The intersection of social risk and race and ethnicity on mental health care utilization is understudied. This study examined disparities in health care treatment, adjusting for clinical need, among ...25,780 Medicare Advantage beneficiaries with a diagnosis of a psychiatric disorder. We assessed contributions to disparities from racial and ethnic differences in the composition and returns of social risk variables. Black and Hispanic beneficiaries had lower rates of mental health outpatient visits than Whites. Assessing composition, Black and Hispanic beneficiaries experienced greater financial, food, and housing insecurity than White beneficiaries, factors associated with greater mental health treatment. Assessing returns, food insecurity was associated with an exacerbation of Hispanic-White disparities. Health care systems need to address the financial, food and housing insecurity of racial and ethnic minority groups with psychiatric disorder. Accounting for racial and ethnic differences in social risk adjustment-based payment reforms has significant implications for provider reimbursement and outcomes.
Rewriting nature’s assembly manual for a ssRNA virus Patel, Nikesh; Wroblewski, Emma; Leonov, German ...
Proceedings of the National Academy of Sciences - PNAS,
11/2017, Letnik:
114, Številka:
46
Journal Article
Recenzirano
Odprti dostop
Satellite tobacco necrosis virus (STNV) is one of the smallest viruses known. Its genome encodes only its coat protein (CP) subunit, relying on the polymerase of its helper virus TNV for replication. ...The genome has been shown to contain a cryptic set of dispersed assembly signals in the form of stem-loops that each present a minimal CP-binding motif AXXA in the loops. The genomic fragment encompassing nucleotides 1–127 is predicted to contain five such packaging signals (PSs). We have used mutagenesis to determine the critical assembly features in this region. These include the CP-binding motif, the relative placement of PS stem-loops, their number, and their folding propensity. CP binding has an electrostatic contribution, but assembly nucleation is dominated by the recognition of the folded PSs in the RNA fragment. Mutation to remove all AXXA motifs in PSs throughout the genome yields an RNA that is unable to assemble efficiently. In contrast, when a synthetic 127-nt fragment encompassing improved PSs is swapped onto the RNA otherwise lacking CP recognition motifs, assembly is partially restored, although the virus-like particles created are incomplete, implying that PSs outside this region are required for correct assembly. Swapping this improved region into the wild-type STNV1 sequence results in a better assembly substrate than the viral RNA, producing complete capsids and outcompeting the wild-type genome in head-to-head competition. These data confirm details of the PS-mediated assembly mechanism for STNV and identify an efficient approach for production of stable virus-like particles encapsidating nonnative RNAs or other cargoes.
Hepatitis B virus (HBV) is a major focus of antiviral research worldwide. The International Coalition to Eliminate HBV, together with the World Health Organisation (WHO), have prioritised the search ...for a cure, with the goal of eliminating deaths from viral hepatitis by 2030. We present here a comprehensive model of intracellular HBV infection dynamics that includes all molecular processes currently targeted by drugs and agrees well with the observed outcomes of several clinical studies. The model reveals previously unsuspected kinetic behaviour in the formation of sub-viral particles, which could lead to a better understanding of the immune responses to infection. It also enables rapid comparative assessment of the impact of different treatment options and their potential synergies as combination therapies. A comparison of available and currently developed treatment options reveals that combinations of multiple capsid assembly inhibitors perform best.
We present direct experimental evidence that assembly of a single- stranded RNA virus occurs via a packaging signal-mediated mechanism. We show that the sequences of coat protein recognition motifs ...within multiple, dispersed, putative RNA packaging signals, as well as their relative spacing within a genomic fragment, act collectively to influence the fidelity and yield of capsid self-assembly in vitro. These experiments confirm that the selective advantages for viral yield and encapsidation specificity, predicted from previous modeling of packaging signal-mediated assembly, are found in Nature. Regions of the genome that act as packaging signals also function in translational and transcriptional enhancement, as well as directly coding for the coat protein, highlighting the density of encoded functions within the viral RNA. Assembly and gene expression are therefore direct molecular competitors for different functional folds of the same RNA sequence. The strongest packaging signal in the test fragment, encodes a region of the coat protein that undergoes a conformational change upon contact with packaging signals. A similar phenomenon occurs in other RNA viruses for which packaging signals are known. These contacts hint at an even deeper density of encoded functions in viral RNA, which if confirmed, would have profound consequences for the evolution of this class of pathogens.
This manuscript addresses the problem of determining input excitation for data driven model identification appropriate for cell culture bio-processes in general, and for an industrial bioreactor used ...for the production of monoclonal antibodies, in particular. The design space is set up to give us the operating parameters for the key objective of demonstrating the feasibility of using far more perturbations than typically done in bio process identification, although significantly less than other applications, to yield data rich enough for the purpose of data driven modelling (and subsequently, control). A proprietary mechanistic model developed by Sartorius for their Cellca cell line is first introduced to serve as a test bed, based on AMBR 250® (Sartorius registered trademark for integrated high throughput bioreactor systems). Subsequently, this test bed is used to address the question of determining the frequency of input perturbation sufficient to identify a data driven dynamic model. To this end, the test bed is used to generate data at various frequencies and a linear time invariant model identified. The predictive capability of the identified model is used to ascertain the frequency of changes in data generation such that the changes are acceptable from a biological standpoint, and yet generate sufficiently rich data. In particular, a frequency of perturbations at once every three days is found to balance these tradeoffs for the monoclonal antibody process under consideration. The results from the manuscript are meaningful both from a specific results standpoint (as illustrated by subsequent adoption by Sartorius), but also by providing a mechanism to ascertain such information for other bio-processes.
The roles of RNA sequence/structure motifs, Packaging Signals (PSs), for regulating assembly of an HBV genome transcript have been investigated in an efficient in vitro assay containing only core ...protein (Cp) and RNA. Variants of three conserved PSs, within the genome of a strain not used previously, preventing correct presentation of a Cp-recognition loop motif are differentially deleterious for assembly of nucleocapsid-like particles (NCPs). Cryo-electron microscopy reconstruction of the T = 4 NCPs formed with the wild-type gRNA transcript, reveal that the interior of the Cp shell is in contact with lower resolution density, potentially encompassing the arginine-rich protein domains and gRNA. Symmetry relaxation followed by asymmetric reconstruction reveal that such contacts are made at every symmetry axis. We infer from their regulation of assembly that some of these contacts would involve gRNA PSs, and confirmed this by X-ray RNA footprinting. Mutation of the ε stem-loop in the gRNA, where polymerase binds in vivo, produces a poor RNA assembly substrate with Cp alone, largely due to alterations in its conformation. The results show that RNA PSs regulate assembly of HBV genomic transcripts in vitro, and therefore may play similar roles in vivo, in concert with other molecular factors.
Objectives
To describe a novel technique for partial anatomic penile amputation using a thoracoabdominal stapler in dogs and to report any associated short‐term peri‐operative complications and ...clinical outcomes associated with the procedure.
Materials and methods
Medical records from a tertiary referral hospital were reviewed for dogs undergoing penile amputation and scrotal urethrostomy between October 2007 and December 2019. Data collected included patient signalment, clinical signs on presentation, indication for penile amputation, surgical technique, duration of surgery, post‐operative complications, and short‐term outcome.
Results
Nine dogs were included in the study. Indications for surgery were for treatment of chronic paraphimosis and priapism (n = 3), recurrent urethral prolapse (n = 2), balanoposthitis (n = 1), masses arising from the penis, prepuce, and/or urethra (n = 2), and penile trauma (n = 1). All dogs underwent a scrotal urethrostomy followed by a partial penile amputation with a thoracoabdominal stapler. All dogs suffered mild post‐operative haemorrhage from the urethrostomy stoma. On recovery from general anaesthesia, 2/9 dogs were painful and another 2/9 dogs were dysphoric. Two dogs experienced incisional complications with mild swelling around the urethrostomy stoma. One dog experienced an infection of the penile amputation site 21 days after surgery. The short‐term outcomes for this procedure were excellent in 8/9 dogs. These outcomes were based on owner assessment of comfort and monitoring throughout the recovery period, manual palpation of the surgical site at the time re‐evaluation, and surgeon visualization of successful voluntary urination 14–35 days after surgery.
Clinical significance
Use of a thoracoabdominal stapler is effective in achieving partial anatomic penile amputation in dogs.
The objective of this study was to describe a complete penile amputation technique using a thoracoabdominal stapler in dogs. The use of a thoracoabdominal stapler is an effective and efficient technique to achieve partial penile amputation in dogs in small animal practice.
We present a case of severe symptomatic hyponatremia (94 mEq/L) in a male patient who presented with nausea, vomiting, and multiple falls. The patient was found with symptomatic hypo-osmolar ...hypovolemic hyponatremia secondary to volume loss from vomiting, diuretic use, and consumption of solute-free water. To manage such a severely hyponatremic patient, concomitant 3% hypertonic saline and DDAVP were initiated with successful slow and sustained correction of sodium without complications of osmotic demyelination syndrome.
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