% of alert patients had uncontrolled pain, 39% had uncontrolled dyspnea, and 35% had uncontrolled anxiety. Conclusion Hospitalized patients triggering RRT events have a high degree of uncontrolled symptoms that are infrequently assessed and treated. Although these patients experience an acute change in medical status and are at high risk for adverse outcomes, goals-of-care discussions with RRT patients or families are rarely documented in the period after the events.

Acute respiratory compromise describes a deterioration in respiratory function with a high likelihood of rapid progression to respiratory failure and death. Identifying patients at risk for respiratory compromise coupled with monitoring of patients who have developed respiratory compromise might allow earlier interventions to prevent or mitigate further decompensation. The National Association for the Medical Direction of Respiratory Care (NAMDRC) organized a workshop meeting with representation from many national societies to address the unmet needs of respiratory compromise from a clinical practice perspective. Respiratory compromise may arise de novo or may complicate preexisting lung disease. The group identified distinct subsets of respiratory compromise that present similar opportunities for early detection and useful intervention to prevent respiratory failure. The subtypes were characterized by the pathophysiological mechanisms they had in common: impaired control of breathing, impaired airway protection, parenchymal lung disease, increased airway resistance, hydrostatic pulmonary edema, and right-ventricular failure. Classification of acutely ill respiratory patients into one or more of these categories may help in selecting the screening and monitoring strategies that are most appropriate for the patient's particular pathophysiology. Standardized screening and monitoring practices for patients with similar mechanisms of deterioration may enhance the ability to predict respiratory failure early and prevent its occurrence.

To compare the differences in characteristics and outcomes of cancer center patients with other subspecialty medical patients reviewed by rapid response teams.A retrospective cohort study of hospitalized general medicine patients, subspecialty medicine patients, and oncology patients requiring rapid response team activation over a 2-year period from September 2009 to August 2011.Five hundred fifty-seven subspecialty medical patients required rapid response team intervention.A single academic medical center in the southeastern United States (800+ bed) with a dedicated 50-bed inpatient comprehensive cancer care center.Data abstraction from computerized medical records and a hospital quality improvement rapid response database.Of the 557 patients, 135 were cancer center patients. Cancer center patients had a significantly higher Charlson Comorbidity Score (4.4 vs 2.9,0.001). Cancer center patients had a significantly longer hospitalization period prior to rapid response team activation (11.4 vs 6.1 d, p0.001). There was no significant difference between proportions of patients requiring ICU transfer between the two groups (odds ratio, 1.2; 95% CI, 0.8-1.8). Cancer center patients had a significantly higher in-hospital mortality compared with the other subspecialty medical patients (33% vs 18%; odds ratio, 2.2; 95% CI, 1.50-3.5). If the rapid response team event required an ICU transfer, this finding was more pronounced (56% vs 23%; odds ratio, 4.0; 95% CI, 2.0-7.8). The utilization of rapid response team resources during the 2-year period studied was also much higher for the oncology patients with 37.34 activations per 1,000 patient discharges compared with 20.86 per 1,000 patient discharges for the general medical patients.Oncology patients requiring rapid response team activation have a significantly higher in-hospital mortality rate, particularly if the rapid response team requires ICU transfer. Oncology patients also utilize rapid response team resources at a much higher rate.

Respiratory conditions, both acute and chronic, continue to have a significant impact on worldwide health because of their high prevalence, the high disease burden they place on individual health, and their enormous cost to the health care system. There are also unmeasured indirect economic costs due to loss of productivity. Despite advances in our understanding of the complex pathophysiology of respiratory diseases, as well as the availability of relatively straightforward primary prevention measures, the prevalence of chronic respiratory diseases continues to rise. In addition, periodic outbreaks of acute infectious respiratory conditions result in significant cost and even mortality, and the incidence of these conditions fluctuates widely from year to year. Although we have seen recent developments in medical therapies for respiratory diseases, and there are established and well-publicized disease management guidelines, morbidity and mortality remain high. One intervention that has lagged behind has been smoking prevention and cessation, which is the mainstay of prevention for chronic obstructive pulmonary disease and lung cancer. The persistence of these conditions underscores vulnerabilities within our national and regional health care systems. Several of the articles in this issue of the NCMJ describe innovative programs to address these challenges.

Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.

Cell migration is one of the hallmarks of metastatic disease and thus identification of migration promoting proteins is crucial for the understanding of metastasis formation. Here we show that the neuron-specific, F-actin bundling inositol-1,4,5-trisphosphate-3-kinase-A (ITPKA) is ectopically expressed in tumor cells and critically involved in migration. Down-regulation of ITPKA expression in transformed cell-lines with ectopic expression of ITPKA significantly decreased migration and the number of linear and branched cell protrusion. Conversely, up-regulation of ITPKA in tumor cell lines with low endogenous ITPKA expression increased migration and formation of cell processes. In vitro, ITPKA alone induced the formation of linear actin filaments, whereas ITPKA mediated formation of branched protrusions seems to result from interaction between ITPKA and the F-actin cross-linking protein filamin C. Based on these actin-modulating and migration-promoting effects of ITPKA we examined its expression in clinical samples of different tumor entities, starting with the analysis of multiple tumor tissue arrays. As in lung adenocarcinoma specimens, the highest ITPKA expression rate was found, this tumor entity was examined in more detail. ITPKA was expressed early in adenocarcinoma progression (pN0) and was largely maintained in invasive and metastatic tumor cell populations (pN1/2, lymph node metastases). Together with our result that high expression of ITPKA increases motility of tumor cells we conclude that the observed expression of ITPKA early in tumor development increases the metastatic potential of lung adenocarcinoma cells. Therefore, we suggest that ITPKA may be a promising therapeutic molecular target for anti metastatic therapy of lung cancer.

Cellular migration is an essential prerequisite for metastatic dissemination of cancer cells. This study demonstrates that the neuron/testis-specific F-actin-targeted inositol 1,4,5-trisphosphate 3-kinase-A (ITPKA) is ectopically expressed in different human tumor cell lines and during tumor progression in the metastatic tumor model Balb-neuT. High expression of ITPKA increases invasive migration in vitro and metastasis in a xenograft SCID mouse model. Mechanistic studies show that ITPKA promotes migration of tumor cells by two different mechanisms as follows: growth factor independently high levels of ITPKA induce the formation of large cellular protrusions by directly modulating the actin cytoskeleton. The F-actin binding activity of ITPKA stabilizes and bundles actin filaments and thus increases the levels of cellular F-actin. In growth factor-stimulated cells, the catalytically active domain enhances basal ITPKA-induced migration by activating store-operated calcium entry through production of inositol 1,3,4,5-tetrakisphosphate and subsequent inhibition of inositol phosphate 5-phosphatase. These two functional activities of ITPKA stimulating tumor cell migration place the enzyme among the potential targets of anti-metastatic therapy.

Over the past three years there have been many positive changes to the quality of services (for example, the colorectal department) and to the number of services offered by Hinchingbrooke (provision of in-house urology; ear, nose, and throat; and plastic and hand surgery). Recent data on mortality show that it is significantly lower than in other hospitals and the overall trend for mortality is reducing.1 We have had no …

Purpose: Combined surgery for glaucoma and cataract may not achieve as low intraocular pressure (IOP) as compared with trabeculectomy alone. The aim of this study was to assess the IOP control of 5-fluorouracil (5FU) phacotrabeculectomies compared with 5-fluorouracil trabeculectomies.Methods: A retrospective, nonrandomized study of consecutive primary 5FU phacotrabeculectomies and primary 5FU trabeculectomies. The main outcome measures were preoperative and postoperative IOP, number of medications, visual acuity, and complications.Results: Forty-five 5FU phacotrabeculectomies and 47 5FU trabeculectomies were performed with a mean follow-up of 43.1 and 36.6 months, respectively. The absolute success rate as defined as an IOP equal to or less than 16 mm Hg on no glaucoma drops was 62.2% for the phacotrabeculectomy group and 63.8% for the trabeculectomy group. These success rates were not statistically significantly different (log-rank test P = 0.81 for absolute success). and P = 0.29 for relative success. The magnitude of the treatment effect was found to be significantly greater in the T group compared with the PT group (a 44.6% reduction in IOP in the T group compared with a 31.2% reduction in the PT group). The phacotrabectomy group underwent significantly more postoperative 5FU injections compared with the trabeculectomy group (P = 0.008).Conclusions: 5FU phacotrabeculectomy seems to be a safe and effective treatment option in terms of IOP control. Patients with both coexistent glaucoma and cataract could be considered for combined surgery.

Background: WC and NS contributed equally. Non-tuberculous mycobacteria (NTM) frequently colonise patients with end stage cystic fibrosis (CF), but its impact on the course of the disease following lung transplantation is unknown. Methods: Lung transplant recipients with CF who underwent lung transplantation at our institution between January 1990 and May 2003 (n = 146) and CF patients awaiting lung transplantation in May 2003 (n = 31) were studied retrospectively. Results: The prevalence rate of NTM isolated from respiratory cultures in patients with end stage CF referred for lung transplantation was 19.7%, compared with a prevalence rate of 13.7% for NTM isolates in CF lung transplant recipients. The overall prevalence of invasive NTM disease after lung transplantation was low (3.4%) and was predicted most strongly by pre-transplant NTM isolation (p = 0.001, Fisher’s exact test, odds ratio (OR) 6.13, 95% CI 3.2 to 11.4). This association was restricted to Mycobacterium abscessus (p = 0.005, Fisher’s exact test, OR 7.45, 95% CI 2.9 to 16.9). While NTM disease caused significant morbidity in a small number of patients after transplantation, it was successfully treated and did not influence the post-transplant course of the disease. Conclusion: The isolation of NTM before transplantation in CF patients should not be an exclusion criterion for lung transplantation, but it may alert the clinician to patients at risk of recurrence following transplantation.

Amyotrophic lateral sclerosis (ALS)-linked mutations in UBQLN2 and some members of the heterogeneous nuclear ribonucleoproteins (hnRNPs) family cause ALS. Most mutations in UBQLN2 are missense mutations that occur in and around a PXX repeat motif located in the central domain of the encoded protein. However, neither the function of the PXX motif nor the mechanism by which mutations in UBQLN2 cause ALS is known. We screened a yeast two-hybrid library using the central domain of ubiquilin-2 hoping to identify proteins whose binding is affected by the UBQLN2 mutations. Three such interactors were identified-hnRNPA1, hnRNPA3 and hnRNPU-all members of the hnRNP family. The interacting region in each of these proteins was their glycine-rich domain, the domain most frequently mutated in hnRNP-related proteins that cause ALS. We focused on hnRNPA1, because a mutation in the protein causes ALS. We confirmed the interaction between wild-type (WT) ubiquilin-2 and hnRNPA1 proteins in vitro and in cells. In contrast, all five ALS mutations in ubiquilin-2 that we examined had reduced binding with WT hnRNPA1. In addition, hnRNPA1 carrying the D262V missense mutation that causes ALS failed to bind WT ubiquilin-2. Overexpression of ubiquilin-2 containing the ALS mutations increased cell death and, for several of the mutants, this correlated with increased translocation of hnRNPA1 to the cytoplasm. Knockdown of ubiquilin-2 led to increased turnover of hnRNPA1, indicating ubiquilin-2 functions to stabilize hnRNPA1. The discovery that ubiquilin-2 interacts with hnRNP proteins and that mutation in either protein disrupts interaction suggests a connection between proteostasis and RNA metabolism.

The focused ultrasound examination has become increasingly recognized as a safe and valuable diagnostic tool for the bedside assessment of the critically ill patient. We implemented a dedicated on-site critical care ultrasonography curriculum with the goal of developing a model for teaching ultrasound skills to pulmonary and critical care medicine fellows.The program was comprised of blended didactic and bedside sessions in the following topic domains: fundamentals; vascular access and diagnosis; and abdominal, thoracic, and cardiac ultrasonography. Formal knowledge and image acquisition assessments were performed before and after the program to assess success in meeting predefined learning objectives. Participants completed surveys (on Likert scale 1-5) before and after the program to assess their confidence in ultrasonography knowledge and skills as well as their perception as to training effectiveness.The preintervention knowledge and bedside image acquisition scores were 71 and 32%, respectively. The global preintervention score was 51%. All postintervention measures demonstrated significant improvement: 89% (P0.01), 86% (P0.0001), and 87% (P0.0001). Preintervention participant confidence in their ultrasound knowledge and skill was 2.9/5, which improved to 4.3/5 (P = 0.007) after intervention. Participants rated the curriculum as meeting course objectives at a mean of 4.8/5.At one academic medical center, the knowledge of eight adult pulmonary and critical care fellowship trainees regarding critical care ultrasound was high at baseline; however, bedside image acquisition skills were poor. A dedicated 6-week educational intervention resulted in highly significant improvements in subject knowledge and image acquisition skills. These preliminary results warrant validation studies at other medical centers.

Antonio M Fea,1 Jose I Belda,2 Marek Rękas,3 Anselm Jünemann,4 Lydia Chang,5 Luis Pablo,6 Lilit Voskanyan,7 L Jay Katz81Università degli Studi di Torino, Clinica Oculistica, Torino, Italy; 2Hospital Torrevieja Salud, UTE, Servicio de Oftalmologia, Alicante, Spain; 3Military Institute of Medicine, Department of Ophthalmology, Warsaw, Poland; 4Universitätsaugenklinik, Erlangen, Germany; 5Hinchingbrooke Hospital NHS Trust and Moorfields Bedford Hospital NHS Trust, United Kingdom; 6Hospital Universitario Miguel Servet, Servicio Oftalmologico, Zaragoza, Spain; 7SV Malayan Ophthalmological Center, Yerevan, Armenia; 8Wills Eye Institute, Jefferson Medical College, Philadelphia, PA, USAPurpose: The purpose of this study was to compare outcomes of subjects with open-angle glaucoma (OAG) not controlled on one medication who underwent either implantation of two iStent inject® trabecular micro-bypass devices or received medical therapy consisting of a fixed combination of latanoprost/timolol.Patients and methods: Of 192 subjects who qualified for the study and were enrolled, 94 were randomized to surgery with implantation of two iStent inject® devices in the treated eye and 98 to receive medical therapy.Results: At the month 12 visit, 94.7% of eyes (89/94) in the stent group reported an unmedicated intraocular pressure (IOP) reduction of ≥20% versus baseline unmedicated IOP, and 91.8% of eyes (88/98) in the medical therapy group reported an IOP reduction ≥20% versus baseline unmedicated IOP. A 17.5% between-group treatment difference in favor of the iStent inject group was statistically significant (P=0.02) at the ≥50% level of IOP reduction. An IOP ≤18 mmHg was reported in 92.6% of eyes (87/94) in the iStent inject group and 89.8% of eyes (88/98) in the medical therapy group. Mean (standard deviation) IOP decreases from screening of 8.1 (2.6) mmHg and 7.3 (2.2) mmHg were reported in the iStent inject and medical therapy groups, respectively. A high safety profile was also noted in this study in both the iStent inject and medical therapy groups, as measured by stable best corrected visual acuity, cup-to-disc ratio, and adverse events.Conclusion: These data show that the use of iStent inject is at least as effective as two medications, with the clinical benefit of reducing medication burden and assuring continuous treatment with full compliance to implant therapy as well as having a highly favorable safety profile.Keywords: ab interno, intraocular pressure, trabecular bypass, OAG, IOP reduction

Huntington's Disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in huntingtin (htt) protein. The expansion leads to increased htt aggregation and toxicity. Factors that aid in the clearance of mutant huntingtin proteins should relieve the toxicity. We previously demonstrated that overexpression of ubiqulin-1, which facilitates protein clearance through the proteasome and autophagy pathways, reduces huntingtin aggregates and toxicity in mammalian cell and invertebrate models of HD. Here we tested whether overexpression of ubiquilin-1 delays or prevents neurodegeneration in R6/2 mice, a well-established model of HD. We generated transgenic mice overexpressing human ubiquilin-1 driven by the neuron-specific Thy1.2 promoter. Immunoblotting and immunohistochemistry revealed robust and widespread overexpression of ubiquilin-1 in the brains of the transgenic mice. Similar analysis of R6/2 animals revealed that ubiquilin is localized in huntingtin aggregates and that ubiquilin levels decrease progressively to 30% during the end-stage of disease. We crossed our ubiquilin-1 transgenic line with R6/2 mice to assess whether restoration of ubiquilin levels would delay HD symptoms and pathology. In the double transgenic progeny, ubiquilin levels were fully restored, and this correlated with a 20% increase in lifespan and a reduction in htt inclusions in the hippocampus and cortex. Furthermore, immunoblots indicated that endoplasmic reticulum stress response that is elevated in the hippocampus of R6/2 animals was attenuated by ubiquilin-1 overexpression. However, ubiquilin-1 overexpression neither altered the load of htt aggregates in the striatum nor improved motor impairments in the mice.

Purpose To report on the medical treatments used for pediatric glaucomas. Patients and methods A retrospective case series consisting of reviewing the medical notes of pediatric glaucoma patients under the care of the Glaucoma Service at Moorfields Eye Hospital NHS Foundation Trust. The medical notes of 200 patients were selected. The following outcomes were assessed: (1) the use of individual medical therapies; (2) the intraocular pressure (IOP) reduction effect of individual medicines; (3) the reporting of side effects. Results Medicines were prescribed 1592 times (200 patients). The median % IOP reduction for latanoprost 50 mcg/mL was -17.2% and for the topical beta blockers was -17.7% (as monotherapy), with no statistical difference in IOP-lowering effect between all the medicines (P=0.19). Side effects were reported in 19.5% of all patients-the highest occurrence with brimonidine tartrate 0.2% (in 17% patients) and the lowest occurrence with the prostaglandin analogue and prostamide medicines (in 3.8% patients). The combination of dorzolamide hydrochloride 2%, timolol maleate 0.5% had the greatest persistence of 1 year. Conclusions The IOP-lowering effects of all the glaucoma medicines were not significantly different although the combination of dorzolamide hydrochloride 2%, timolol maleate 0.5% had the greatest persistence.

Under physiologic conditions, the inositol-1,4,5-trisphosphate (InsP3)-metabolizing, F-actin–bundling InsP3-kinase-A (ITPKA) is expressed only in neurons. Tumor cells that have gained the ability to express ITPKA show an increased metastatic potential due to the migration-promoting properties of ITPKA. Here we investigated the mechanism how tumor cells have gained the ability to reexpress ITPKA by using a breast cancer cell line (T47D) with no expression and a lung carcinoma cell line (H1299) with ectopic ITPKA expression. Cloning of a 1,250-bp ITPKA promoter fragment revealed that methylation of CpG islands was reduced in H1299 as compared with T47D cells, but DNA demethylation did not alter the expression of ITPKA. Instead, we showed that the repressor-element-1–silencing transcription factor (REST)/neuron-restrictive silencer factor (NRSF), which suppresses expression of neuronal genes in nonneuronal tissues, regulates expression of ITPKA. Knockdown of REST/NRSF induced expression of ITPKA in T47D cells, whereas its overexpression in H1299 cells strongly reduced the level of ITPKA. In T47D cells, REST/NRSF was bound to the RE-1 site of the ITPKA promoter and strongly reduced its activity. In H1299 cells, in contrast, expressing comparable REST/NRSF levels as T47D cells, REST/NRSF only slightly reduced ITPKA promoter activity. This reduced suppressor activity most likely results from expression of a dominant-negative isoform of REST/NRSF, REST4, which impairs binding of REST/NRSF to the RE-1 site. Thus, ITPKA may belong to the neuronal metastasis-promoting proteins whose ectopic reexpression in tumor cells is associated with impaired REST/NRSF activity. Mol Cancer Res; 9(4); 497–506. ©2011 AACR.

o minimize patient discomfortin the intensive care unit (ICU),sedation and analgesia have be-come an integral part of criticalcare practice. Sedation and analgesia re-ducethestressresponse,provideanxiolysis,improve tolerance of ventilator support,and facilitate nursing care. Unfortunately,sedatives and analgesics have adverse ef-fects including respiratory depression anddelirium that can prolong mechanical ven-tilation. This problem can worsen patientoutcome and substantially increase healthcare costs (1, 2). Deliberate approaches tothe administration of sedatives includingdefined nurse-directed protocols (3, 4) anddaily interruption of continuous infusionsof sedatives (5) can lead to significant de-creases in duration of mechanical ventila-tion. Important complexity remains, how-ever, regarding the choice of appropriatesedative medications and methods of ad-ministration (6). A number of effective sed-ative agents are available, but they differconsiderably with regard to adverse effectsand costs.Clinical practice guidelines (7) assem-bled by the American College of CriticalCare Medicine of the Society of CriticalCare Medicine (SCCM) recommend the useof lorazepam given as intermittent intrave-nous bolus or continuous intravenous in-fusion for most patients. This recommen-dation is based in part on lower drugacquisition costs for lorazepam comparedwith other benzodiazepines such as midazo-lam, with equal or better levels of sedation inpatients requiring long-term sedation (8, 9).Many physicians and pharmacists prefer in-termittent bolus dosing of lorazepam ratherthan continuous infusions because of highlevels of drug accumulation and oversedationassociated with continuous infusions (10),and because of concerns regarding precipita-tion of drug in intravenous tubing (9, 11).

Many patients presenting with acute gastrointestinal hemorrhage (GIH) are admitted to the intensive care unit (ICU) for monitoring. A simple triage protocol based upon validated risk factors could decrease ICU utilization.Records of 188 patients admitted with GIH from the emergency department (ED) were reviewed for BLEED criteria (visualized red blood, systolic blood pressure below 100 mm Hg, elevated prothrombin time [PT], erratic mental status, and unstable comorbid disease) and complication within the first 24 hours of admission. Variables associated with early complication were reassessed in 132 patients prospectively enrolled as a validation cohort. A triage model was developed using significant predictors.We studied 188 patients in the development set and 132 in the validation set. Red blood (relative risk [RR] 4.53, 95% confidence interval [CI] 2.04, 10.07) and elevated PT (RR 3.27, 95% CI 1.53, 7.01) were significantly associated with complication in the development set. In the validation cohort, the combination of red blood or unstable comorbidity had a sensitivity of 0.73, a specificity of 0.55, a positive predictive value of 0.24, and a negative predictive value of 0.91 for complication within 24 hours. In simulation studies, a triage model using these variables could reduce ICU admissions without increasing the number of complications.Patients presenting to the ED with GIH who have no evidence of ongoing bleeding or unstable comorbidities are at low risk for complication during hospital admission. A triage model based on these variables should be tested prospectively to optimize critical care resource utilization in this common condition.