Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

PURPOSE: Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs . METHODS: We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) . RESULTS: Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (N = 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (N = 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (N = 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (- 1, 21) vs 10 (- 1, to 21) in subphenotype-2; 1.5 (- 1, 21) vs 12 (- 1, to 21) in suphenotype-3, and 0 (- 1, 21) vs 0 (- 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects p = 0.008). CONCLUSIONS: We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.

Goodbye SIRS? Innate, trained and adaptive immunity and pathogenesis of organ dysfunction.

The novel concepts within Sepsis­3 criteria include a focus on dysregulated host responses, removal of the systemic inflammation response syndrome (SIRS) criteria from sepsis diagnosis, the use of Sepsis-related (Sequential) Organ Failure Assessment (SOFA) scores to define organ dysfunction, and the explicit recognition of the septic shock as a subset of sepsis. Protection against infection requires a surveillance system, an effector response against "perceived" pathogens, a method for regaining immune homeostasis following an immune response, and generation of immunological memory. In comparison to normally regulated responses to infection, the innate immune system shows profoundly abnormal neutrophil and macrophage function. Similarly, the adaptive immune system is typically depleted numerically of lymphocytes and functionally with T and B cell exhaustion. Although there are numerous proposed mechanisms by which these dysregulated immune responses may be associated with organ failure, it is unclear what the unifying organ failure mechanisms in sepsis are. Furthermore, in sepsis survivors, the epigenetic changes on immune cells and widespread changes to lymphocyte populations may increase the risk of adverse events such as rehospitalisation and mortality. Finally, our current gaps in understanding of the immune response trajectory and the associated modifiable mechanisms in sepsis leave us a long way from successful immunomodulation for these patients. This article is freely available.

Effect of variation in hemorheology between human and animal blood on the binding efficacy of vascular-targeted carriers.

Animal models are extensively used to evaluate the in vivo functionality of novel drug delivery systems (DDS). However, many variations likely exist in vivo between the animals and human physiological environment that significantly alter results obtained with animal models relative to human system. To date, it is not clear if the variation in hemorheology and hemodynamics between common animal and human models affect the functionality of DDS. This study investigates the role of hemorheology of humans and various animal models in dictating the binding efficiency of model vascular-targeted carriers (VTCs) to the wall in physiological blood flows. Specifically, the adhesion of sLe(A)-coated nano- and micro-spheres to inflamed endothelial cells monolayers were conducted via a parallel plate flow chamber assay with steady and disturbed red blood cells (RBCs)-in-buffer and whole blood flows of common animal models. Our results suggest that the ratio of carrier size to RBC size dictate particle binding in blood flow. Additionally, the presence of white blood cells affects the trend of particle adhesion depending on the animal species. Overall, this work sheds light on some deviation in VTC vascular wall interaction results obtained with in vivo animal experimentation from expected outcome and efficiency in vivo in human.

Long-term use of ticagrelor in patients with prior myocardial infarction.

BACKGROUND: The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y12 receptor antagonist with established efficacy after an acute coronary syndrome, in this context. METHODS: We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. RESULTS: The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively. CONCLUSIONS: In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.).

Retained asymptomatic third molars and risk for second molar pathology.

Prophylactic extraction of unerupted asymptomatic third molars is the most common oral surgery procedure in the United States. However, limited evidence exists to justify its costs and associated morbidity. We analyzed data collected over 25 years from 416 adult men enrolled in the Veterans Affairs Dental Longitudinal Study to evaluate the association of retained asymptomatic third molars with risk of adjacent second molar pathology (caries and/or periodontitis), based on third molar status (i.e., absent, erupted, or unerupted). Unerupted molars were further categorized as either "soft tissue" or "bony" impacted. We found that the lowest prevalence and incidence of second molar pathology occurred when the adjacent third molar was absent. The presence of a third molar that was soft tissue impacted increased the risk of incident second molar pathology 4.88-fold (95% confidence interval: 2.62, 9.08). Having an erupted or "bony" impacted third molar increased the risk of incident second molar pathology by 1.74 (95% confidence interval: 1.34, 2.25) and 2.16 (95% confidence interval: 1.56, 2.99), respectively. The retention of third molars is associated with increased risk of second molar pathology in middle-aged and older adult men.

Prevalence and pattern of cognitive impairment in a community cohort of men in South Wales: methodology and findings from the Caerphilly Prospective Study.

BACKGROUND/AIMS: The prevalence of dementia and cognitive impairment not dementia was investigated in the Caerphilly Prospective Study cohort (men currently aged 65-84 years). METHODS: Of 1,633 men eligible for cognitive screening, 1,225 (75%) were seen, with those failing the screening criteria (CAMCOG <83 or decline in CAMCOG >9) being neurologically examined. RESULTS: For dementia, diagnosed by DSM-IV criteria, the population prevalence was 5.2% rising to 6.1% in the screened population. For cognitive impairment not dementia, the prevalence in the screened population was 15.6% giving an overall prevalence of cognitive impairment of 21.8%. Prevalence rose fivefold between ages of 65 and 84 years to reach over 50%. CONCLUSION: These figures are likely to underestimate actual prevalence in this population, and developing effective interventions should be a public health priority.

[A concept of nephrologic care at the end of life]. / Ein Konzept für die nephrologische Pflege am Ende des Lebens.

BACKGROUND: A care pathway for the end-of-life had been implemented onto the two renal wards. An audit was performed to highlight potential issues and areas for development. METHOD: The audit consisted of a base review of documentation from the medical notes of 10 patients who had died an 'expected' death prior to commencing the renal Integrated Care Pathway (ICP) for the end of life and then 10 patients who had died whilst using the ICP documentation. A questionnaire was also given out to nursing staff who had used the ICP documentation. The results were collated and analysed. RESULTS: In the base review 100% of the documentation looked at did not provide a regular documented assessment of symptoms that are common in the terminal phase of life. The ICP provided a documented assessment of all of these main symptoms. The base review indicated a good response by doctors to meet the potential needs of the patient, but the ICP improved on this. This was through the use of a pre-emptive prescription. 80% of all patients were pain free, not agitated, had no nausea or vomiting or respiratory secretions. The 2 patients that had pain received further analgesia and were then pain free at the next assessment. One of the most positive aspects of the audit was that 90% of relatives were aware that the patient was dying and 100% had the plan of care discussed with them. CONCLUSION: Implementing the ICP has generated the opportunity to deliver a hospice model of care to a busy renal unit. It has allowed best practice, and a measurable standard of care, in the final stages of patients' lives. Staff find the documentation easy to use and also see it as enhancing patient care.

Naked cuticle targets dishevelled to antagonize Wnt signal transduction.

In Drosophila embryos the protein Naked cuticle (Nkd) limits the effects of the Wnt signal Wingless (Wg) during early segmentation. nkd loss of function results in segment polarity defects and embryonic death, but how nkd affects Wnt signaling is unknown. Using ectopic expression, we find that Nkd affects, in a cell-autonomous manner, a transduction step between the Wnt signaling components Dishevelled (Dsh) and Zeste-white 3 kinase (Zw3). Zw3 is essential for repressing Wg target-gene transcription in the absence of a Wg signal, and the role of Wg is to relieve this inhibition. Our double-mutant analysis shows that, in contrast to Zw3, Nkd acts when the Wg pathway is active to restrain signal transduction. Yeast two hybrid and in vitro experiments indicate that Nkd directly binds to the basic-PDZ region of Dsh. Specially timed Nkd overexpression is capable of abolishing Dsh function in a distinct signaling pathway that controls planar-cell polarity. Our results suggest that Nkd acts directly through Dsh to limit Wg activity and thus determines how efficiently Wnt signals stabilize Armadillo (Arm)/beta-catenin and activate downstream genes.

Health development meets the end of state socialism: visions of democratization, women's health, and social well-being for contemporary Russia.

As development organizations undertake the task of improving the public health in former socialist states, their interventions are shaped by a particular cultural logic and predetermined frame of possible action. In the context of local encounters, however, they often confront competing interpretations of a society's prevailing needs. How they manage such differences may not only explain the outcomes of a given project, but may also reveal the capacities and limitations of development agencies to engineer post-socialist change. This article examines a recent WHO project in St. Petersburg, Russia, which defined women's "social well-being" as a local health concern. While the project employed a discourse of "democracy" to promote women's empowerment in the clinic, its parameters of intervention neither incorporated local knowledge nor addressed the structural relations underlying clinic-level conflicts. Two kinds of results ensued: the ideology of democracy was rejected, while WHO's recommendations were partially appropriated as profit-making strategies.

Strategies used by hospital nurses to cope with a national crisis: a manager's perspective.

This article explores the anxiety level of, and coping strategies used by, hospital nurses, during a national state of emergency. The study was guided by a stress and coping framework, developed by Lazarus & Folkman, and was conducted at a large teaching hospital, located in the centre of Israel, during the Iraqi crisis in January and February, 1998. Data were collected from a sample of 100 female nurses, and a descriptive correlational design was used. The findings indicated that approximately 33% of the nurses expressed feelings of stress, tension and a sense of discomfort. The dominant coping strategy used by the nurses was direct-active, which was found to be the most effective strategy. As they were unable to remove or control the stressor, stress management intervention by nursing managers focused mainly on communicating with staff and providing social support - informational and emotional--to buffer the stressful experience. Providing support and help in finding practical solutions is important for maintaining emotional stability of staff, thereby helping them to improve their nursing interventions in assisting people to cope with stressful situations.

A descriptive evaluation with follow-up of the clinical significance of atypical immature squamous metaplasia of the cervix.

OBJECTIVES: We set out to determine the clinical significance of atypical immature squamous metaplasia (AIM). METHODS: We performed in a military, hospital-based colposcopy clinic a descriptive, retrospective review of patients who had a diagnosis of AIM. Patients were examined at 3- to 4-month intervals for at least 1 year after a diagnosis of AIM was established. A gynecological pathologist reviewed all histological and cytological specimens. Initial histological or cytological specimens were tested for the presence of HPV DNA using in situ hybridization. RESULTS: High-risk HPV DNA types 16 or 18 were detected in 3% of patients with AIM. Concurrent cervical intraepithelial neoplasia 3 (CIN3) was noted in 3% of patients with AIM. One-third of patients with initially diagnosed AIM had complete resolution of this lesion after 1 year of follow-up. CONCLUSIONS: This descriptive, retrospective review shows that AIM does not appear to be associated with high-risk HPV DNA or with CIN3. In this limited study, a concurrent diagnosis of AIM likely does not influence the 1-year behavior of CIN. The degree of CIN should dictate treatment recommendations. A larger prospective trial is needed.

A putative Drosophila homolog of the Huntington's disease gene.

The Huntington's disease (HD) gene encodes a protein, huntingtin, with no known function and no detectable sequence similarity to other proteins in current databases. To gain insight into the normal biological role of huntingtin, we isolated and sequenced a cDNA encoding a protein that is a likely homolog of the HD gene product in Drosophila melanogaster. We also determined the complete sequence of 43 125 contiguous base pairs of genomic DNA that encompass the Drosophila HD gene, allowing the intron-exon structure and 5'- and 3'-flanking regions to be delineated. The predicted Drosophila huntingtin protein has 3583 amino acids, which is several hundred amino acids larger than any other previously characterized member of the HD family. Analysis of the genomic and cDNA sequences indicates that Drosophila HD has 29 exons, compared with the 67 exons present in vertebrate HD genes, and that Drosophila huntingtin lacks the polyglutamine and polyproline stretches present in its mammalian counterparts. The Drosophila HD mRNA is expressed in a broad range of developmental stages and in the adult, a temporal pattern of expression similar to that observed for mammalian HD transcripts. We can discern five regions of high similarity from multiple sequence alignments between Drosophila and vertebrate huntingtins. These regions may define functionally important domains within the protein.

Sexuality education in Russia: defining pleasure and danger for a fledgling democratic society.

Public health indicators have plummeted throughout Russia since the collapse of the Soviet Union, with exponential increases in sexually transmitted diseases reported among this society's young adults. Newly developing sexuality education programs provide insights into the ways local health providers interpret such public health challenges and conceptualize the educational needs of Russian youth. Moreover, these initiatives reveal the impact of both Soviet-era discourses and more recent, international anti-abortion activism on contemporary thinking about sexual health matters. This article explores the implicit and sometimes explicit ways that sex education lectures are being driven by debates over the significance of the Soviet past and anxieties over the perceived chaos of current transformations. Drawing on material from lectures, fieldwork, and interviews with sex educators, I argue that sexuality education efforts reveal a persistent ambivalence between the hope to promote individual autonomy from state interests and the presumed need to control sexual expression and reproductive practices within an emerging moral economy of post-Soviet Russia.

A Drosophila Axin homolog, Daxin, inhibits Wnt signaling.

The vertebrate Axin protein, the product of the mouse fused gene, binds to beta-catenin to inhibit Wnt signaling. We have identified a homolog of Axin in Drosophila, Daxin. Using double-stranded RNA interference, we generated loss-of-function phenotypes that are similar to overexpression of the Drosophila Wnt gene wingless (wg). Overexpression of Daxin produces phenotypes similar to loss of wg. In addition, we show that Daxin overexpression can modify phenotypes elicited by wg and another Drosophila Wnt gene, DWnt-2. Using immunoprecipitation of endogenous Daxin protein from embryos we show that Daxin interacts with Armadillo and Zeste-white 3. The loss-of-function and overexpression phenotypes show that Daxin, like its mammalian counterpart, acts as a negative regulator of wg/Wnt signaling.

Frizzled and Dfrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development.

In cell culture assays, Frizzled and Dfrizzled2, two members of the Frizzled family of integral membrane proteins, are able to bind Wingless and transduce the Wingless signal. To address the role of these proteins in the intact organism and to explore the question of specificity of ligand-receptor interactions in vivo, we have conducted a genetic analysis of frizzled and Dfrizzled2 in the embryo. These experiments utilize a small gamma-ray-induced deficiency that uncovers Dfrizzled2. Mutants lacking maternal frizzled and zygotic frizzled and Dfrizzled2 exhibit defects in the embryonic epidermis, CNS, heart and midgut that are indistinguishable from those observed in wingless mutants. Epidermal patterning defects in the frizzled, Dfrizzled2 double-mutant embryos can be rescued by ectopic expression of either gene. In frizzled, Dfrizzled2 mutant embryos, ectopic production of Wingless does not detectably alter the epidermal patterning defect, but ectopic production of an activated form of Armadillo produces a naked cuticle phenotype indistinguishable from that produced by ectopic production of activated Armadillo in wild-type embryos. These experiments indicate that frizzled and Dfrizzled2 function downstream of wingless and upstream of armadillo, consistent with their proposed roles as Wingless receptors. The lack of an effect on epidermal patterning of ectopic Wingless in a frizzled, Dfrizzled2 double mutant argues against the existence of additional Wingless receptors in the embryo or a model in which Frizzled and Dfrizzled2 act simply to present the ligand to its bona fide receptor. These data lead to the conclusion that Frizzled and Dfrizzled2 function as redundant Wingless receptors in multiple embryonic tissues and that this role is accurately reflected in tissue culture experiments. The redundancy of Frizzled and Dfrizzled2 explains why Wingless receptors were not identified in earlier genetic screens for mutants defective in embryonic patterning.

Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing.

In Drosophila wing imaginal discs, the Wingless (Wg) protein acts as a morphogen, emanating from the dorsal/ventral (D/V) boundary of the disc to directly define cell identities along the D/V axis at short and long range. Here, we show that high levels of a Wg receptor, Drosophila frizzled 2 (Dfz2), stabilize Wg, allowing it to reach cells far from its site of synthesis. Wg signaling represses Dfz2 expression, creating a gradient of decreasing Wg stability moving toward the D/V boundary. This repression of Dfz2 is crucial for the normal shape of Wg morphogen gradient as well as the response of cells to the Wg signal. In contrast to other ligand-receptor relationships where the receptor limits diffusion of the ligand, Dfz2 broadens the range of Wg action by protecting it from degradation.

Benign keratotic squamous epithelial neoplasm of the palate: a unique lesion.

BACKGROUND: This case report describes a unique palatal tumor with features of a dermal neoplasm. Microscopically, the lesion appeared similar to a trichoepithelioma and trichoadenoma. METHODS: Light microscopic and immunohistochemical studies were performed to arrive at the final diagnosis. RESULTS: The lesion arose from the surface epithelium and had features of a dermal tumor. CONCLUSIONS: The case report describes a unique benign palatal neoplasm.