Blood pressure elevations in hospital.

Long-term hypertension control in the community significantly reduces cardiovascular risk. However, the benefit of controlling acute elevations of blood pressure in hospitalised patients is unclear. In-hospital elevations of blood pressure are relatively common and might not reflect poorly controlled blood pressure before admission. The measurement of blood pressure in hospital patients significantly differs from the best practice recommended for primary care and outpatients. Recent observational studies suggest that the pharmacological treatment of acute, asymptomatic, in-hospital elevations of blood pressure may have no benefit. However, it may increase the risk of in-hospital and post-discharge complications. Pending the development of robust inpatient measurement protocols, acute blood pressure elevations in hospitalised patients should not routinely require antihypertensive treatment in the absence of symptoms or acute end-organ damage. Rather, such elevations should facilitate follow-up of blood pressure and other cardiovascular risk factors after discharge.

Excessive Matrix Metalloproteinase-1 and Hyperactivation of Endothelial Cells Occurred in COVID-19 Patients and Were Associated With the Severity of COVID-19.

BACKGROUND: Systemic vascular injury occurs in coronavirus disease 2019 (COVID-19) patients; however, the underlying mechanisms remain unknown. METHODS: To clarify the role of inflammatory factors in COVID-19 vascular injury, we used a multiplex immunoassay to profile 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). RESULTS: COVID-19 patients had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only 1 cytokine, macrophage migration inhibitory factor (MIF), was among these altered analytes, while the rest were chemokines/growth factors. Additionally, only matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor A (VEGF-A) were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. We further studied MMP-1 enzymatic activity and multiple endothelial cell (EC) activation markers (soluble forms of CD146, intercellular adhesion molecule 1 [ICAM-1], and vascular cell adhesion molecule 1 [VCAM-1]) and found that they were highly dysregulated in COVID-19 patients. CONCLUSIONS: COVID-19 patients have a unique inflammatory profile, and excessive MMP-1 and hyperactivation of ECs are associated with the severity of COVID-19.

Population pharmacokinetic model of subcutaneous fentanyl in older acute care patients.

PURPOSE: Subcutaneous fentanyl injection is commonly prescribed to manage acute pain in older patients; however, there is a gap in the literature describing the pharmacokinetic parameters for this route of administration in this population. The aim of this study was to develop and evaluate a population pharmacokinetic model for subcutaneous fentanyl injection in older patients. METHODS: Twenty-one patients who received subcutaneous fentanyl injections (50 to 75 µg) were recruited. Fentanyl concentrations were determined using a validated liquid chromatography/tandem mass spectrometry method. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. A base model was selected based on the Akaike information criterion. Age, sex, body weight, number of previous fentanyl doses, number of prescribed medications, creatinine clearance, Charlson Comorbidity Index, Identification of Seniors at Risk score and concurrent use of CYP3A4 inhibitors were covariates considered for inclusion. A p value of < 0.05 was considered statistically significant for inclusion of covariates in the final model by stepwise addition. The simulation performance of the model was assessed by visual predictive check. RESULTS: A one-compartment, first-order absorption with lag time and linear elimination model was the best to fit to the fentanyl concentration data. The absorption rate constant was 0.136 h-1 (between subject variability (BSV), 46%), lag time 0.66 h (BSV 51%), apparent volume of distribution 6.28 L (BSV 30%), and apparent clearance 16.3 L.h-1 (BSV 54%). The Charlson Comorbidity Index was the only covariate included in the final model, where a higher value of the index increased fentanyl exposure and Cmax. CONCLUSION: This is the first report of subcutaneous fentanyl population pharmacokinetic model to evaluate fentanyl pharmacokinetic in older patients. The between subject variability in clearance and subcutaneous absorption rate was relatively high, and some patients recorded high fentanyl concentrations in the context of their titration to effect.

Hospital admission as a deprescribing triage point for patients discharged to Residential Aged Care Facilities.

BACKGROUND: Deprescribing may benefit older frail patients experiencing polypharmacy. We investigated the scope for deprescribing in acutely hospitalised patients and the long-term implications of continuation of medications that could potentially be deprescribed. METHODS: Acutely hospitalised patients (n = 170) discharged to Residential Aged Care Facilities, ≥75 years and receiving ≥5 regular medications were assessed during admission to determine eligibility for deprescribing of key drug classes, along with the actual incidence of deprescribing. The impact of continuation of nominated drug classes (anticoagulants, antidiabetics, antiplatelets, antipsychotics, benzodiazepines, proton pump inhibitors (PPIs), statins) on a combined endpoint (death/readmission) was determined. RESULTS: Hyperpolypharmacy (>10 regular medications) was common (49.4%) at admission. Varying rates of deprescribing occurred during hospitalisation for the nominated drug classes (8-53%), with considerable potential for further deprescribing (34-90%). PPI use was prevalent (56%) and 89.5% of these had no clear indication. Of the drug classes studied, only continued PPI use at discharge was associated with increased mortality/readmission at 1 year (hazard ratio 1.54, 95% confidence interval (1.06-2.26), P = 0.025), driven largely by readmission. CONCLUSION: There is considerable scope for acute hospitalisation to act as a triage point for deprescribing in older patients. PPIs in particular appeared overprescribed in this susceptible patient group, and this was associated with earlier readmission. Polypharmacy in older hospitalised patients should be targeted for possible deprescribing during hospitalisation, especially PPIs.

Inter-hospital lateral transfer does not increase length of stay.

OBJECTIVE: The aim of the present study was to assess the effect of an inter-hospital transfer on efficiency and quality of in-patient care. METHODS: A retrospective cohort study from 2010 to 2012 inclusive was conducted in two tertiary-referral urban hospitals within a single area healthcare network. The study included 14 571 acutely unwell patients admitted to a general medical service. The main outcome measures were length of in-patient stay, relative stay index, readmission rate within 7 and 28 days of discharge and in-hospital mortality rate. RESULTS: Compared with patients who were transferred to a long-stay ward within the original hospital (n = 3465), transferred patients (n = 1531) were older (71 vs 80 years, respectively; P < 0.001) but suffered less comorbidity (Charlson index 0.84 vs 1.22, respectively; P < 0.001). Transferred patients spent a shorter time in hospital (5.69 vs 6.25 days; P < 0.001) and were less likely to be re-admitted within 7 days (1.5% vs 4.0%; P < 0.001) or 28 days (6.3% vs 9.3%; P < 0.001) than patients who were not transferred. Mortality was lower in the transferred patients (1.1% vs 4.1%). CONCLUSION: Appropriate patients for inter-hospital transfer can be selected within 24 h of arrival at an index hospital. The efficiency of their care at the receiving hospital appears not to be compromised. The present study provides support for inter-hospital transfer as a strategy to optimise regional bed capacity.

A general medical short-stay unit is not more efficient than a traditional model of care.

OBJECTIVES: To assess the efficiency of a short-stay unit (SSU) for undifferentiated medical patients and evaluate its effect on the overall efficiency of a general medicine department. DESIGN, SETTING AND PATIENTS: Retrospective study of all general medical patients admitted to the SSU at Flinders Medical Centre, South Australia, during its 5 years of operation (2005-2009), compared with 4 years before its institution and 2 years after its closure. MAIN OUTCOME MEASURES: Relative stay index (RSI); inhospital mortality; readmissions within 7 and 28 days. RESULTS: 23 790 general medical patients were admitted overall, and 10 764 of these (45.2%) were admitted to the SSU. The RSI for the SSU during its years of operation was 0.79, compared with 1.34 for the long-stay unit. The overall RSI for the department did not improve during those years and was not significantly different to the periods before or after. CONCLUSIONS: We found no evidence that an SSU for undifferentiated medical patients creates bed capacity. It does, however, appear to be safe.

Ground penetrating radar observations of the contact between the western delta and the crater floor of Jezero crater, Mars.

The delta deposits in Jezero crater contain sedimentary records of potentially habitable conditions on Mars. NASA's Perseverance rover is exploring the Jezero western delta with a suite of instruments that include the RIMFAX ground penetrating radar, which provides continuous subsurface images that probe up to 20 meters below the rover. As Perseverance traversed across the contact between the Jezero crater floor and the delta, RIMFAX detected a distinct discontinuity in the subsurface layer structure. Below the contact boundary are older crater floor units exhibiting discontinuous inclined layering. Above the contact boundary are younger basal delta units exhibiting regular horizontal layering. At one location, there is a clear unconformity between the crater floor and delta layers, which implies that the crater floor experienced a period of erosion before the deposition of the overlying delta strata. The regularity and horizontality of the basal delta sediments observed in the radar cross sections indicate that they were deposited in a low-energy lake environment.

Deprescribing Antihypertensive Medications in Older People: A Narrative Review, Part 1.

The problem of polypharmacy is complex, pervasive, and expanding. Appropriate prescribing of antihypertensive therapy for older people might help reduce medication burden, but it begins with a better understanding of what the evidence offers and where the evidence is quiet.In the first of this three-part series on antihypertensive medications for older people, we will trace the history of treating blood pressure with medication, from the expert opinion opposing treatment, to the observational data that led to paradigm shifts. We will follow the trail of evidence to randomized controlled trials (RCT) demonstrating the clear benefit of better control of blood pressure for all adults, regardless of age.RCT first evaluated any treatment against placebo, then began comparing one medication with another, and finally, more intensive control compared with less intensive control. Eventually professional societies bundled the evidence into guidelines to help busy prescribers and pharmacists wisely advise the consumers at the coal-face.In this first part of this series, we will present the evidence that favors intensive therapy in older people, that lower is better. In the second part, we will present evidence that highlights the dangers of going too low, and that stopping blood pressure-lowering medication might help. In the third part, we will discuss the evidence, new and old, that shows what happens when you stop.

Use of Single-Dose Dexamethasone in Patients With Diabetes Undergoing Surgery: A Systematic Review and Meta-Analysis.

The purpose of this review was to examine the effect of single-dose dexamethasone on perioperative blood glucose in diabetic patients. We used PubMed, Cochrane Library, MEDLINE, CINAHL, Google Scholar, and grey literature for our search. Only randomized controlled trials were included. Risk ratio (RR) and mean difference (MD) were used to estimate outcomes with suitable effect models. Quality of evidence was assessed using the Risk of Bias and GRADE systems. We analyzed seven trials involving 1,321 patients. Diabetic patients treated with single-dose dexamethasone had statistically significant changes in blood glucose levels from baseline by 33.61 mg/dL (MD, 33.61; 95% CI, 17.59 to 49.63; P < .0001). Dexamethasone increased blood glucose levels 1-4 hours (MD, 29.02; 95% CI, 7.09 to 50.94; P = .010), 8-24 hours (MD, 30.81; 95% CI, 9.21 to 52.41; P = .005) after administration and increased risks of hyperglycemia. However, there was no difference in surgical site infection (SSI) (RR, 0.81; 95% CI, 0.59 to 1.11; P = .19). Effect size imprecision, substantial heterogeneity, and publication bias was the study's limitations. We found that single-dose dexamethasone increased glucose concentration 24 hours after surgery with little to no effect on SSI. Extrapolation of these findings to clinical settings must take into consideration the review's limitations.

Rational Prescribing and Deprescribing of Antihypertensive Medications in Older People, a Three-Part Narrative Review, Part 3.

What happens when you stop? This is the third of a three-part series on antihypertensive medication use in older people. In the first, we reviewed the importance of better blood pressure (BP) control, even in older people with hypertension. In the second, we discussed the limitations of the evidence favoring intensive therapy for some older people. For older people with advanced frailty or those with a limited life expectancy, medications taken for BP can actually be a source of morbidity. Guidelines encourage clinical judgment and rational prescribing. Sometimes the best action is to stop prescribing. De-prescribing of medical therapy is now considered good practice for a range of medications for suitable patients; should this include antihypertensives? In part three of this three-part series, we will review some of the evidence available thus far, demonstrating de-intensification of antihypertensive medications is not a new idea. We will offer a guide to identifying the most suitable patients for de-prescribing: cognitive impairment, frailty, when circumstances change, or when BP is (too) well-controlled. This is an area of equipoise and needs more research. There is a path forward that we hope to illuminate.

Rational Prescribing and Deprescribing of Antihypertensive Medications in Older People, Part 2.

The evidence is strong in favor of blood pressure (BP) control in robust older people as a way to reduce morbidity and mortality in the same way that treatment improves the lives of middle-aged people. Expert editorials have been written over the last five decades persuasively arguing for or against more intensive treatment of older people with hypertension, supported by the specificity of (then) contemporaneous randomized controlled trials (RCTs) or the generalizability of observational studies. But there are limitations.First, there has always been such a thing as too low. Early epidemiological studies showed an upward inflection in mortality curves that resemble a slanted letter J. Second, certain complex older people encountered routinely in a clinic, pharmacy, or nursing facility were often excluded from the RCTs showing benefit from intensive BP control. Cohort studies of these complex people showed a different truth, that the point of "too low" might move up and that BP targets for adults might be too low for select older people. Not all older people are the same. Some are burdened by frailty superimposed on cardiovascular disease and a limited life-expectancy. It is one thing not to start BP-lowering medications for this patient; it is an entirely different matter to stop.

Serum from COVID-19 patients early in the pandemic shows limited evidence of cross-neutralization against variants of concern.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) results in a variety of clinical symptoms ranging from no or mild to severe disease. Currently, there are multiple postulated mechanisms that may push a moderate to severe disease into a critical state. Human serum contains abundant evidence of the immune status following infection. Cytokines, chemokines, and antibodies can be assayed to determine the extent to which a patient responded to a pathogen. We examined serum and plasma from a cohort of patients infected with SARS-CoV-2 early in the pandemic and compared them to negative-control sera. Cytokine and chemokine concentrations varied depending on the severity of infection, and antibody responses were significantly increased in severe cases compared to mild to moderate infections. Neutralization data revealed that patients with high titers against an early 2020 SARS-CoV-2 isolate had detectable but limited neutralizing antibodies against the emerging SARS-CoV-2 Alpha, Beta and Delta variants. This study highlights the potential of re-infection for recovered COVID-19 patients.

Soluble Immune Checkpoints Are Dysregulated in COVID-19 and Heavy Alcohol Users With HIV Infection.

Immune checkpoints (ICPs) consist of paired receptor-ligand molecules that exert inhibitory or stimulatory effects on immune defense, surveillance, regulation, and self-tolerance. ICPs exist in both membrane and soluble forms in vivo and in vitro. Imbalances between inhibitory and stimulatory membrane-bound ICPs (mICPs) in malignant cells and immune cells in the tumor immune microenvironment (TIME) have been well documented. Blockades of inhibitory mICPs have emerged as an immense breakthrough in cancer therapeutics. However, the origin, structure, production regulation, and biological significance of soluble ICPs (sICPs) in health and disease largely remains elusive. Soluble ICPs can be generated through either alternative mRNA splicing and secretion or protease-mediated shedding from mICPs. Since sICPs are found in the bloodstream, they likely form a circulating immune regulatory system. In fact, there is increasing evidence that sICPs exhibit biological functions including (1) regulation of antibacterial immunity, (2) interaction with their mICP compartments to positively or negatively regulate immune responses, and (3) competition with their mICP compartments for binding to the ICP blocking antibodies, thereby reducing the efficacy of ICP blockade therapies. Here, we summarize current data of sICPs in cancer and infectious diseases. We particularly focus on sICPs in COVID-19 and HIV infection as they are the two ongoing global pandemics and have created the world's most serious public health challenges. A "storm" of sICPs occurs in the peripheral circulation of COVID-19 patients and is associated with the severity of COVID-19. Similarly, sICPs are highly dysregulated in people living with HIV (PLHIV) and some sICPs remain dysregulated in PLHIV on antiretroviral therapy (ART), indicating these sICPs may serve as biomarkers of incomplete immune reconstitution in PLHIV on ART. We reveal that HIV infection in the setting of alcohol misuse exacerbates sICP dysregulation as PLHIV with heavy alcohol consumption have significantly elevated plasma levels of many sICPs. Thus, both stimulatory and inhibitory sICPs are present in the bloodstream of healthy people and their balance can be disrupted under pathophysiological conditions such as cancer, COVID-19, HIV infection, and alcohol misuse. There is an urgent need to study the role of sICPs in immune regulation in health and disease.

Ground penetrating radar observations of subsurface structures in the floor of Jezero crater, Mars.

The Radar Imager for Mars Subsurface Experiment instrument has conducted the first rover-mounted ground-penetrating radar survey of the Martian subsurface. A continuous radar image acquired over the Perseverance rover's initial ~3-kilometer traverse reveals electromagnetic properties and bedrock stratigraphy of the Jezero crater floor to depths of ~15 meters below the surface. The radar image reveals the presence of ubiquitous strongly reflecting layered sequences that dip downward at angles of up to 15 degrees from horizontal in directions normal to the curvilinear boundary of and away from the exposed section of the Séitah formation. The observed slopes, thicknesses, and internal morphology of the inclined stratigraphic sections can be interpreted either as magmatic layering formed in a differentiated igneous body or as sedimentary layering commonly formed in aqueous environments on Earth. The discovery of buried structures on the Jezero crater floor is potentially compatible with a history of igneous activity and a history of multiple aqueous episodes.

Wischnewski spots in a case of accidental hypothermia.

Accidental hypothermia can be fatal, and is often associated with confusion and paradoxical undressing. Wischnewski spots are a classic manifestation of hypothermia at autopsy.

Hepatic angiosarcoma: Pitfalls in establishing a diagnosis.

Hepatic angiosarcomas are rare, deceptive and aggressive malignancies that remain notoriously difficult to diagnose and treat. This case report discusses some of the common challenges faced by clinicians, and potential clinical, radiological and histological clues to this often elusive diagnosis.

Prospective cohort study of nonspecific deprescribing in older medical inpatients being discharged to a nursing home.

Background: Older patients from nursing homes are commonly exposed to polypharmacy before a hospital admission. Deprescribing has been promoted as a solution to this problem, though systematic reviews have not found benefit. The aim of this study was to understand if in-hospital deprescribing of certain classes of medications is associated with certain benefits or risks. Methods: We conducted a prospective, multicentre, cohort study in 239 medical inpatients ⩾75 years (mean age 87.4 years) who were exposed to polypharmacy (⩾5 medications) prior to admission and discharged to a nursing home for permanent placement. Patients were categorised by whether deprescribing occurred, mortality and readmissions were assessed 30 and 90 days after hospital discharge. The EQ-5D-5 L health survey assessed changes in health-related quality of life (HRQOL) at 90 days, with comparison to EQ-5D-5 L results at day 30. Latent class analysis (LCA) was used to investigate associations between patterns of prescribed and deprescribed medications and mortality. Results: Patients for whom deprescribing occurred had a higher Charlson Index; there were no differences between the groups in principal diagnosis, total or Beers list number of medications on admission. The number of Beers list medications increased in both groups before discharge. Patients who had medications deprescribed had nonsignificantly greater odds of dying within 90 days [odds ration (OR) = 3.23 (95% confidence interval (CI): 0.68, 14.92; p = 0.136]. Deprescribing of certain classes was associated with higher 90-day mortality: antihypertensives (OR = 2.27, 95% CI: 1.004, 5; p = 0.049) and statins (OR = 5, 95% CI: 1.61, 14.28; p = 0.005). Readmissions and 1-year mortality rates were similar. There was no deterioration in HRQOL when medications were deprescribed. LCA showed that patients with the least medication changes had the lowest mortality. Conclusion: Deprescribing certain classes of medications during hospitalisation was associated with worse mortality, but not readmissions or overall HRQOL. Larger controlled deprescribing studies targeting specific medications are warranted to further investigate these findings.This study was registered with the Australian and New Zealand Clinical Trials Registry, ACTRN1 2616001336471. Plain language summary: Background: When an older person living in a nursing home is admitted to hospital, does stopping long-term medications help them?Many older people from nursing homes take a large number of medications each day to treat symptoms and prevent adverse events. "Polypharmacy" is a term used to describe taking multiple long-term medications, and it is associated with many negative outcomes such as increased number of falls, cognitive decline, hospital readmission, even death. Deprescribing of nonessential medications - whether stopping or reducing the dose - is promoted as good hospital practice and is assumed to help older frail people live longer and feel better. However, we often don't fully understand what is and is not essential.We wanted to better understand the effect of deprescribing long-term medications for older frail patients during an unplanned hospital admission as they were going to a nursing home to live.Methods: While admitted to hospital, medications are often reviewed by a clinical pharmacist and specialist physician. Sometimes medications are ceased; sometimes they are not. This gave us the opportunity to study two groups of older frail people from nursing homes: those who had regular, long-term medications ceased or reduced and those who did not. We wanted to see if one group did better. For example, did they feel worse if we stopped certain medications? Did they suffer other bad events compared with those patients for whom no medications were ceased? Were they readmitted to hospital earlier or more often?Results and conclusion: Despite the assumption that stopping medications for this type of patient is good practice, we found no benefit. We were also surprised to find stopping or reducing certain drug classes (e.g. antihypertensives and cholesterol-lowering drugs) was associated with greater mortality. Larger, randomised studies will better answer these important questions.

Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19.

COVID-19 starts as a respiratory disease that can progress to pneumonia, severe acute respiratory syndrome (SARS), and multi-organ failure. Growing evidence suggests that COVID-19 is a systemic illness that primarily injures the vascular endothelium, yet the underlying mechanisms remain unknown. SARS-CoV-2 infection is believed to trigger a cytokine storm that plays a critical role in the pathogenesis of endothelialitis and vascular injury, eventually leading to respiratory and multi-organ failure in COVID-19 patients. We used a multiplex immunoassay to systematically profile and compare 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). Patients with severe/critical and mild/moderate COVID-19 had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only one cytokine (MIF) was among these altered analytes, while the rest were chemokines and growth factors. In addition, only MMP-1 and VEGF-A were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. Given that excessive MMP-1 plays a central role in tissue destruction in a wide variety of vascular diseases and that elevated VEGF-A, an EC activation marker, increases vascular permeability, we further studied MMP-1 enzymatic activity and other EC activation markers such as soluble forms of CD146, ICAM-1, and VCAM-1. We found that plasma MMP-1 enzymatic activity and plasma levels of MMP-1 and EC activation markers were highly dysregulated in COVID-19 patients. Some dysregulations were associated with patients' age or gender, but not with race. Our results demonstrate that COVID-19 patients have distinct inflammatory profiles that are distinguished from the cytokine storms in other human diseases. Excessive MMP-1 and hyperactivation of ECs occur in COVID-19 patients and are associated with the severity of COVID-19.