Effectiveness and diagnostic accuracy of teledermatology for the assessment of skin conditions.

BACKGROUND: Teledermatology provides a platform for swift specialist advice without the potential need for face-to-face review. Our objectives were to investigate the effectiveness, accuracy and diagnostic concordance of the platform with regard to the remote management of skin conditions. METHODS: We undertook a single-centre, retrospective chart review over a 1-year period, comprising a total of 1703 teledermatology referrals. Two physicians independently assessed the diagnostic concordance between telederm diagnosis (TD), in-person diagnosis (ID) and histopathological diagnosis (HD). RESULTS: There were a total of 1703 TD referrals, of which 341 were rejected, leaving 1362 referrals for evaluation. Sixty-five per cent of these referrals were managed remotely and discharged with advice, although 4.6% of these were later re-referred for an in-person review. A total of 20% of referrals were rejected, of which the majority was due to a lack of appropriate imaging. The total concordance of TD compared to ID was 76.4%. When comparing the TD and ID/HD, we obtained a Kappa value of 0.636 indicating substantial agreement. In terms of accuracy, there were 49 biopsy-proven skin cancers picked up by the service in this cohort of data. Of these, 61.2% were given an accurate diagnosis on first impression via teledermatology, 14.3% were given a different diagnosis but correctly categorised as skin cancer and 24.5% could not be assessed; however, they were triaged and escalated based upon clinical suspicion. CONCLUSION: Our study demonstrates that teledermatology is an effective platform in terms of diagnosis and remote management, with adequate diagnostic accuracy and concordance to in-person diagnosis.

Social Risk Factors and Racial and Ethnic Disparities in Health Care Resource Utilization Among Medicare Advantage Beneficiaries With Psychiatric Disorders.

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.

Evaluation of the Panbio™ COVID-19 IgG rapid test device performance.

Background: The Panbio™ COVID-19 IgG Rapid Test Device ("Panbio™") detects IgG antibodies against the SARS-CoV-2 spike protein from viral infection or vaccination. Objectives: To determine the diagnostic sensitivity and specificity of the Panbio™ professional use test, using fingerstick whole blood and venous plasma. Study design: Fingerstick whole blood and venous plasma from each participant were tested with Panbio™ and compared against the SARS-CoV-2 IgG II assay on the Abbott Architect™ platform (Europe) or the equivalent AdviseDx SARS-CoV-2 IgG II Abbott Alinity i™ platform (US). 447 evaluable participants were enrolled across 6 US and 9 European clinical centers. Results: For unvaccinated participants with PCR-confirmed infection ≥21 days post-symptom onset, the Panbio™ sensitivity with fingerstick whole blood was 92.6 % (95 % CI: 85.9, 96.7), and the specificity was 97.0 % (95 % CI: 93.1, 99.0). For venous plasma, the sensitivity was 90.0 % (95 % CI: 79.5, 96.2) for participants with PCR-confirmed infection and symptom onset 22-180 days ago; the specificity was 96.3 % (92.2, 98.6). For vaccinated participants, the sensitivity was 98.4 % (95 % CI: 91.2, 100.0) for fingerstick whole blood and 96.7 % (95 % CI: 88.7, 99.6) for venous plasma. Conclusion: The Panbio™ test had high sensitivity and specificity for detecting IgG against the SARS-CoV-2 spike protein.

Concern for Increased Prevalence of Heyde's Syndrome in Patients on Hemodialysis.

The association between aortic stenosis and increased gastrointestinal arteriovenous malformations is known as Heyde's syndrome. An acquired von Willebrand deficiency mediates the connection between these two seemingly dispersed pathologies. As von Willebrand factor passes through a stenosed aorta, it is broken down and can no longer inhibit angiogenesis, leading to angiodysplasias. Heyde's syndrome can manifest with chronic, refractory anemia requiring multiple hospitalizations for symptomatic gastrointestinal bleeding and transfusion. Hitherto, Heyde's syndrome has been considered exceptionally rare, with 1-3% of populations with aortic stenosis. However, given that 31.7% of patients with gastrointestinal angioplasty have aortic stenosis and gastrointestinal arteriovenous malformations are not screened for in patients without anemia, the prevalence of Heyde's syndrome is most likely higher than currently reflected in the literature. Also, the prevalence of Heyde's syndrome in populations who are predisposed to angiodysplasias, such as those on hemodialysis, is understudied. We aim to impart a need for increased research on the prevalence of Heyde's syndrome, especially in high-risk patients. This case report presents a patient with severe Heyde's syndrome on hemodialysis, showing an unconsidered risk factor for Heyde's syndrome in need of further research.

Light-up split aptamers: binding thermodynamics and kinetics for sensing.

Due to their programmable structures, many aptamers can be readily split into two halves while still retaining their target binding function. While split aptamers are prevalent in the biosensor field, fundamental studies of their binding are still lacking. In this work, we took advantage of the fluorescence enhancement property of a new aptamer named OTC5 that can bind to tetracycline antibiotics to compare various split aptamers with the full-length aptamer. The split aptamers were designed to have different stem lengths. Longer stem length aptamers showed similar dissociation constants (Kd) to the full-length aptamer, while a shorter stem construct showed an 85-fold increase in Kd. Temperature-dependent fluorescence measurements confirmed the lower thermostability of split aptamers. Isothermal titration calorimetry indicated that split aptamer binding can release more heat but have an even larger entropy loss. Finally, a colorimetric biosensor using gold nanoparticles was designed by pre-assembling two thiolated aptamer halves, which can then link gold nanoparticles to give a red-to-blue color change.

Improving Quantum Well Tube Homogeneity Using Strained Nanowire Heterostructures.

Bottom-up grown nanostructures often suffer from significant dimensional inhomogeneity, and for quantum confined heterostructures, this can lead to a corresponding large variation in electronic properties. A high-throughput characterization methodology is applied to >15,000 nanoskived sections of highly strained GaAsP/GaAs radial core/shell quantum well heterostructures revealing high emission uniformity. While scanning electron microscopy shows a wide nanowire diameter spread of 540-60+60 nm, photoluminescence reveals a tightly bounded band-to-band transition energy of 1546-3+4 meV. A highly strained core/shell nanowire design is shown to reduce the dependence of emission on the quantum well width variation significantly more than in the unstrained case.

Anogenital dermatology: caseload analysis of new outpatient referrals at a single dermatology centre.

Little is known about the volume of outpatient referrals for anogenital dermatoses received by NHS dermatology departments. We undertook a caseload analysis at our centre and found 6.0% of GP referrals to Dermatology were for anogenital dermatoses. This has important implications for training in this field of dermatology as well as for service provision.

Dataset of high-throughput ligand screening against the RNA Packaging Signals regulating Hepatitis B Virus nucleocapsid formation.

Multiple ssRNA viruses which infect bacteria, plants or humans use RNA Packaging Signal (PS)-mediated regulation during assembly to package their genomes faithfully and efficiently. PSs typically comprise short nucleotide recognition motifs, most often presented in the unpaired region of RNA stem-loops, and often bind their cognate coat proteins (CPs) with nanomolar affinity. PSs identified to date are resilient in the face of the typical error prone replication of their virus-coded polymerases, making them potential drug targets. An immobilised array of small molecular weight, drug-like compounds was panned against a fluorescently-labelled oligonucleotide encompassing the most conserved Hepatitis B Virus (HBV) PS, PS1, known to be a major determinant in nucleocapsid formation. This identified > 70 compounds that bind PS1 uniquely in the array. The commercially available 66 of these were tested for their potential effect(s) on HBV nucleocapsid-like particle (NCP) assembly in vitro, which identified potent assembly inhibitors. Here, we describe a high-throughput screen for such effects using employing fluorescence anisotropy in a 96-well microplate format. HBV genomic RNAs (gRNA) and short oligonucleotides encompassing PS1 were 5' labelled with an Alexa Fluor 488 dye. Excess (with respect to stoichiometric T = 4 NCP formation) HBV core protein (Cp) dimers were titrated robotically into solutions containing each of these RNAs stepwise, using a Biomek 4000 liquid handling robot. The anisotropy values of these mixtures were monitored using a POLARstar microplate reader. NCP-like structures were challenged with RNase A to identify reactions that did not result in complete NCP formation. The results imply that ∼50% of the compounds prevent complete NCP formation, highlighting both PS-meditated assembly and the PS-binding compounds as potential directly-acting anti-virals with a novel molecular target. Importantly, this method allows high-throughput in vitro screening for assembly inhibitors in this major human pathogen.

Dysregulation of Hepatitis B Virus Nucleocapsid Assembly in vitro by RNA-binding Small Ligands.

RNA sequences/motifs dispersed across the genome of Hepatitis B Virus regulate formation of nucleocapsid-like particles (NCPs) by core protein (Cp) in vitro, in an epsilon/polymerase-independent fashion. These multiple RNA Packaging Signals (PSs) can each form stem-loops encompassing a Cp-recognition motif, -RGAG-, in their loops. Drug-like molecules that bind the most important of these PS sites for NCP assembly regulation with nanomolar affinities, were identified by screening an immobilized ligand library with a fluorescently-labelled, RNA oligonucleotide encompassing this sequence. Sixty-six of these "hits", with affinities ranging from low nanomolar to high micromolar, were purchased as non-immobilized versions. Their affinities for PSs and effects on NCP assembly were determined in vitro by Surface Plasmon Resonance. High-affinity ligand binding is dependent on the presence of an -RGAG- motif within the loop of the PS, consistent with ligand cross-binding between PS sites. Simple structure-activity relationships show that it is also dependent on the presence of specific functional groups in these ligands. Some compounds are potent inhibitors of in vitro NCP assembly at nanomolar concentrations. Despite appropriate logP values, these ligands do not inhibit HBV replication in cell culture. However, modelling confirms the potential of using PS-binding ligands to target NCP assembly as a novel anti-viral strategy. This also allows for computational exploration of potential synergic effects between anti-viral ligands directed at distinct molecular targets in vivo. HBV PS-regulated assembly can be dysregulated by novel small molecule RNA-binding ligands opening a novel target for developing directly-acting anti-virals against this major pathogen.

Partial penile amputation using a thoracoabdominal stapler in nine dogs.

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.

In vitro functional analysis of gRNA sites regulating assembly of hepatitis B virus.

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.

Evolution of a virus-like architecture and packaging mechanism in a repurposed bacterial protein.

Viruses are ubiquitous pathogens of global impact. Prompted by the hypothesis that their earliest progenitors recruited host proteins for virion formation, we have used stringent laboratory evolution to convert a bacterial enzyme that lacks affinity for nucleic acids into an artificial nucleocapsid that efficiently packages and protects multiple copies of its own encoding messenger RNA. Revealing remarkable convergence on the molecular hallmarks of natural viruses, the accompanying changes reorganized the protein building blocks into an interlaced 240-subunit icosahedral capsid that is impermeable to nucleases, and emergence of a robust RNA stem-loop packaging cassette ensured high encapsidation yields and specificity. In addition to evincing a plausible evolutionary pathway for primordial viruses, these findings highlight practical strategies for developing nonviral carriers for diverse vaccine and delivery applications.

An Intracellular Model of Hepatitis B Viral Infection: An In Silico Platform for Comparing Therapeutic Strategies.

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.

How low can you go? Severe hyponatremia with a sodium of 94 mg/dL corrected with proactive strategy.

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.

Single-Incision Laparoscopic Deroofing and Omentalization of a Cystic Renal Adenoma in a Dog.

A 12 yr old 13.5 kg male castrated Pembroke Welsh corgi was presented for evaluation of a suspected renal cyst following multiple episodes of lethargy and abdominal pain. Abdominal imaging revealed a large, thin-walled, hypoechoic cystic lesion associated with the cranial pole of the left kidney and a second smaller cystic lesion on the caudal pole. The larger cystic lesion was repeatedly drained percutaneously, but the lesion returned to initial size and clinical signs returned within weeks. Percutaneous ethanol sclerotherapy achieved only transient improvement in lesion size and abdominal discomfort. Laparoscopic deroofing and omentalization of the larger left renal cystic lesion was performed. The resected cystic wall was histopathologically consistent with a renal adenoma. Abdominal ultrasonography performed 1 mo postoperatively found no recurrence of the cystic renal adenoma. Repeated ultrasonography at 3 mo postoperatively detected a small cystic lesion at the cranial pole of the left kidney, which remained static in appearance at 11 and 18 mo postoperatively. During all follow-up visits, the dog was reported to be doing well with no recurrence of clinical signs. Renal cysts causing clinical signs and renal adenomas are rare in veterinary medicine; laparoscopic deroofing and omentalization provides a minimally invasive treatment approach.

The frailest of the frail? Addressing the palliative care needs of frail older patients.

Managing patients with frailty is an increasing element of acute hospital care, constituting around 40% of acute hospital inpatients. Up to half of these patients may be approaching the end of their life, and many also have repeated hospital admissions. We therefore undertook a quality improvement project to help us identify the prevalence of frail older inpatients approaching end of life and to better identify these patients in advance. We also developed and evaluated a pro forma to assist in initiating an advance care planning conversation with the patient and/or family. Fifty percent of our frail older inpatients were assessed as approaching end of life. Factors identifying older inpatients as more likely to die during the hospital admission included residence in a care home, two or more hospital admissions over the preceding 12 months, and a diagnosis of some form of dementia for more than 3 years. A novel goals and priorities of care (GPOC) document was found to support and guide palliative care conversations. Acute hospital care could be organised more effectively to recognise the potential need for palliative care in frail older patients. Identifying those at higher risk and using structured interviews and documentation is helpful, ultimately resulting in more appropriate care. Well-developed communication skills are needed for these complex care planning conversations.

Rewriting nature's assembly manual for a ssRNA virus.

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.

HBV RNA pre-genome encodes specific motifs that mediate interactions with the viral core protein that promote nucleocapsid assembly.

Formation of the hepatitis B virus nucleocapsid is an essential step in the viral lifecycle, but its assembly is not fully understood. We report the discovery of sequence-specific interactions between the viral pre-genome and the hepatitis B core protein that play roles in defining the nucleocapsid assembly pathway. Using RNA SELEX and bioinformatics, we identified multiple regions in the pre-genomic RNA with high affinity for core protein dimers. These RNAs form stem-loops with a conserved loop motif that trigger sequence-specific assembly of virus-like particles (VLPs) at much higher fidelity and yield than in the absence of RNA. The RNA oligos do not interact with preformed RNA-free VLPs, so their effects must occur during particle assembly. Asymmetric cryo-electron microscopy reconstruction of the T = 4 VLPs assembled in the presence of one of the RNAs reveals a unique internal feature connected to the main core protein shell via lobes of density. Biophysical assays suggest that this is a complex involving several RNA oligos interacting with the C-terminal arginine-rich domains of core protein. These core protein-RNA contacts may play one or more roles in regulating the organization of the pre-genome during nucleocapsid assembly, facilitating subsequent reverse transcription and acting as a nucleation complex for nucleocapsid assembly.