In outpatients with mild to moderate COVID-19, low-dose fluvoxamine did not reduce time to sustained recovery.

SOURCE CITATION: McCarthy MW, Naggie S, Boulware DR, et al. Effect of fluvoxamine vs placebo on time to sustained recovery in outpatients with mild to moderate COVID-19: a randomized clinical trial. JAMA. 2023;329:296-305. 36633838.

No Association of Polymorphisms in the Genes Encoding Interleukin-6 and Interleukin-6 Receptor Subunit Alpha with the Risk of Keloids in Polish Patients.

A keloid is a benign fibroproliferative hypertrophy of scar tissue that extends outside the original wound and invades adjacent healthy skin. Keloid formation is thought to be a complex process including overactivity of the interleukin-6 signaling pathway and genetic susceptibility. The aim of the study was to investigate possible associations between rs1800797, rs1800796, and rs1800795 polymorphisms in the promoter of the IL6 gene encoding interleukin-6 and the rs2228145 polymorphism in the IL6R gene encoding the interleukin-6 receptor subunit alpha with the predisposition to keloids in Polish patients. The genetic polymorphisms were identified either using Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) or sequencing of samples of genomic DNA extracted from blood leukocytes of 86 adult patients with keloids and 100 newborns comprising a control group. No significant differences in the distributions of IL6 or IL6R alleles or genotypes were found between keloid patients and newborn controls. There were also no significant differences between both groups in the distribution of IL6 haplotypes. The IL6 rs1800797, rs1800796 and rs1800795 and IL6R rs2228145 polymorphisms were not found to predispose individuals in the study group to keloids. IL6 promoter haplotypes were not found to be associated with a higher risk of keloids in the studied group.

Sideband cooling beyond the quantum backaction limit with squeezed light.

Quantum fluctuations of the electromagnetic vacuum produce measurable physical effects such as Casimir forces and the Lamb shift. They also impose an observable limit-known as the quantum backaction limit-on the lowest temperatures that can be reached using conventional laser cooling techniques. As laser cooling experiments continue to bring massive mechanical systems to unprecedentedly low temperatures, this seemingly fundamental limit is increasingly important in the laboratory. Fortunately, vacuum fluctuations are not immutable and can be 'squeezed', reducing amplitude fluctuations at the expense of phase fluctuations. Here we propose and experimentally demonstrate that squeezed light can be used to cool the motion of a macroscopic mechanical object below the quantum backaction limit. We first cool a microwave cavity optomechanical system using a coherent state of light to within 15 per cent of this limit. We then cool the system to more than two decibels below the quantum backaction limit using a squeezed microwave field generated by a Josephson parametric amplifier. From heterodyne spectroscopy of the mechanical sidebands, we measure a minimum thermal occupancy of 0.19 ± 0.01 phonons. With our technique, even low-frequency mechanical oscillators can in principle be cooled arbitrarily close to the motional ground state, enabling the exploration of quantum physics in larger, more massive systems.

'Beyond places of safety' - a qualitative study exploring the implementation of mental health crisis care innovations across England.

BACKGROUND: Mental health acute and crisis care consumes a large share of mental health budgets internationally but is often experienced as unsatisfactory and difficult to access. As a result, there is an increasing move towards developing innovative community crisis services, to improve patient experience and relieve pressure on inpatient and emergency services. This study aims to understand what helps and hinders the implementation of innovative mental health crisis care projects in England. METHODS: Using a qualitative approach, 18 interviews were conducted with crisis care service managers exploring their experiences and views of the development and implementation of their service developed with support from an English national capital funding programme. A framework analysis was conducted informed by implementation science. RESULTS: Key facilitators to implementation of innovative crisis services included bottom-up development, service user involvement, strong collaborative working, and leadership and management buy-in. Key barriers that affected the projects implementation included the complexities of crisis care, workforce challenges and resourcing issues. CONCLUSION: There is a recognised need to improve, update, and innovate current crisis care offers. Results from this study suggest that a range of models can help address the heterogenous needs of local populations and that new approaches can be implemented where they utilise a whole-systems approach, involving service users and relevant professional stakeholders beyond mental health services in planning and developing the service.

Solitary fibrous tumor of the orbit in a 1-year-old patient: a case report.

Solitary fibrous tumors (SFTs) are rare neoplasms of mesenchymal origin. While the mean age of presentation is 58 years old, we report the case of the youngest documented patient with an SFT of the orbit. A 13-month-old child was evaluated for eyelid asymmetry and then referred to the oculoplastic service. On examination, a soft tissue mass of the right inferomedial orbit was observed. MRI demonstrated a well-circumscribed, extraocular lesion in the inferomedial right orbit, potentially fibrous in nature. Excision was performed without complications. Pathologic examination demonstrated fibrous tissue proliferation with a staghorn vascular pattern, as well as benign fibrous cells with tapering nuclei and abundant pericellular reticulin. Immunohistochemistry (IHC) demonstrated that the cells stain diffusely positive for CD34 and vimentin. With the MRI findings, pathology, and IHC, the diagnosis was confirmed to be SFT. SFTs of the orbit, although rare, may occur in the pediatric population.

The effects of drug safety warnings on drug sales and share prices.

Current regulations require that when seeking approval for new drugs, pharmaceutical companies must demonstrate their short- but not long-term safety and efficacy. Instead, post-approval, clinicians report adverse reactions to regulators, who may issue additional safety warnings. We investigate the incentives this creates for pharmaceutical companies to seek approval for new drugs with unknown long-term effects. We first construct models predicting that (1) long-run effects can be reasonably approximated from observational follow-up of short-term randomized control trials, and (2) companies will trade-off short-term sales against possible later adverse demand effects. We then test whether regulator warnings over diabetic, analgesic, analeptic, or psychoanaleptic drugs sold in the US and UK hospital and retail sectors affect the sales of individual drugs or the share prices of companies that sell them. With some exceptions, we find that pharmaceutical companies generally face no adverse market reaction in sales or share price from newly issued warnings in these four drug categories.

A spectroscopic approach to measuring meibum lipid composition and conformation in donors with SjÓ§gren's syndrome.

Patients with SjÓ§gren's syndrome (SS) have dry eye associated with meibomian gland dysfunction (MGD). The meibum from donors with dry eye due to MGD but without SS (MMGD) presents with lower levels of cholesteryl ester, less straight chains, and more ordered hydrocarbon chains compared with meibum from donors without MGD (Mn). The aim of the current study was to compare the composition and hydrocarbon chain conformation of meibum from donors with Sjögren's syndrome (Mss) to Mn and MMGD. Meibum was expressed from patients with SS using an ILUX instrument (Alcon Inc., Fort Worth TX). All of the nine meibum donors with SS were female. Meibum composition was characterized using 1H-NMR and meibum hydrocarbon chain conformation was measured using fourier transform infrared spectroscopy. Meibum from every donor with SS measured contained a significantly (P < 0.01) higher cholesteryl ester/wax ester ratio and more straight chains compared with donors without SS or dry eye. None of the nine phase transitional parameters were significantly different, P > 0.05, for Mss compared with Mn. Nor was the CH3/CH2 band height ratio used to estimate the number of hydrocarbon CH3 and CH2 moieties different, P = 0.22, for Mss compared with Mn. In conclusion, the compositional differences between Mss compared with Mn did not result in differences in any of the nine meibum lipid phase transitional parameters measured. The compositional differences observed between Mss and Mn could be markers for or contribute to SS as the differences could lead to tear film lipid packing differences other than conformational differences.

Emerging models and trends in mental health crisis care in England: a national investigation of crisis care systems.

BACKGROUND: Inpatient psychiatric care is unpopular and expensive, and development and evaluation of alternatives is a long-standing policy and research priority around the world. In England, the three main models documented over the past fifty years (teams offering crisis assessment and treatment at home; acute day units; and residential crisis services in the community) have recently been augmented by several new service models. These are intended to enhance choice and flexibility within catchment area acute care systems, but remain largely undocumented in the research literature. We therefore aimed to describe the types and distribution of crisis care models across England through a national survey. METHODS: We carried out comprehensive mapping of crisis resolution teams (CRTs) using previous surveys, websites and multiple official data sources. Managers of CRTs were invited to participate as key informants who were familiar with the provision and organisation of crisis care services within their catchment area. The survey could be completed online or via telephone interview with a researcher, and elicited details about types of crisis care delivered in the local catchment area. RESULTS: We mapped a total of 200 adult CRTs and completed the survey with 184 (92%). Of the 200 mapped adult CRTs, there was a local (i.e., within the adult CRT catchment area) children and young persons CRT for 84 (42%), and an older adults CRT for 73 (37%). While all but one health region in England provided CRTs for working age adults, there was high variability regarding provision of all other community crisis service models and system configurations. Crisis cafes, street triage teams and separate crisis assessment services have all proliferated since a similar survey in 2016, while provision of acute day units has reduced. CONCLUSIONS: The composition of catchment area crisis systems varies greatly across England and popularity of models seems unrelated to strength of evidence. A group of emerging crisis care models with varying functions within service systems are increasingly prevalent: they have potential to offer greater choice and flexibility in managing crises, but an evidence base regarding impact on service user experiences and outcomes is yet to be established.

Development of a multivariable risk model integrating urinary cell DNA methylation and cell-free RNA data for the detection of significant prostate cancer.

BACKGROUND: Prostate cancer exhibits severe clinical heterogeneity and there is a critical need for clinically implementable tools able to precisely and noninvasively identify patients that can either be safely removed from treatment pathways or those requiring further follow up. Our objectives were to develop a multivariable risk prediction model through the integration of clinical, urine-derived cell-free messenger RNA (cf-RNA) and urine cell DNA methylation data capable of noninvasively detecting significant prostate cancer in biopsy naïve patients. METHODS: Post-digital rectal examination urine samples previously analyzed separately for both cellular methylation and cf-RNA expression within the Movember GAP1 urine biomarker cohort were selected for a fully integrated analysis (n = 207). A robust feature selection framework, based on bootstrap resampling and permutation, was utilized to find the optimal combination of clinical and urinary markers in a random forest model, deemed ExoMeth. Out-of-bag predictions from ExoMeth were used for diagnostic evaluation in men with a clinical suspicion of prostate cancer (PSA ≥ 4 ng/mL, adverse digital rectal examination, age, or lower urinary tract symptoms). RESULTS: As ExoMeth risk score (range, 0-1) increased, the likelihood of high-grade disease being detected on biopsy was significantly greater (odds ratio = 2.04 per 0.1 ExoMeth increase, 95% confidence interval [CI]: 1.78-2.35). On an initial TRUS biopsy, ExoMeth accurately predicted the presence of Gleason score ≥3 + 4, area under the receiver-operator characteristic curve (AUC) = 0.89 (95% CI: 0.84-0.93) and was additionally capable of detecting any cancer on biopsy, AUC = 0.91 (95% CI: 0.87-0.95). Application of ExoMeth provided a net benefit over current standards of care and has the potential to reduce unnecessary biopsies by 66% when a risk threshold of 0.25 is accepted. CONCLUSION: Integration of urinary biomarkers across multiple assay methods has greater diagnostic ability than either method in isolation, providing superior predictive ability of biopsy outcomes. ExoMeth represents a more holistic view of urinary biomarkers and has the potential to result in substantial changes to how patients suspected of harboring prostate cancer are diagnosed.

A novel stratification framework for predicting outcome in patients with prostate cancer.

BACKGROUND: Unsupervised learning methods, such as Hierarchical Cluster Analysis, are commonly used for the analysis of genomic platform data. Unfortunately, such approaches ignore the well-documented heterogeneous composition of prostate cancer samples. Our aim is to use more sophisticated analytical approaches to deconvolute the structure of prostate cancer transcriptome data, providing novel clinically actionable information for this disease. METHODS: We apply an unsupervised model called Latent Process Decomposition (LPD), which can handle heterogeneity within individual cancer samples, to genome-wide expression data from eight prostate cancer clinical series, including 1,785 malignant samples with the clinical endpoints of PSA failure and metastasis. RESULTS: We show that PSA failure is correlated with the level of an expression signature called DESNT (HR = 1.52, 95% CI = [1.36, 1.7], P = 9.0 × 10-14, Cox model), and that patients with a majority DESNT signature have an increased metastatic risk (X2 test, P = 0.0017, and P = 0.0019). In addition, we develop a stratification framework that incorporates DESNT and identifies three novel molecular subtypes of prostate cancer. CONCLUSIONS: These results highlight the importance of using more complex approaches for the analysis of genomic data, may assist drug targeting, and have allowed the construction of a nomogram combining DESNT with other clinical factors for use in clinical management.

Relationship between aortic wall oxidative stress/proteolytic enzyme expression and intraluminal thrombus thickness indicates a novel pathomechanism in the progression of human abdominal aortic aneurysm.

The possibility that oxidative stress promotes degradation of the extracellular matrix and a relationship between intraluminal thrombus (ILT) thickness and proteolytic activity within the abdominal aortic aneurysm (AAA) wall has been suggested. In the present study, the hypothesis that thin ILT is correlated with an increase in oxidative stress-related enzymes and matrix metalloproteinase-9 (MMP-9) expression within the human AAA wall was investigated. We also studied the antioxidant activity of superoxide dismutases, catalase, glutathione peroxidase, glutathione reductase, and thioredoxin within the full-thickness AAA wall and through fluoroimmunohistochemical staining of catalase and MMP-9 expression within the inner and outer media, in relation to ILT thickness. Reactive oxygen species control the degradation and remodeling of the extracellular matrix by up-regulating proteolytic enzymes, such as MMPs. Results showed that oxidative stress and proteolytic enzyme expression were simultaneously, significantly higher within thin thrombus (≤10 mm)-covered aneurysm wall when compared with the wall covered by thick thrombus (≥25 mm). These findings provide the first demonstration, to our knowledge, of a causative link between oxidative stress instigating proteolytic enzyme expression at the tissue level and human AAA development. Presence of a thin circumferential thrombus should always be considered as a risk factor for the greatest increase in aneurysm growth rate and rupture, giving an indication for surgery timing.-Wiernicki, I., Parafiniuk, M., Kolasa-Wolosiuk, A., Gutowska, I., Kazimierczak, A., Clark, J., Baranowska-Bosiacka, I., Szumilowicz, P., Gutowski, P. Relationship between aortic wall oxidative stress/proteolytic enzyme expression and intraluminal thrombus thickness indicates a novel pathomechanism in the progression of human abdominal aortic aneurysm.

The role of haptoglobin and hemopexin in the prevention of delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage: a review of current literature.

Delayed cerebral ischaemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) is a major cause of mortality and morbidity. The pathophysiology of DCI after aSAH is thought to involve toxic mediators released from lysis of red blood cells within the subarachnoid space, including free haemoglobin and haem. Haptoglobin and hemopexin are endogenously produced acute phase proteins that are involved in the clearance of these toxic mediators. The aim of this review is to investigate the pathophysiological mechanisms involved in DCI and the role of both endogenous as well as exogenously administered haptoglobin and hemopexin in the prevention of DCI.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

A four-group urine risk classifier for predicting outcomes in patients with prostate cancer.

OBJECTIVES: To develop a risk classifier using urine-derived extracellular vesicle (EV)-RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS). PATIENTS AND METHODS: Post-digital rectal examination urine-derived EV-RNA expression profiles (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO-based continuation ratio model was built to generate four prostate urine risk (PUR) signatures for predicting the probability of normal tissue (PUR-1), D'Amico low-risk (PUR-2), intermediate-risk (PUR-3), and high-risk (PUR-4) prostate cancer. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub-cohort (n = 87) for prognostic evaluation. RESULTS: Each PUR signature was significantly associated with its corresponding clinical category (P < 0.001). PUR-4 status predicted the presence of clinically significant intermediate- or high-risk disease (area under the curve = 0.77, 95% confidence interval [CI] 0.70-0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub-cohort (n = 87), groups defined by PUR status and proportion of PUR-4 had a significant association with time to progression (interquartile range hazard ratio [HR] 2.86, 95% CI 1.83-4.47; P < 0.001). PUR-4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26-20.81; P < 0.001). CONCLUSION: Urine-derived EV-RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.

Post-operative epiphora following the transcutaneous medial canthal incision.

PURPOSE: The safety profile of the transcutaneous medial canthal incision for access to the medial orbit is assessed with a focus on the risk of post-operative iatrogenic epiphora. METHODS: A retrospective chart review of patients undergoing medial orbitotomy via the transcutaneous medial canthal incision was performed. Patients with a minimum of 3 months of follow-up were included and post-operative complications were assessed and characterized. RESULTS: One-hundred-fifty patients were included in the study. A total of 4 complications were identified, including one each of the following: nasolacrimal duct obstruction, hypertrophic scar, suture granuloma and soft tissue infection. Only the nasolacrimal duct obstruction required surgical intervention. DISCUSSION: Access to the medial orbit has been achieved through a variety of approaches, each with their own benefits and risk profile. The transcaruncular approach has increased in usage as a means to avoid a visible cutaneous scar and decrease the risk of iatrogenic epiphora, however, there are specific patients who may have relative contraindications to this approach. The current study demonstrates the low risk profile of the transcutaneous medial canthal incision, specifically the minimal risk of iatrogenic damage to the nasolacrimal outflow system. This approach is another useful tool which orbit surgeons should be familiar with to offer as an option to patients requiring medial orbitotomy.

Lived experience of young widowed individuals: A qualitative study.

Young widowhood is a unique experience that has received little in-depth attention in research and clinical settings. The present study examined the lived experiences of young men and women who had lost a spouse. Eleven men and women between the ages of 18 and 49 were interviewed about their experiences postloss using phenomenological methods. After coding the interviews, three themes emerged: (1) relationship prior to death, (2) coping, and (3) concerns. Clinical implications included the need for more accessible resources for young widowed individuals, such as therapeutic services, finances, and childcare.

Hairpulling causing vision loss: a case report.

Subperiosteal extension of a subgaleal hematoma (SGH) to the orbit is a reported, but rare complication of trauma. This report details a 13-year-old African-American male who originally presented to the emergency department after trauma with headache and was found on CT imaging to have a contained subgaleal hemorrhage. He presented 2 days later with increased pain and proptosis of the left eye with findings of decreased visual acuity, elevated intraocular pressure, proptosis, and complete external ophthalmoplegia. Repeat imaging revealed enlargement of the SGH with subperiosteal extension into the left orbit. He required an emergent lateral canthotomy with inferior and superior cantholysis, followed by surgical drainage of the subperiosteal and SGH. Hematologic workup for coagulopathy was negative. The authors urge point-of-care providers to consider ophthalmic evaluation for patients with large SGHs where orbital extension and vision loss may occur. Furthermore, SGH causing orbital compartment syndrome may develop in patients who have normal blood work and clotting factors.

Anterior vestibule salvaging technique to limit silicone orbital implant extrusion following evisceration.

Purpose: The anterior vestibule salvaging ('Birdcage') technique may limit orbital implant extrusion following evisceration. Methods: A 10-year retrospective chart review from 2005 to 2015 of individuals who underwent evisceration procedures utilizing the vestibule salvaging technique was performed. Results: A total of 96 patients (61 male; 35 female; average age 64 years; range 17-96 years) underwent evisceration with a technique avoiding anterior scleral relaxing incisions. Three (3.1%) patients had documented extrusion of the silicone implant. Time from evisceration to extrusion ranged from 26 to 372 days. Conclusions: Maintenance of the anterior scleral vestibule during evisceration may decrease extrusion rates after surgery compared with traditional evisceration techniques that utilize anterior relaxing incisions.