High-throughput super-resolution analysis of influenza virus pleomorphism reveals insights into viral spatial organization.

Many viruses form highly pleomorphic particles. In influenza, virion structure is of interest not only in the context of virus assembly, but also because pleomorphic variations may correlate with infectivity and pathogenicity. We have used fluorescence super-resolution microscopy combined with a rapid automated analysis pipeline, a method well-suited to the study of large numbers of pleomorphic structures, to image many thousands of individual influenza virions; gaining information on their size, morphology and the distribution of membrane-embedded and internal proteins. We observed broad phenotypic variability in filament size, and Fourier transform analysis of super-resolution images demonstrated no generalized common spatial frequency patterning of HA or NA on the virion surface, suggesting a model of virus particle assembly where the release of progeny filaments from cells occurs in a stochastic way. We also showed that viral RNP complexes are located preferentially within Archetti bodies when these were observed at filament ends, suggesting that these structures may play a role in virus transmission. Our approach therefore offers exciting new insights into influenza virus morphology and represents a powerful technique that is easily extendable to the study of pleomorphism in other pathogenic viruses.

Quality Indicators for Major Depressive Disorder in Adults: A Review of Performance Measures by the American College of Physicians.

Major depressive disorder (MDD) is a severe mood disorder that affects at least 8.4% of the adult population in the United States. Characteristics of MDD include persistent sadness, diminished interest in daily activities, and a state of hopelessness. The illness may progress quickly and have devastating consequences if left untreated. Eight performance measures are available to evaluate screening, diagnosis, and successful management of MDD. However, many performance measures do not meet the criteria for validity, reliability, evidence, and meaningfulness.The American College of Physicians (ACP) embraces performance measurement as a means to externally validate the quality of care of practices, medical groups, and health plans and to drive reimbursement processes. However, a plethora of performance measures that provide low or no value to patient care have inundated physicians, practices, and systems and burdened them with collecting and reporting of data. The ACP's Performance Measurement Committee (PMC) reviews performance measures using a validated process to inform regulatory and accreditation bodies in an effort to recognize high-quality performance measures, address gaps and areas for improvement in performance measures, and help reduce reporting burden. Out of 8 performance measures, the PMC found only 1 measure (suicide risk assessment) that was valid at all levels of attribution. This paper presents a review of MDD performance measures and highlights opportunities to improve performance measures addressing MDD management.

Metastatic Infiltration of Nervous Tissue and Periosteal Nerve Sprouting in Multiple Myeloma-Induced Bone Pain in Mice and Human.

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with cell cycle, immune response and neuronal signaling. The MM transcriptional signature was consistent with metastatic MM infiltration to the DRG, a never-before described feature of the disease that we further demonstrated histologically. In the DRG, MM cells caused loss of vascularization and neuronal injury, which may contribute to late-stage MIBP. Interestingly, the transcriptional signature of a MM patient was consistent with MM cell infiltration to the DRG. Overall, our results suggest that MM induces a plethora of peripheral nervous system alterations that may contribute to the failure of current analgesics and suggest neuroprotective drugs as appropriate strategies to treat early onset MIBP.SIGNIFICANCE STATEMENT Multiple myeloma (MM) is a painful bone marrow cancer that significantly impairs the quality of life of the patients. Analgesic therapies for myeloma-induced bone pain (MIBP) are limited and often ineffective, and the mechanisms of MIBP remain unknown. In this manuscript, we describe cancer-induced periosteal nerve sprouting in a mouse model of MIBP, where we also encounter metastasis to the dorsal root ganglia (DRG), a never-before described feature of the disease. Concomitant to myeloma infiltration, the lumbar DRGs presented blood vessel damage and transcriptional alterations, which may mediate MIBP. Explorative studies on human tissue support our preclinical findings. Understanding the mechanisms of MIBP is crucial to develop targeted analgesic with better efficacy and fewer side effects for this patient population.

Amino Functionality Enables Aqueous Synthesis of Carboxylic Acid-Based MOFs at Room Temperature by Biomimetic Crystallization.

Enzyme immobilization within metal-organic frameworks (MOFs) is a promising solution to avoid denaturation and thereby utilize the desirable properties of enzymes outside of their native environments. The biomimetic mineralization strategy employs biomacromolecules as nucleation agents to promote the crystallization of MOFs in water at room temperature, thus overcoming pore size limitations presented by traditional postassembly encapsulation. Most biomimetic crystallization studies reported to date have employed zeolitic imidazole frameworks (ZIFs). Herein, we expand the library of MOFs suitable for biomimetic mineralization to include zinc(II) MOFs incorporating functionalized terephthalic acid linkers and study the catalytic performance of the enzyme@MOFs. Amine functionalization of terephthalic acids is shown to accelerate the formation of crystalline MOFs enabling new enzyme@MOFs to be synthesized. The structure and morphology of the enzyme@MOFs were characterized by PXRD, FTIR, and SEM-EDX, and the catalytic potential was evaluated. Increasing the linker length while retaining the amino moiety gave rise to a family of linkers; however, MOFs generated with the 2,2'-aminoterephthalic acid linker displayed the best catalytic performance. Our data also illustrate that the pH of the reaction mixture affects the crystal structure of the MOF and that this structural transformation impacts the catalytic performance of the enzyme@MOF.

Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 1).

DESCRIPTION: Strategies to manage COVID-19 in the outpatient setting continue to evolve as new data emerge on SARS-CoV-2 variants and the availability of newer treatments. The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the best available evidence on the treatment of adults with confirmed COVID-19 in an outpatient setting. These practice points do not evaluate COVID-19 treatments in the inpatient setting or adjunctive COVID-19 treatments in the outpatient setting. METHODS: The SMPC developed these living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). The SMPC will maintain these practice points as living by monitoring and assessing the impact of new evidence. PRACTICE POINT 1: Consider molnupiravir to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 to 7 days of the onset of symptoms and at high risk for progressing to severe disease. PRACTICE POINT 2: Consider nirmatrelvir-ritonavir combination therapy to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at high risk for progressing to severe disease. PRACTICE POINT 3: Consider remdesivir to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 7 days of the onset of symptoms and at high risk for progressing to severe disease. PRACTICE POINT 4: Do not use azithromycin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 5: Do not use chloroquine or hydroxychloroquine to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 6: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 7: Do not use nitazoxanide to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 8: Do not use lopinavir-ritonavir combination therapy to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 9: Do not use casirivimab-imdevimab combination therapy to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting unless it is considered effective against a SARS-CoV-2 variant or subvariant locally in circulation. PRACTICE POINT 10: Do not use regdanvimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting unless it is considered effective against a SARS-CoV-2 variant or subvariant locally in circulation. PRACTICE POINT 11: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting unless it is considered effective against a SARS-CoV-2 variant or subvariant locally in circulation. PRACTICE POINT 12: Do not use convalescent plasma to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 13: Do not use ciclesonide to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 14: Do not use fluvoxamine to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.

Performance Measures for Physicians Providing Clinical Care Using Telemedicine: A Position Paper From the American College of Physicians.

There has been an exponential growth in the use of telemedicine services to provide clinical care, accelerated by the COVID-19 pandemic. Clinical care delivered via telemedicine has become a major and accepted method of health care delivery for many patients. There is an urgent need to understand quality of care in the telemedicine environment. This American College of Physicians position paper presents 6 recommendations to ensure the appropriate use of performance measures to evaluate quality of clinical care provided in the telemedicine environment.

Quality Indicators for Osteoporosis in Adults: A Review of Performance Measures by the American College of Physicians.

Primary osteoporosis is characterized by decreasing bone mass and density and reduced bone strength that leads to a higher risk for fracture, especially hip and spine fractures. The prevalence of osteoporosis in the United States is estimated at 12.6% for adults older than 50 years. Although it is most frequently diagnosed in White and Asian females, it still affects males and females of all ethnicities. Osteoporosis is considered a major health issue, which has prompted the development and use of several performance measures to assess and improve the effectiveness of screening, diagnosis, and treatment. These performance measures are often used in accountability, public reporting, and/or payment programs. However, the reliability, validity, evidence, attribution, and meaningfulness of performance measures have been questioned. The purpose of this paper is to present a review of current performance measures on osteoporosis and inform physicians, payers, and policymakers in their selection of performance measures for this condition. The Performance Measurement Committee identified 6 osteoporosis performance measures relevant to internal medicine physicians, only 1 of which was found valid at all levels of attribution. This paper also proposes a performance measure concept to address a performance gap for the initial approach to therapy for patients with a new diagnosis of osteoporosis based on the current American College of Physicians guideline.

Outpatient Treatment of Confirmed COVID-19: Living, Rapid Practice Points From the American College of Physicians (Version 2).

DESCRIPTION: Evidence for the use of outpatient treatments in adults with confirmed COVID-19 continues to evolve with new data. This is version 2 of the American College of Physicians (ACP) living, rapid practice points focusing on 22 outpatient treatments for COVID-19, specifically addressing the dominant SARS-CoV-2 Omicron variant. METHODS: The Population Health and Medical Science Committee (formerly the Scientific Medical Policy Committee) developed this version of the living, rapid practice points on the basis of a living, rapid review done by the ACP Center for Evidence Reviews at Cochrane Austria at the University for Continuing Education Krems (Danube University Krems). This topic will be maintained as living and rapid by continually monitoring and assessing the impact of new evidence. PRACTICE POINT 1: Consider molnupiravir to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. PRACTICE POINT 2: Consider nirmatrelvir-ritonavir combination therapy to treat symptomatic patients with confirmed mild to moderate COVID-19 in the outpatient setting who are within 5 days of the onset of symptoms and at a high risk for progressing to severe disease. PRACTICE POINT 3: Do not use ivermectin to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting. PRACTICE POINT 4: Do not use sotrovimab to treat patients with confirmed mild to moderate COVID-19 in the outpatient setting.

What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 2).

DESCRIPTION: The Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) developed these living, rapid practice points to summarize the current best available evidence on the antibody response to SARS-CoV-2 infection and protection against reinfection with SARS-CoV-2. This is version 2 of the ACP practice points, which serves to update version 1, published on 16 March 2021. These practice points do not evaluate vaccine-acquired immunity or cellular immunity. METHODS: The SMPC developed this version of the living, rapid practice points based on an updated living, rapid, systematic review conducted by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. PRACTICE POINT 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. PRACTICE POINT 2: Do not use SARS-CoV-2 antibody tests to predict the degree or duration of natural immunity conferred by antibodies against reinfection, including natural immunity against different variants. RETIREMENT FROM LIVING STATUS: Although natural immunity remains a topic of scientific interest, this topic is being retired from living status given the availability of effective vaccines for SARS-CoV-2 and widespread recommendations for and prevalence of their use. Currently, vaccination is the best clinical recommendation for preventing infection, reinfection, and serious illness from SARS-CoV-2 and its variants.

Structures and systems influencing quality improvement in Australian early childhood education and care centres.

This study assessed the impact of structural characteristics on quality rating and improvement systems (QRIS) outcomes in an Australian national study. Data from the Australian Children's Education and Care Quality Authority (ACECQA) repository of National Quality Standard (NQS) ratings were used to identify long day care services that had improved from Working Towards NQS to Meeting or Exceeding NQS or had no change over two assessments. QRIS outcomes were examined for state/territory jurisdiction, urban-rural location, community socio-economic status, type and size of provider organisation, centre size and stability of centre owner/provider using multinomial logistic regression analyses. Controlling for jurisdiction, results showed that improvement to Meeting NQS was more likely for not-for-profit versus for-profit providers and for large multi-site provider organisations versus small, stand-alone providers. Improvement to Exceeding NQS was also associated with not-for-profit and larger provider organisations, as well as larger versus smaller centres, and centres that had stable ownership.

The Development of Living, Rapid Practice Points: Summary of Methods From the Scientific Medical Policy Committee of the American College of Physicians.

In response to the COVID-19 pandemic, the Scientific Medical Policy Committee (SMPC) of the American College of Physicians (ACP) began developing "practice points" to provide clinical advice based on the best available evidence for the public, patients, clinicians, and public health professionals. As one of the first organizations in the United States to develop evidence-based clinical guidelines, ACP continues to lead and advance the science of evidence-based medicine by implementing new methods to rapidly publish practice points and maintain them as living advice that regularly assesses and incorporates new evidence. The overarching aim of practice points is to answer targeted key questions for which there is a timely need to synthesize evidence for decision making. The SMPC believes these methods can potentially be adapted to address various clinical and public health topics beyond the COVID-19 pandemic. This article presents an overview of the SMPC's living, rapid practice points development process, which includes a rapid systematic review, use of the GRADE (Grading of Recommendations Assessment, Development and Evaluation) method, use of stringent policies on the disclosure of interests and management of conflicts of interest, incorporating a public (nonclinician) perspective, and maintenance of the documents as living through ongoing surveillance and synthesis of new evidence as it emerges.

Appropriate Use of Short-Course Antibiotics in Common Infections: Best Practice Advice From the American College of Physicians.

DESCRIPTION: Antimicrobial overuse is a major health care issue that contributes to antibiotic resistance. Such overuse includes unnecessarily long durations of antibiotic therapy in patients with common bacterial infections, such as acute bronchitis with chronic obstructive pulmonary disease (COPD) exacerbation, community-acquired pneumonia (CAP), urinary tract infections (UTIs), and cellulitis. This article describes best practices for prescribing appropriate and short-duration antibiotic therapy for patients presenting with these infections. METHODS: The authors conducted a narrative literature review of published clinical guidelines, systematic reviews, and individual studies that addressed bronchitis with COPD exacerbations, CAP, UTIs, and cellulitis. This article is based on the best available evidence but was not a formal systematic review. Guidance was prioritized to the highest available level of synthesized evidence. BEST PRACTICE ADVICE 1: Clinicians should limit antibiotic treatment duration to 5 days when managing patients with COPD exacerbations and acute uncomplicated bronchitis who have clinical signs of a bacterial infection (presence of increased sputum purulence in addition to increased dyspnea, and/or increased sputum volume). BEST PRACTICE ADVICE 2: Clinicians should prescribe antibiotics for community-acquired pneumonia for a minimum of 5 days. Extension of therapy after 5 days of antibiotics should be guided by validated measures of clinical stability, which include resolution of vital sign abnormalities, ability to eat, and normal mentation. BEST PRACTICE ADVICE 3: In women with uncomplicated bacterial cystitis, clinicians should prescribe short-course antibiotics with either nitrofurantoin for 5 days, trimethoprim-sulfamethoxazole (TMP-SMZ) for 3 days, or fosfomycin as a single dose. In men and women with uncomplicated pyelonephritis, clinicians should prescribe short-course therapy either with fluoroquinolones (5 to 7 days) or TMP-SMZ (14 days) based on antibiotic susceptibility. BEST PRACTICE ADVICE 4: In patients with nonpurulent cellulitis, clinicians should use a 5- to 6-day course of antibiotics active against streptococci, particularly for patients able to self-monitor and who have close follow-up with primary care.

What Is the Antibody Response and Role in Conferring Natural Immunity After SARS-CoV-2 Infection? Rapid, Living Practice Points From the American College of Physicians (Version 1).

DESCRIPTION: The widespread availability of SARS-CoV-2 antibody tests raises important questions for clinicians, patients, and public health professionals related to the appropriate use and interpretation of these tests. The Scientific Medical Policy Committee (SMPC) of the American College of Physicians developed these rapid, living practice points to summarize the current and best available evidence on the antibody response to SARS-CoV-2 infection, antibody durability after initial infection with SARS-CoV-2, and antibody protection against reinfection with SARS-CoV-2. METHODS: The SMPC developed these rapid, living practice points based on a rapid and living systematic evidence review done by the Portland VA Research Foundation and funded by the Agency for Healthcare Research and Quality. Ongoing literature surveillance is planned through December 2021. When new studies are identified and a full update of the evidence review is published, the SMPC will assess the new evidence and any effect on the practice points. PRACTICE POINT 1: Do not use SARS-CoV-2 antibody tests for the diagnosis of SARS-CoV-2 infection. PRACTICE POINT 2: Antibody tests can be useful for the purpose of estimating community prevalence of SARS-CoV-2 infection. PRACTICE POINT 3: Current evidence is uncertain to predict presence, level, or durability of natural immunity conferred by SARS-CoV-2 antibodies against reinfection (after SARS-CoV-2 infection).

Self-Assembled Anion-Binding Cryptand for the Selective Liquid-Liquid Extraction of Phosphate Anions.

The ligands L1 and L2 form trinuclear self-assembled complexes with Cu2+ (i.e. [(L1 )2 Cu3 ]6+ or [(L2 )2 Cu3 ]6+ ) both of which act as a host to a variety of anions. Inclusion of long aliphatic chains on these ligands allows the assemblies to extract anions from aqueous media into organic solvents. Phosphate can be removed from water efficiently and highly selectively, even in the presence of other anions.

Gastrostomies Preserve But Do Not Increase Quality of Life for Patients and Caregivers.

BACKGROUND & AIMS: Gastrostomies are widely used to provide long-term enteral nutrition to patients with neurologic conditions that affect swallowing (eg, following a cerebrovascular accident or for patients with motor neuron disease) or with oropharyngeal malignancies. The benefits derived from this intervention are uncertain for patients and caregivers. We conducted a prospective, multicenter cohort study to determine how gastrostomies affect health-related quality of life (HRQoL) in recipients and caregivers. METHODS: We performed a study of 100 patients who received gastrostomies (55% percutaneous endoscopic gastrostomy, 45% radiologically inserted) at 5 centers in the United Kingdom, 100 caregivers, and 200 population control subjects. We used the EuroQol-5D (comprising a questionnaire, index, visual analogue scale) to assess HRQoL for patients and caregivers before the gastrostomy insertion and then 3 months afterward; findings were compared with those from control subjects. Ten patients and 10 caregivers were also interviewed after the procedure to explore quantitative findings. Findings from the EuroQol-5D and semi-structured interviews were integrated using a mixed-methods matrix. RESULTS: Six patients died before the 3-month HRQoL reassessments. We observed no significant longitudinal changes in mean EuroQol-5D index scores for patients (0.70 before vs 0.710 after; P = .83) or caregivers (0.95 before vs 0.95 after; P = .32) following gastrostomy insertion. The semi-structured interviews revealed problems in managing gastrostomy tubes, social isolation, and psychological and emotional consequences that reduced HRQoL. CONCLUSIONS: We performed a mixed-methods prospective study of the effects of gastrostomy feeding on HRQoL. HRQoL did not significantly improve after gastrostomy insertion for patients or caregivers. The lack of significant decrease in HRQoL after the procedure indicates that gastrostomies may help maintain HRQoL. Findings have relevance to those involved in gastrostomy insertion decisions and indicate the importance of carefully selecting patients for this intervention, despite the relative ease of insertion.

The Effects of Cumulative Victimization on Mental Health Among Lesbian, Gay, Bisexual, and Transgender Adolescents and Young Adults.

OBJECTIVES: To examine the effects of the cumulative victimization experienced by lesbian, gay, bisexual, and transgender youths on mental disorders. METHODS: We recruited 248 participants from the Chicago, Illinois, area in 7 waves of data collected over 4 years, beginning in 2007 (83.1% retention rate). Mean age at enrollment was 18.7 years, and 54.7% were Black. We measured depression and posttraumatic stress disorder using structured psychiatric interviews. RESULTS: Latent class analyses of victimization over time identified a 4-class solution. Class 1 (65.4%) had low, decreasing victimization. Class 2 (10.3%) had moderate, increasing victimization. Class 3 (5.1%) had high, steady victimization. Class 4 (19.2%) had high, decreasing victimization. Controlling for baseline diagnoses and birth sex, lesbian, gay, bisexual, and transgender youths in classes 2 and 3 were at higher risk for depression than were those in class 1; youths in classes 2, 3, and 4 were at elevated risk for posttraumatic stress disorder. CONCLUSIONS: Lesbian, gay, bisexual, and transgender youths with steadily high or increasing levels of victimization from adolescence to early adulthood are at higher risk for depression and posttraumatic stress disorder.