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.

RASP: Optimal Single Puncta Detection in Complex Cellular Backgrounds.

Super-resolution and single-molecule microscopies have been increasingly applied to complex biological systems. A major challenge of these approaches is that fluorescent puncta must be detected in the low signal, high noise, heterogeneous background environments of cells and tissue. We present RASP, Radiality Analysis of Single Puncta, a bioimaging-segmentation method that solves this problem. RASP removes false-positive puncta that other analysis methods detect and detects features over a broad range of spatial scales: from single proteins to complex cell phenotypes. RASP outperforms the state-of-the-art methods in precision and speed using image gradients to separate Gaussian-shaped objects from the background. We demonstrate RASP's power by showing that it can extract spatial correlations between microglia, neurons, and α-synuclein oligomers in the human brain. This sensitive, computationally efficient approach enables fluorescent puncta and cellular features to be distinguished in cellular and tissue environments, with sensitivity down to the level of the single protein. Python and MATLAB codes, enabling users to perform this RASP analysis on their own data, are provided as Supporting Information and links to third-party repositories.

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.

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.

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.

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.

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.

The role of digital technologies in supporting quality improvement in Australian early childhood education and care settings.

This national study explored the role of digital technologies in early childhood education and care settings and whether they could contribute to quality improvement as reported by educators and assessors of quality in Australia. In this paper, data from Stage 2 of the Quality Improvement Research Project were used, which comprised 60 Quality Improvement Plans from educators linked with 60 Assessment and Rating reports from the assessors who visited early childhood centres as part of the administration of the National Quality Standards by each of Australia's State and Territory jurisdictions. Bronfenbrenner's ecological systems theory ( Bronfenbrenner, U. (1995). Developmental ecology through space and time: A future perspective. In P. Moen, G. H. Elder, Jr., & K. Lüscher (Eds.), Examining lives in context: Perspectives on the ecology of human development (pp. 619-647). American Psychological Association. 10.1037/10176-018; Bronfenbrenner & Ceci, Bronfenbrenner and Ceci, Psychological Review 101:568-586, 1994) was adopted to facilitate a systemic and dynamic view on the use of digital technologies in these 60 ECEC settings. References (e.g. comments/ suggestions/ examples) made by the educators about the implementation of digital technologies were counted and thematically analysed. Results revealed the strong role new technologies (e.g. documentation and management platforms, tablets, apps, etc.) play in the majority of ECEC settings and especially in relation to three of the seven Quality Areas: Educational programme and practice (Quality Area 1); Collaborative partnerships with families and communities (Quality Area 6) and Governance and leadership (Quality Area 7). Future directions for research are suggested and implications for embracing a more holistic, integrated and broad view on the use of digital technologies are discussed.

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.

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.

Synthesis and characterisation of an integratively self-sorted [Fe4L6]8+ tetrahedron.

Isolating metal-organic cage structures which incorporate more than one distinct ligand has been challenging due to competing pressures from narcissistic and social sorting phenomena. Here we report the first example of exclusive formation of a single tetrahedral product from a reaction mixture containing two different bidentate ligands. Exclusive formation of the tetrahedron, which incorporates one unique metal vertex, relies on a triamine to orientate the heteroditopic ligand. Inclusion of perchlorate counterions during the self-assembly process is also found to be a requirement if social sorting is to be avoided. The C3-symmetric structure is characterised by HR-MS, NMR spectroscopy and X-ray crystallography, and provides proof of principle for use of heteroditopic ligands in classical M4L6 supramolecular structures, opening exciting possibilities for their use in separation, storage and catalysis applications.

Hiccups and Acute Symptomatic Hyponatremia: A Rare Manifestation of COVID-19.

We report a rare case of a patient presenting with a very unusual manifestation of coronavirus disease 2019 (COVID-19). A 62-year-old male presented to the emergency department (ED) with complaints of headache, nausea, vomiting, and intractable hiccups for two days. Laboratory results showed that he had profound hyponatremia (Na+: 103 mEq/L) and hypokalemia (K+: 2.3 mEq/L) with a positive RT-PCR for COVID-19. He was treated with an intravenous (IV) bolus of 3% saline solution followed by continuous infusion. The patient was discharged after eight days when his electrolytes returned to normal, and a significant symptomatic relief was achieved.

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.

Nuclear-localized human respiratory syncytial virus NS1 protein modulates host gene transcription.

Human respiratory syncytial virus (RSV) is a common cause of lower respiratory tract infections in the pediatric, elderly, and immunocompromised individuals. RSV non-structural protein NS1 is a known cytosolic immune antagonist, but how NS1 modulates host responses remains poorly defined. Here, we observe NS1 partitioning into the nucleus of RSV-infected cells, including the human airway epithelium. Nuclear NS1 coimmunoprecipitates with Mediator complex and is chromatin associated. Chromatin-immunoprecipitation demonstrates enrichment of NS1 that overlaps Mediator and transcription factor binding within the promoters and enhancers of differentially expressed genes during RSV infection. Mutation of the NS1 C-terminal helix reduces NS1 impact on host gene expression. These data suggest that nuclear NS1 alters host responses to RSV infection by binding at regulatory elements of immune response genes and modulating host gene transcription. Our study identifies another layer of regulation by virally encoded proteins that shapes host response and impacts immunity to RSV.

Myeloma Bone Disease: The Osteoblast in the Spotlight.

Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.