Lehigh Valley Health Network

According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious issue to public health In the last twenty years, several viral epidemics such as the severe acute respiratory syndrome (SARS-CoV) in 2002 to 2003, and H1N1 influenza in 2009, have been recorded Most recently, the Middle East respiratory syndrome (MERS-CoV) was first identified in Saudi Arabia in 2012 In a timeline that reaches the present day, an epidemic of cases with unexplained low respiratory infections detected in Wuhan, the largest metropolitan area in China's Hubei province, was first reported to the WHO Country Office in China, on December 31, Published literature can trace the beginning of symptomatic individuals back to the beginning of December As they were unable to identify the causative agent, these first cases were classified as pneumonia of unknown etiology The Chinese Center for Disease Control and Prevention (CDC) and local CDCs organized an intensive outbreak investigation program The etiology of this illness is now attributed to a novel virus belonging to the (CoV) family, COVID-19 On February 11, 2020, the WHO Director-General, Dr Tedros Adhanom Ghebreyesus, announced that the disease caused by this new CoV was a which is the acronym of coronavirus disease 2019 In the past twenty years, two additional epidemics have occurred  SARS-CoV provoked a large-scale epidemic beginning in China and involving two dozen countries with approximately 8000 cases and 800 deaths, and the MERS-CoV that began in Saudi Arabia and has approximately 2,500 cases and 800 deaths and still causes as sporadic cases This new virus seems to be contagious and has quickly spread globally In a meeting on January 30, 2020, per the International Health Regulations (IHR, 2005), the outbreak was declared by the WHO a Public Health Emergency of International Concern (PHEIC) as it had spread to 18 countries with four countries reporting human-to-human transmission An additional landmark occurred on February 26, 2020, as the first case of the disease, not imported from China, was recorded in the United States Initially, the new virus was called 2019-nCoV Subsequently, the task of experts of the International Committee on Taxonomy of Viruses (ICTV) termed it the SARS-CoV-2 virus as it is similar to the one that caused the SARS outbreak (SARS-CoVs) The CoVs have become the major pathogens of emerging respiratory disease outbreaks They are a large family of single-stranded RNA viruses (+ssRNA) that can be isolated in different animal species  For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS  Interestingly, these latter viruses have probably originated from bats and then moving into other mammalian hosts — the Himalayan palm civet for SARS-CoV, and the dromedary camel for MERS-CoV — before jumping to humans The dynamics of SARS-Cov-2 are currently unknown, but there is speculation that it also has an animal origin The potential for these viruses to grow to become a pandemic worldwide seems to be a serious public health risk Concerning COVID-19, the WHO raised the threat to the CoV epidemic to the very high level, on February 28, 2020 Probably, the effects of the epidemic caused by the new CoV has yet to emerge as the situation is quickly evolving World governments are at work to establish countermeasures to stem possible devastating effects Health organizations coordinate information flows and issues directives and guidelines to best mitigate the impact of the threat At the same time, scientists around the world work tirelessly, and information about the transmission mechanisms, the clinical spectrum of disease, new diagnostics, and prevention and therapeutic strategies are rapidly developing Many uncertainties remain with regard to both the virus-host interac ion and the evolution of the epidemic, with specific reference to the times when the epidemic will reach its peak At the moment, the therapeutic strategies to deal with the infection are only supportive, and prevention aimed at reducing transmission in the community is our best weapon Aggressive isolation measures in China have led to a progressive reduction of cases in the last few days In Italy, in geographic regions of the north of the peninsula, political and health authorities are making incredible efforts to contain a shock wave that is severely testing the health system In the midst of the crisis, the authors have chosen to use the Statpearls platform because, within the PubMed scenario, it represents a unique tool that may allow them to make updates in real-time  The aim, therefore, is to collect information and scientific evidence and to provide an overview of the topic that will be continuously updated

BACKGROUND: Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non-small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)-positive NSCLC. METHODS: We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. RESULTS: Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS: Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533 .).

BACKGROUND: Data from trials investigating the effects and risks of endovascular thrombectomy for the treatment of stroke due to basilar-artery occlusion are limited. METHODS: We conducted a multicenter, prospective, randomized, controlled trial of endovascular thrombectomy for basilar-artery occlusion at 36 centers in China. Patients were assigned, in a 2:1 ratio, within 12 hours after the estimated time of basilar-artery occlusion to receive endovascular thrombectomy or best medical care (control). The primary outcome was good functional status, defined as a score of 0 to 3 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]), at 90 days. Secondary outcomes included a modified Rankin scale score of 0 to 2, distribution across the modified Rankin scale score categories, and quality of life. Safety outcomes included symptomatic intracranial hemorrhage at 24 to 72 hours, 90-day mortality, and procedural complications. RESULTS: Of the 507 patients who underwent screening, 340 were in the intention-to-treat population, with 226 assigned to the thrombectomy group and 114 to the control group. Intravenous thrombolysis was used in 31% of the patients in the thrombectomy group and in 34% of those in the control group. Good functional status at 90 days occurred in 104 patients (46%) in the thrombectomy group and in 26 (23%) in the control group (adjusted rate ratio, 2.06; 95% confidence interval [CI], 1.46 to 2.91, P<0.001). Symptomatic intracranial hemorrhage occurred in 12 patients (5%) in the thrombectomy group and in none in the control group. Results for the secondary clinical and imaging outcomes were generally in the same direction as those for the primary outcome. Mortality at 90 days was 37% in the thrombectomy group and 55% in the control group (adjusted risk ratio, 0.66; 95% CI, 0.52 to 0.82). Procedural complications occurred in 14% of the patients in the thrombectomy group, including one death due to arterial perforation. CONCLUSIONS: In a trial involving Chinese patients with basilar-artery occlusion, approximately one third of whom received intravenous thrombolysis, endovascular thrombectomy within 12 hours after stroke onset led to better functional outcomes at 90 days than best medical care but was associated with procedural complications and intracerebral hemorrhage. (Funded by the Program for Innovative Research Team of the First Affiliated Hospital of USTC and others; ATTENTION ClinicalTrials.gov number, NCT04751708.).

The patient-centered medical home (PCMH) is four things: 1) the fundamental tenets of primary care: first contact access, comprehensiveness, integration/coordination, and relationships involving sustained partnership; 2) new ways of organizing practice; 3) development of practices' internal capabilities, and 4) related health care system and reimbursement changes. All of these are focused on improving the health of whole people, families, communities and populations, and on increasing the value of healthcare. The value of the fundamental tenets of primary care is well established. This value includes higher health care quality, better whole-person and population health, lower cost and reduced inequalities compared to healthcare systems not based on primary care. The needed practice organizational and health care system change aspects of the PCMH are still evolving in highly related ways. The PCMH will continue to evolve as evidence comes in from hundreds of demonstrations and experiments ongoing around the country, and as the local and larger healthcare systems change. Measuring the PCMH involves the following: Giving primacy to the core tenets of primary care. Assessing practice and system changes that are hypothesized to provide added value Assessing development of practices' core processes and adaptive reserve. Assessing integration with more functional healthcare system and community resources. Evaluating the potential for unintended negative consequences from valuing the more easily measured instrumental features of the PCMH over the fundamental relationship and whole system aspects. Recognizing that since a fundamental benefit of primary care is its adaptability to diverse people, populations and systems, functional PCMHs will look different in different settings. Efforts to transform practice to patient-centered medical homes must recognize, assess and value the fundamental features of primary care that provide personalized, equitable health care and foster individual and population health.

BACKGROUND: Heart failure with preserved ejection fraction (HFPEF) is common and characterized by exercise intolerance and lack of proven effective therapies. Exercise training has been shown to be effective in improving cardiorespiratory fitness (CRF) in patients with systolic heart failure. In this meta-analysis, we aim to evaluate the effects of exercise training on CRF, quality of life, and diastolic function in patients with HFPEF. METHODS AND RESULTS: Randomized controlled clinical trials that evaluated the efficacy of exercise training in patients with HFPEF were included in this meta-analysis. Primary outcome of the study was change in CRF (measured as change in peak oxygen uptake). Effect of exercise training on quality of life (estimated using Minnesota living with heart failure score), and left ventricular systolic and diastolic function was also assessed. The study included 276 patients who were enrolled in 6 randomized controlled trials. In the pooled data analysis, patients with HFPEF undergoing exercise training had significantly improved CRF (mL/kg per min; weighted mean difference, 2.72; 95% confidence interval, 1.79-3.65) and quality of life (weighted mean difference, -3.97; 95% confidence interval, -7.21 to -0.72) when compared with the control group. However, no significant change was observed in the systolic function (EF-weighted mean difference, 1.26; 95% confidence interval, -0.13% to 2.66%) or diastolic function (E/A-weighted mean difference, 0.08; 95% confidence interval, -0.01 to 0.16) with exercise training in patients with HFPEF. CONCLUSIONS: Exercise training in patients with HFPEF is associated with an improvement in CRF and quality of life without significant changes in left ventricular systolic or diastolic function.

The patient-centered medical home (PCMH) is emerging as a potential catalyst for multiple health care reform efforts. Demonstration projects are beginning in nearly every state, with a broad base of support from employers, insurers, state and federal agencies, and professional organizations. A sense of urgency to show the feasibility of the PCMH, along with a 3-tiered recognition process of the National Committee on Quality Assurance, are influencing the design and implementation of many demonstrations. In June 2006, the American Academy of Family Physicians launched the first National Demonstration Project (NDP) to test a model of the PCMH in a diverse national sample of 36 family practices. The authors make up an independent evaluation team for the NDP that used a multimethod evaluation strategy, including direct observation, in-depth interviews, chart audit, and patient and practice surveys. Early lessons from the real-time qualitative analysis of the NDP raise some serious concerns about the current direction of many of the proposed PCMH demonstration projects and point to some positive opportunities. We describe 6 early lessons from the NDP that address these concerns and then offer 4 recommendations for those assisting the transformation of primary care practices and 4 recommendations for individual practices attempting transformation.

BACKGROUND: The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1). METHODS: This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks. RESULTS: Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised. CONCLUSIONS: Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

OBJECTIVE: To assess the effect of a tissue-engineered human dermis (Dermagraft) in healing diabetic foot ulcers. RESEARCH DESIGN AND METHODS: This controlled prospective multicenter randomized single-blinded pilot study evaluated healing over a 12-week period in 50 patients with diabetic foot ulcers. These patients were randomized into four groups (three different dosage regimens of Dermagraft and one control group). All patients received identical care except for the use of Dermagraft tissue. Ulcer healing was assessed by percentage of wounds achieving complete or 50% closure, time to complete or 50% closure, and volume and area measurements. RESULTS: Ulcers treated with the highest dosage of Dermagraft, one piece applied weekly for 8 weeks (group A), healed significantly more often than those treated with conventional wound closure methods; 50% (6 of 12) of the Dermagraft-treated and 8% (1 of 13) of the control ulcers healed completely (P = 0.03). The percentage of wounds achieving 50% closure was also significantly higher (75 vs. 23%; P = 0.018), and the time to complete or 50% closure was faster (P = 0.056). The group A regimen was more effective than other treatment regimens. All three were better than the control, however, and a dose-response was observed. There were no safety concerns. After a mean of 14 months of follow-up (range 11-22 months), there were no recurrences in the Dermagraft-healed ulcers. CONCLUSIONS: Dermagraft was associated with more complete and rapid healing in diabetic foot ulcers. The recurrence data may indicate an improved quality of wound healing.

Coronavirus disease 2019 (COVID-19), the illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a devastating effect on the world's population resulting in more than 2 8 million deaths worldwide and emerging as the most significant global health crisis since the influenza pandemic of 1918 Since being declared a global pandemic by the World Health Organization (WHO) on March 11, 2020, the virus continues to cause devastation, with many countries enduring a second or a third wave of outbreaks of this viral illness Adaptive mutations in the viral genome can alter the virus's pathogenic potential Even a single amino acid exchange can drastically affect a virus's ability to evade the immune system and complicate the vaccine development progress against the virus [1] SARS-CoV-2, like other RNA viruses, is prone to genetic evolution while adapting to their new human hosts with the development of mutations over time, resulting in the emergence of multiple variants that may have different characteristics compared to its ancestral strains Periodic genomic sequencing of viral samples helps detect any new genetic variants of SARS-CoV-2 circulating in communities, especially in a global pandemic setting The genetic evolution of SARS-CoV-2 was minimal during the early phase of the pandemic with the emergence of a globally dominant variant called D614G, which was associated with higher transmissibility but without increased disease severity of its ancestral strain [2] Another variant was identified in humans, attributed to transmission from infected farmed mink in Denmark, which was not associated with increased transmissibility [3] Since then, multiple variants of SARS-CoV-2 have been described, of which a few are considered variants of concern (VOCs), given their impact on public health VOCs are associated with enhanced transmissibility or virulence, reduction in neutralization by antibodies obtained through natural infection or vaccination, the ability to evade detection, or a decrease in therapeutics or vaccination effectiveness The first VOC, the B 1 1 7 lineage (or VOC 202012), was described in the United Kingdom (UK) in late December 2020, followed shortly by the detection of the B 1 351 lineage (or 501Y V2) in South Africa In early January 2021, a new VOC, B 1 1 248/B1 1 28/P1 (or 501Y V3), was reported in Brazil, and more recently, the B 1 427/B 1 429 lineage was identified in California The B 1 427/B 1 429 lineage is classified as VOC by the US Centers for Disease Control and Prevention (CDC) but is considered a variant of interest by the WHO All three reported VOCs (B 1 1 7 variant, B 1 351 variant, and P 1 variant) harbor mutations in the receptor-binding domain (RBD) and the N-terminal domain (NTD), of which the N501Y mutation located on the RBD is common to all variants RBD plays a vital role in facilitating viral entry into the host cell by binding to the host cell angiotensin-converting enzyme-2 (ACE-2) receptors Along with NBD, it is the dominant neutralization target and facilitates antibody production in response to antisera or vaccines [4] Two recent preprint studies (not peer-reviewed) reported that a single mutation of N501Y alone increases the affinity between RBD and ACE2 approximately ten times more than the ancestral strain (N501-RBD) Interestingly the binding affinity of B 1 351 variant and P 1 variant with mutations N417/K848/Y501-RBD and ACE2 was much lower than that of N501Y-RBD and ACE2 [5][6] Despite the extraordinary speed of vaccine development against COVID-19 and continued mass vaccination efforts across the world, the emergence of these new variant strains of SARS-CoV-2 threatens to overturn the significant progress made so far in halting the spread of SARS-CoV-2 This review article aims to comprehensively describe these new variants of concern, the latest therapeutics available in managing COVID-19 in adults, and the efficacy of different available vaccines against this virus and its new variants SARS-CoV-2 Variant

PURPOSE: The purpose of this study was to determine the complication rate of a consecutive series of patients undergoing arthroscopic rotator cuff repair. METHODS: From January 2003 to June 2003, all patients undergoing primary arthroscopic rotator cuff repair were identified. A total of 263 patients were identified. Medical records were reviewed to identify complications in the study patients. RESULTS: A total of 28 patients (10.6%) sustained a complication. Complications included shoulder stiffness, failure of healing, infection, reflex sympathetic dystrophy, deep venous thrombosis, and death. CONCLUSIONS: The most common complication was recognized as persistent stiffness that usually responded to extensive physical therapy. Complications after arthroscopic rotator cuff repair are similar to results published for open rotator cuff repair. LEVEL OF EVIDENCE: Level IV, therapeutic case series.

A total of 1355 patients underwent internal sphincterotomy for chronic fissure in ano between 1980 and 1985. Surgical data were obtained for 1102 patients, and 829 patients responded to a questionnaire. Of the 1057 for whom the time of healing was recorded, 1033 (97.7 per cent) healed by a mean time of 5.6 weeks. No significant differences in satisfaction with the outcome or in deficits in continence were noted between groups undergoing lateral, bilateral or posterior midline sphincterotomy. Excision of the fissure was found to be unnecessary. According to responses on the questionnaires, deficits in continence ranging from 'sometimes' to 'frequently' included lack of control of flatus (35.1 per cent), soiling of underclothing (22.0 per cent) and accidental bowel movements (5.3 per cent). A significantly higher proportion of patients who had accidental bowel movements were aged over 40 years.

Many commentators view the conversion of small, independent primary care practices into patient-centered medical homes as a vital step in creating a better-performing health care system. The country's first national medical home demonstration, which ran from June 1, 2006, to May 31, 2008, and involved thirty-six practices, showed that this transformation can be lengthy and complex. Among other features, the transformation process requires an internal capability for organizational learning and development; changes in the way primary care clinicians think about themselves and their relationships with patients as well as other clinicians on the care team; and awareness on the part of primary care clinicians that they will need to make long-term commitments to change that may require three to five years of external assistance. Additionally, transforming primary care requires synchronizing practice redesign with development of the health care "neighborhood," which is made up of a broad range of health and health care resources available to patients. It also requires payment reform that supports practice development and a policy environment that sets reasonable expectations and time frames for the adoption of appropriate innovations.

In everyday complex listening situations, sound emanating from several different sources arrives at the ears of a listener both directly from the sources and as reflections from arbitrary directions. For localization of the active sources, the auditory system needs to determine the direction of each source, while ignoring the reflections and superposition effects of concurrently arriving sound. A modeling mechanism with these desired properties is proposed. Interaural time difference (ITD) and interaural level difference (ILD) cues are only considered at time instants when only the direct sound of a single source has non-negligible energy in the critical band and, thus, when the evoked ITD and ILD represent the direction of that source. It is shown how to identify such time instants as a function of the interaural coherence (IC). The source directions suggested by the selected ITD and ILD cues are shown to imply the results of a number of published psychophysical studies related to source localization in the presence of distracters, as well as in precedence effect conditions.

Hyperlipidemia is a well-established risk factor for developing cardiovascular disease (CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein (LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsinkexin type 9 (PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.

Importance: Single-center and claims-based studies have described substantial changes in the landscape of care in the cardiac intensive care unit (CICU). Professional societies have recommended research to guide evidence-based CICU redesigns. Objective: To characterize patients admitted to contemporary, advanced CICUs. Design, Setting, and Participants: This study established the Critical Care Cardiology Trials Network (CCCTN), an investigator-initiated multicenter network of 16 advanced, tertiary CICUs in the United States and Canada. For 2 months in each CICU, data for consecutive admissions were submitted to the central data coordinating center (TIMI Study Group). The data were collected and analyzed between September 2017 and 2018. Main Outcomes and Measures: Demographics, diagnoses, management, and outcomes. Results: Of 3049 participants, 1132 (37.1%) were women, 797 (31.4%) were individuals of color, and the median age was 65 years (25th and 75th percentiles, 55-75 years). Between September 2017 and September 2018, 3310 admissions were included, among which 2557 (77.3%) were for primary cardiac problems, 337 (10.2%) for postprocedural care, 253 (7.7%) for mixed general and cardiac problems, and 163 (4.9%) for overflow from general medical ICUs. When restricted to the initial 2 months of medical CICU admissions for each site, the primary analysis population included 3049 admissions with a high burden of noncardiovascular comorbidities. The top 2 CICU admission diagnoses were acute coronary syndrome (969 [31.8%]) and heart failure (567 [18.6%]); however, the proportion of acute coronary syndrome was highly variable across centers (15%-57%). The primary indications for CICU care included respiratory insufficiency (814 [26.7%]), shock (643 [21.1%]), unstable arrhythmia (521 [17.1%]), and cardiac arrest (265 [8.7%]). Advanced CICU therapies or monitoring were required for 1776 patients (58.2%), including intravenous vasoactive medications (1105 [36.2%]), invasive hemodynamic monitoring (938 [30.8%]), and mechanical ventilation (652 [21.4%]). The overall CICU mortality rate was 8.3% (95% CI, 7.3%-9.3%). The CICU indications that were associated with the highest mortality rates were cardiac arrest (101 [38.1%]), cardiogenic shock (140 [30.6%]), and the need for renal replacement therapy (51 [34.5%]). Notably, patients admitted solely for postprocedural observation or frequent monitoring had a mortality rate of 0.2% to 0.4%. Conclusions and Relevance: In a contemporary network of tertiary care CICUs, respiratory failure and shock predominated indications for admission and carried a poor prognosis. While patterns of practice varied considerably between centers, a substantial, low-risk population was identified. Multicenter collaborative networks, such as the CCCTN, could be used to help redesign cardiac critical care and to test new therapeutic strategies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are drugs with analgesic, anti-inflammatory, and antipyretic activity. Their effect is achieved by the reduction in synthesis of prostanoids. Inhibition of prostanoids is responsible for a substantial risk of adverse effects. The risk of side effects affecting the gastrointestinal tract and kidneys has long been known. The possibilities of blood pressure elevation and the development of congestive heart failure are also widely recognized. Increased incidence of acute myocardial infarction in clinical trials with rofecoxib drew attention to the potential cardiotoxicity of selective cyclooxygenase-2 inhibitors, and similarly, concerns have been raised regarding the cardiovascular safety of non-selective NSAIDs. The safety of NSAIDs with regards to cardiovascular events has been studied in recent years in a large number of retrospective and prospective clinical studies and meta-analyses. The results indicate that cardiotoxicity is a class effect, but the magnitude of the risk is widely variable between individual NSAID drugs. This article aims to summarize the available data on the risk of adverse cardiovascular events with NSAIDs, the clinical impact of these events and possible underlying mechanisms.

UNLABELLED: An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the noncanonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Furthermore, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In patients with melanoma treated with the BRAF inhibitor vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance. SIGNIFICANCE: These data show for the fi rst time that a single signaling pathway, the Wnt signaling pathway, can effectively guide the phenotypic plasticity of tumor cells, when primed to do so by a hypoxic microenvironment. Importantly, this increased Wnt5A signaling can give rise to a subpopulation of highly invasive cells that are intrinsically less sensitive to novel therapies for melanoma, and targeting the Wnt5A/ROR2 axis could improve the efficacy and duration of response for patients with melanoma on vemurafenib.

OBJECTIVE: To review the use of screening criteria (also known as "triggers") as a mechanism for engaging palliative care consultants to assist with care of critically ill patients and their families in the ICU. DATA SOURCES: We searched the MEDLINE database from inception to December 2012 for all English-language articles using the terms "trigger," "screen," "referral," "tool," "triage," "case-finding," "assessment," "checklist," "proactive," or "consultation," together with "intensive care" or "critical care" and "palliative care," "supportive care," "end-of-life care," or "ethics." We also hand-searched reference lists and author files and relevant tools on the Center to Advance Palliative Care website. STUDY SELECTION: Two members (a physician and a nurse with expertise in clinical research, intensive care, and palliative care) of the interdisciplinary Improving Palliative Care in the ICU Project Advisory Board presented studies and tools to the full Board, which made final selections by consensus. DATA EXTRACTION: We critically reviewed the existing data and tools to identify screening criteria for palliative care consultation, to describe methods for selecting, implementing, and evaluating such criteria, and to consider alternative strategies for increasing access of ICU patients and families to high-quality palliative care. DATA SYNTHESIS: The Improving Palliative Care in the ICU Advisory Board used data and experience to address key questions relating to: existing screening criteria; optimal methods for selection, implementation, and evaluation of such criteria; and appropriateness of the screening approach for a particular ICU. CONCLUSIONS: Use of specific criteria to prompt proactive referral for palliative care consultation seems to help reduce utilization of ICU resources without changing mortality, while increasing involvement of palliative care specialists for critically ill patients and families in need. Existing data and resources can be used in developing such criteria, which should be tailored for a specific ICU, implemented through an organized process involving key stakeholders, and evaluated by appropriate measures. In some settings, other strategies for increasing access to palliative care may be more appropriate.

OBJECTIVE: To describe the relationships among functional health status measures (SF-12 physical and mental components summary scores), traditional measures of community health status, and social determinants of health among respondents to community health status surveys conducted in nine different communities. DATA SOURCES/STUDY SETTING: Data collected as part of comprehensive community health status assessments conducted in each of nine communities (in seven states) between 1992 and 1997. The purpose of each assessment was to gather data to plan and evaluate population health improvement initiatives. STUDY DESIGN AND DATA COLLECTION: This is an opportunistic study drawing on the universe of community health survey data collected by the authors to support local health improvement initiatives. Both community-level as well as an aggregate of individual-level measures are used in the analysis. Within each locality, survey respondents were randomly selected using a telephone-facilitated, mailed survey methodology. PRINCIPAL FINDINGS: The key variables reported here are functional health status measures (SF-12) and social determinants of health variables. SF-12 physical and mental component scales correlated with two of four traditional measures of community health status. At the aggregate level of analysis, significant relationships were found for seven of nine social determinants of health measures when compared with SF-12 component summary scores. Relationships between social determinants measures and PCS-12 and MCS-12 scores suggest both application possibilities and the need for additional analysis in order to understand the nature of those relationships. CONCLUSIONS: Physical and mental health functioning summary scores as measured by the SF-12 are useful in describing overall community health status when compared with traditional measures such as total deaths, age-adjusted mortality, or physician to population ratio. The SF-12 can also be used to measure the relationship between physical and mental health functioning (as proxies for community health status) and the social determinants of health. This analysis can help to refine our understanding of how social determinants and health status interact in a community or population as a precursor to the development of models of community or population health.

BACKGROUND: There is good evidence for the efficacy of inpatient palliative care in improving clinical care, patient and provider satisfaction, quality of life, and health care utilization. However, the evidence for the efficacy of nonhospice outpatient palliative care is less well known and has not been comprehensively reviewed. OBJECTIVE: To review and assess the evidence of the impact of outpatient palliative care. METHODS: Our study was a review of published, peer-reviewed outcomes research, including both observational studies and controlled trials of nonhospice outpatient palliative care services. We assessed patient, family caregiver, and clinician satisfaction; clinical outcomes including symptom management, quality of life, and mortality; and heath care utilization outcomes including readmission rates, hospice use, and cost. RESULTS: Four well-designed randomized interventions as well as a growing body of nonrandomized studies indicate that outpatient palliative care services can: 1) improve patient satisfaction, 2) improve symptom control and quality of life, 3) reduce health care utilization, and 4) lengthen survival in a population of lung cancer patients. CONCLUSIONS: The available evidence supports the ongoing expansion of innovative outpatient palliative care service models throughout the care continuum to all patients with serious illness.