A Symptom-Based Rule for Diagnosis of COVID-19.

SARS-CoV-19 PCR testing has a turn-around time that makes it impractical for real-time decision-making, and current point-of-care tests have limited sensitivity, with frequent false negatives. The study objective was to develop a clinical prediction rule to use with a point-of-care test to diagnose COVID-19 in symptomatic outpatients. A standardized clinical questionnaire was administered prior to SARS-CoV-2 PCR testing. Data was extracted by a physician blinded to the result status. Individual symptoms were combined into 326 unique clinical phenotypes. Multivariable logistic regression was used to identify independent predictors of COVID-19, from which a weighted clinical prediction rule was developed, to yield stratified likelihood ratios for varying scores. A retrospective cohort of 120 SARS-CoV-2-positive cases and 120 SARS-CoV-2-negative matched controls among symptomatic outpatients in a Connecticut HMO was used for rule development. A temporally distinct cohort of 40 cases was identified for validation of the rule. Clinical phenotypes independently associated with COVID-19 by multivariable logistic regression include loss of taste or smell (olfactory phenotype, 2 points) and fever and cough (febrile respiratory phenotype, 1 point). Wheeze or chest tightness (reactive airways phenotype, - 1 point) predicted non-COVID-19 respiratory viral infection. The AUC of the model was 0.736 (0.674-0.798). Application of a weighted C19 rule yielded likelihood ratios for COVID-19 diagnosis for varying scores ranging from LR 15.0 for 3 points to LR 0.1 for - 1 point. Using a Bayesian diagnostic approach, combining community prevalence with the evidence-based C19 rule to adjust pretest probability, clinicians can apply a point of care test with limited sensitivity across a range of clinical scenarios to differentiate COVID-19 infection from influenza and respiratory viral infection.

Inferior vena cava filter retrieval provides no advantage in the average patient.

BACKGROUND: Inferior vena cava (IVC) filter placement is performed to mitigate the risk of pulmonary embolism (PE) when anticoagulation is contraindicated or ineffective. Technical advances now allow catheter-based filter retrieval. Many believe the benefits of retrieval are self-evident, yet retrieval carries an inherent complication risk and cost. The purpose of this study was to quantitatively weigh the risks and benefits of IVC filter retrieval using formal decision analysis. METHODS: A Markov state-transition model was used to simulate two clinical scenarios: to leave a previously placed IVC filter or to retrieve it. Analysis was performed during the lifetime of the individual, and outcomes were expressed in quality-adjusted life-years (QALYs). The base case is a 60-year-old man with a filter placed within 3 months who no longer requires mechanical thromboprophylaxis. Potential events included PE, filter complications, and death from all other causes during each cycle. Tolls were used to incorporate the disutility of short-term treatment for PE and filter complications. For the base case and sensitivity analyses, we used utilities and probabilities derived from the literature. RESULTS: In the base case scenario, leaving the filter in place was preferred to filter retrieval, yielding 22.3 vs 21.9 QALYs. One-way sensitivity analysis demonstrated that filter retrieval may be preferable if the utility of living with a filter is <0.98. For all probabilities of retrieval and PE mortality, leaving the filter in place is preferred. CONCLUSIONS: Leaving a previously placed IVC filter provides a 0.4 QALY benefit over retrieving the filter for the average patient. This decision is sensitive to the utility of living with the IVC filter.

FAP20 is an inner junction protein of doublet microtubules essential for both the planar asymmetrical waveform and stability of flagella in Chlamydomonas.

The axoneme-the conserved core of eukaryotic cilia and flagella-contains highly specialized doublet microtubules (DMTs). A long-standing question is what protein(s) compose the junctions between two tubules in DMT. Here we identify a highly conserved flagellar-associated protein (FAP), FAP20, as an inner junction (IJ) component. The flagella of Chlamydomonas FAP20 mutants have normal length but beat with an abnormal symmetrical three-dimensional pattern. In addition, the mutant axonemes are liable to disintegrate during beating, implying that interdoublet connections may be weakened. Conventional electron microscopy shows that the mutant axonemes lack the IJ, and cryo-electron tomography combined with a structural labeling method reveals that the labeled FAP20 localizes at the IJ. The mutant axonemes also lack doublet-specific beak structures, which are localized in the proximal portion of the axoneme and may be involved in planar asymmetric flagellar bending. FAP20 itself, however, may not be a beak component, because uniform localization of FAP20 along the entire length of all nine DMTs is inconsistent with the beak's localization. FAP20 is the first confirmed component of the IJ. Our data also suggest that the IJ is important for both stabilizing the axoneme and scaffolding intra-B-tubular substructures required for a planar asymmetrical waveform.

Quality improvement in hospital management of community-acquired pneumonia: focus on new strategies and current challenges.

Community-acquired pneumonia is a common reason for hospitalization and leads to significant morbidity and mortality. There are published evidence-based guidelines for the diagnosis, treatment, and management of community-acquired pneumonia. Many countries, including the US, have developed national, publically reported quality measures related to the treatment of community-acquired pneumonia. This review highlights recent published innovations aimed at improving the quality of care for patients hospitalized for community-acquired pneumonia. Interventions include standardized protocols and pathways, education and feedback from antimicrobial stewardship teams, and automated pharmacy technology. The importance of multidisciplinary collaboration and multidimensional interventions are discussed. Insight into local context and institutional support are essential to understanding the implementation of improvement efforts and these factors should be reported in future publications related to quality improvement.

Navigating veterans with an abnormal prostate cancer screening test: a quasi-experimental study.

BACKGROUND: Prostate cancer disproportionately affects low-income and minority men. This study evaluates the impact of a patient navigation intervention on timeliness of diagnostic resolution and treatment initiation among veterans with an abnormal prostate cancer screen. METHODS: Participants were enrolled between 2006 and 2010. The intervention involved a social worker and lay health worker navigation team that assisted patients in overcoming barriers to care. For navigated (n = 245) versus control (n = 245) participants, we evaluated rates of diagnostic resolution and treatment and adjusted for race, age, and Gleason score. RESULTS: Of 490 participants, 68% were African American, 47% were ≥ 65 years old, and 35% had cancer. Among those with an abnormal screen, navigation did not have a significant effect on time to diagnostic resolution compared to controls (median days of 97 versus 111; adj. HR 1.17, 95% CI, 0.96-1.43, p = 0.12). On analysis of the period beyond 80 days, navigated men reached resolution faster than controls (median of 151 days versus 190 days; adj. HR 1.41, 95% CI, 1.07-1.86, p = 0.01). Among those with cancer, navigation did not have a significant effect on time to treatment initiation compared to controls (median of 93 days versus 87 days; adj. HR 1.15, 95% CI, 0.82-1.62, p = 0.41). CONCLUSION: Our navigation program did not significantly impact the overall time to resolution or treatment for men with prostate cancer compared to controls. The utility of navigation programs may extend beyond targeted navigation times, however, and future studies focusing on other outcomes measures are therefore needed.

Design of a prostate cancer patient navigation intervention for a Veterans Affairs hospital.

BACKGROUND: Patient navigation programs have been launched nationwide in an attempt to reduce racial/ethnic and socio-demographic disparities in cancer care, but few have evaluated outcomes in the prostate cancer setting. The National Cancer Institute-funded Chicago Patient Navigation Research Program (C-PNRP) aims to implement and evaluate the efficacy of a patient navigation intervention for predominantly low-income minority patients with an abnormal prostate cancer screening test at a Veterans Affairs (VA) hospital in Chicago. METHODS/DESIGN: From 2006 through 2010, C-PNRP implemented a quasi-experimental intervention whereby trained social worker and lay health navigators worked with veterans with an abnormal prostate screen to proactively identify and resolve personal and systems barriers to care. Men were enrolled at a VA urology clinic and were selected to receive navigated versus usual care based on clinic day. Patient navigators performed activities to facilitate timely follow-up such as appointment reminders, transportation coordination, cancer education, scheduling assistance, and social support as needed. Primary outcome measures included time (days) from abnormal screening to diagnosis and time from diagnosis to treatment initiation. Secondary outcomes included psychosocial and demographic predictors of non-compliance and patient satisfaction. Dates of screening, follow-up visits, and treatment were obtained through chart audit, and questionnaires were administered at baseline, after diagnosis, and after treatment initiation. At the VA, 546 patients were enrolled in the study (245 in the navigated arm, 245 in the records-based control arm, and 56 in a subsample of surveyed control subjects). DISCUSSION: Given increasing concerns about balancing better health outcomes with lower costs, careful examination of interventions aimed at reducing healthcare disparities attain critical importance. While analysis of the C-PNRP data is underway, the design of this patient navigation intervention will inform other patient navigation programs addressing strategies to improve prostate cancer outcomes among vulnerable populations.

Dissecting the sequential assembly and localization of intraflagellar transport particle complex B in Chlamydomonas.

Intraflagellar transport (IFT), the key mechanism for ciliogenesis, involves large protein particles moving bi-directionally along the entire ciliary length. IFT particles contain two large protein complexes, A and B, which are constructed with proteins in a core and several peripheral proteins. Prior studies have shown that in Chlamydomonas reinhardtii, IFT46, IFT52, and IFT88 directly interact with each other and are in a subcomplex of the IFT B core. However, ift46, bld1, and ift88 mutants differ in phenotype as ift46 mutants are able to form short flagella, while the other two lack flagella completely. In this study, we investigated the functional differences of these individual IFT proteins contributing to complex B assembly, stability, and basal body localization. We found that complex B is completely disrupted in bld1 mutant, indicating an essential role of IFT52 for complex B core assembly. Ift46 mutant cells are capable of assembling a relatively intact complex B, but such complex is highly unstable and prone to degradation. In contrast, in ift88 mutant cells the complex B core still assembles and remains stable, but the peripheral proteins no longer attach to the B core. Moreover, in ift88 mutant cells, while complex A and the anterograde IFT motor FLA10 are localized normally to the transition fibers, complex B proteins instead are accumulated at the proximal ends of the basal bodies. In addition, in bld2 mutant, the IFT complex B proteins still localize to the proximal ends of defective centrioles which completely lack transition fibers. Taken together, these results revealed a step-wise assembly process for complex B, and showed that the complex first localizes to the proximal end of the centrioles and then translocates onto the transition fibers via an IFT88-dependent mechanism.

Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project.

Progressive multifocal leucoencephalopathy (PML) is a serious and usually fatal CNS infection caused by JC polyoma virus. CD4+ and CD8+ T lymphopenia, resulting from HIV infection, chemotherapy, or immunosuppressive therapy, are the primary risk factors. The immune modulatory monoclonal antibodies rituximab, natalizumab, and efalizumab have received regulatory approval in the USA and Europe for treatment of non-Hodgkin lymphoma, rheumatoid arthritis, and chronic lymphocytic leukaemia (Europe only); multiple sclerosis and Crohn's disease; and psoriasis, respectively. Efalizumab and natalizumab administration is associated with CD4+ T lymphopenia and altered trafficking of T lymphocytes into the CNS, and rituximab leads to prolonged B-lymphocyte depletion. Unexpected cases of PML developing in people who receive these drugs have been reported, with many of the affected individuals dying from this disease. Herein, we review clinical findings, pathology, epidemiology, basic science, and risk-management issues associated with PML infection developing after treatment with these monoclonal antibodies.

Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?

PURPOSE: Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. METHODS: We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. RESULTS: Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. CONCLUSION: AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.

Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons.

Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008).

Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.