HDL in COVID-19 Patients: Evidence from an Italian Cross-Sectional Study

A number of studies have highlighted important alterations of the lipid profile in COVID-19 patients. Besides the well-known atheroprotective function, HDL displays anti-inflammatory, anti-oxidative, and anti-infectious properties. The aim of this retrospective study was to assess the HDL anti-inflammatory and antioxidant features, by evaluation of HDL-associated Serum amyloid A (SAA) enrichment and HDL-paraoxonase 1 (PON-1) activity, in a cohort of COVID-19 patients hospitalized at the Cardiorespiratory COVID-19 Unit of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan. COVID-19 patients reached very low levels of HDL-c (mean ± SD: 27.1 ± 9.7 mg/dL) with a marked rise in TG (mean ± SD: 165.9 ± 62.5 mg/dL). Compared to matched-controls, SAA levels were significantly raised in COVID-19 patients at admission. There were no significant differences in the SAA amount between 83 alive and 22 dead patients for all-cause in-hospital mortality. Similar findings were reached in the case of PON-1 activity, with no differences between alive and dead patients for all-cause in-hospital mortality. In conclusion, although not related to the prediction of in-hospital mortality, reduction in HDL-c and the enrichment of SAA in HDL are a mirror of SARS-CoV-2 positivity even at the very early stages of the infection.

Patterns, trends and determinants of medical opioid utilization in Canada 2005–2020: characterizing an era of intensive rise and fall

Background Into the 21st century, the conflation of high rates of chronic pain, systemic gaps in treatment availability and access, and the arrival of potent new opioid medications (e.g., slow-release oxycodone) facilitated strong increases in medical opioid dispensing in Canada. These persisted until post-2010 alongside rising opioid-related adverse (e.g., morbidity/mortality) outcomes. We examine patterns, trends and determinants of opioid dispensing in Canada, and specifically its 10 provinces, for the years 2005–2020. Methods Raw data on prescription opioid dispensing were obtained from a large national community-based pharmacy database (IQVIA/Compuscript), converted into Defined-Daily-Doses/1,000 population/day for ‘strong’ and ‘weak’ opioid categories per standard methods. Dispensing by opioid category and formulations by province/year was assessed descriptively; regression analysis was applied to examine possible segmentation of over-time strong opioid dispensing. Results All provinces reported starkly increasing strong opioid dispensing peaking 2011–2016, and subsequent marked declines. About half reported lower strong opioid dispensing in 2020 compared to 2005, with continuous inter-provincial differences of > 100 %; weak opioids also declined post-2011/12. Segmented regression suggests breakpoints for strong opioids in 2011/12 and 2015/16, coinciding with main interventions (e.g., selective opioid delisting, new prescribing guidelines) towards more restrictive opioid utilization control. Conclusions We characterized an era of marked rise and fall, while featuring stark inter-provincial heterogeneity in opioid dispensing in Canada. While little evidence for improvements in pain care outcomes exists, the starkly inverting opioid utilization have been associated with extensive population-level harms (e.g., misuse, morbidity, mortality) over-time. This national case study raises fundamental questions for opioid-related health policy and practice.

SOCIAL CLASS AND EARNINGS TRAJECTORIES IN 14 EUROPEAN COUNTRIES

In this paper, we seek to contribute to ongoing discussions of the relationship between income and class in analyses of social inequality and mobility. We argue that while class has sometimes been taken as a proxy for long-term earning levels, it is of greater importance, at least when treated in terms of the EGP schema or the European Socio-Economic Classification (ESEC), in capturing differences in the trajectories that employees’ earnings follow over the course of their working lives. Moving beyond previous single country studies, we examine how far the theory that underlies ESEC is reflected in men’s age-earnings trajectories across 14 European countries, while also taking into account any effects of their educational qualifications. Modelling data from the 2017 EU-SILC survey, and focussing on men’s full year/full-time equivalent gross annual earnings, we find that although the age-earnings trajectories that are estimated for different classes do reveal some cross-national variation, there are major features, of a theoretically expected kind, that are evident with our pooled sample and that regularly recur in individual countries. Class differences in earnings are at their narrowest for men in the youngest age group but then widen across older age groups. This occurs primarily because the earnings of men in the professional and managerial salariat, and especially in the higher salariat, show a marked rise with age, while the earnings of men in other classes rise far less sharply or remain flat. We also find evidence that these diverging trajectories are primarily shaped by individuals’ class positions independently of their level of qualifications – however important the latter is in determining the class positions that they hold. What can be regarded as the logic of different forms of employment relations, as captured by ESEC, leads to a large degree of cross-national commonality in the association that exists between class and the trajectories of earnings over working life.

Activation of the hypothalamic–pituitary–adrenal axis by exogenous and endogenous GDF15

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic–pituitary–adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15−/− mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies.

Prevalence of peripheral neuropathy in pre-diabetes: a systematic review

There is growing evidence of excess peripheral neuropathy in pre-diabetes. We aimed to determine its prevalence, including the impact of diagnostic methodology on prevalence rates, through a systematic review conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive electronic bibliographic search was performed in MEDLINE, EMBASE, PubMed, Web of Science and the Cochrane Central Register of Controlled Trials from inception to June 1, 2020. Two reviewers independently selected studies, extracted data and assessed risk of bias. An evaluation was undertaken by method of neuropathy assessment. After screening 1784 abstracts and reviewing 84 full-text records, 29 studies (9351 participants) were included. There was a wide range of prevalence estimates (2%–77%, IQR: 6%–34%), but the majority of studies (n=21, 72%) reported a prevalence ≥10%. The three highest prevalence estimates of 77% (95% CI: 54% to 100%), 71% (95% CI: 55% to 88%) and 66% (95% CI: 53% to 78%) were reported using plantar thermography, multimodal quantitative sensory testing and nerve conduction tests, respectively. In general, studies evaluating small nerve fiber parameters yielded a higher prevalence of peripheral neuropathy. Due to a variety of study populations and methods of assessing neuropathy, there was marked heterogeneity in the prevalence estimates. Most studies reported a higher prevalence of peripheral neuropathy in pre-diabetes, primarily of a small nerve fiber origin, than would be expected in the background population. Given the marked rise in pre-diabetes, further consideration of targeting screening in this population is required. Development of risk-stratification tools may facilitate earlier interventions.

Alpelisib-Induced Hyperglycemia- A Small Case Series

The phosphoinositide-3-kinase (PI3K) family consists of highly conserved enzymes that are key intermediaries in signal transduction regulating cell survival and mitogenesis. This axis has been implicated in many types of cancers. In 2019 Alpelisib (Piqray), a reversible inhibitor specific to the PI3Kα subunit, in combination with fulvestrant, was approved to treat hormone receptor positive, human epidermal growth factor receptor 2 (Her2) negative, PI3K mutated breast cancer. This approval followed SOLAR-1 trial results showing a 35% risk reduction in cancer progression or death with alpelisib-fulvestrant compared to placebo in a cohort with PI3K mutated breast cancer. PI3K also plays a critical role in the insulin signaling pathway and alpelisib has been shown to cause a dose dependent rise in plasma glucose, insulin and c-peptide. Here we present a case series of severe hyperglycemia induced by alpelisib. A 44-year-old woman with ER+/Her2(-)/PI3K positive metastatic breast cancer was started on alpelisib. Previously, HbA1C was 5.4%. Hyperglycemia developed and HbA1c rose to 9.0% within 6 months of alpelisib 300mg daily. She started metformin and empagliflozin, which she was unable to tolerate due to nausea and vomiting. Her self-monitored blood glucoses were 300-400mg/dL within hours after her morning alpelisib dose. We discontinued empagliflozin when she developed metabolic acidosis with an increased anion gap. However, prior to any dose reduction, oncology discontinued alpelisib due to evidence of cancer progression. A week later, her glucoses normalized. Second case is of a 64-year-old woman with stage IV ER+/Her2(-)/PI3K mutated breast cancer with bony metastases, who was started on alpelisib 250mg. Her prior HbA1C was 5.5%. Ten days after initiation of alpelisib, she developed grade 3 hyperglycemia (blood glucoses 200-500mg/dL). She was started on metformin 2000mg with alpelisib dosed at noon. However, she noted a marked rise in blood glucose in the afternoon, few hours following alpelisib dose. Thus, moving the alpelisib to bedtime allowed better control of glycemia by using overnight basal insulin. Similarly, a 37-year-old woman with a history of ER+/HER2(-) stage IV metastatic breast cancer to the liver, with PI3K mutation was found to have acute, severe hyperglycemia with blood glucose of 300mg/dL, despite HbA1C being only 4.7%. This was attributed to initiation of alpelisib 2 days prior to admission. Given the severity of her insulin resistance (requiring > 100 units of insulin daily), alpelisib dose was reduced from 300mg to 150mg/day. On discharge, she was placed on metformin, dulaglutide, and basal and prandial insulins. Her HbA1C rose to 9.4% within 3 months of alpelisib initiation. This case series demonstrate the unique challenges in managing alpelisib induced reversible hyperglycemia.

Efficacy of Oral Gabapentin for Attenuation of Haemodynamic Responses to Laryngoscopy & Endotracheal Intubation

BACKGROUND Laryngoscopy and endotracheal intubation are basic skills to be acquired by an anaesthesiologist. For many years, laryngoscopy has been used as a conventional way to facilitate endotracheal intubation. These are the most critical events because, they provoke a marked rise in sympathoadrenal response as hypertension and tachycardia. There is an absolute need to decrease these haemodynamic responses, for which various drugs were used, with varying degrees of success. Gabapentin, initially used as an anticonvulsant has extended its role into anaesthesia practice with its multimodal effects. This study was conducted to evaluate the efficacy of oral gabapentin 800 mg in attenuation of haemodynamic responses to laryngoscopy and endotracheal intubation. METHODS After obtaining institutional ethical clearance, a prospective randomised comparative study was undertaken. Written and informed consent was obtained from 80 patients belonging to American Society of Anaesthesiologists (ASA) class I & II scheduled for various elective surgeries under general anaesthesia. They were divided into two groups of 40 each using computer generated random number table. Group G received oral gabapentin 800 mg and group C received empty capsules with sips of water, 2 hours prior to induction. Haemodynamic parameters – heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) were noted and rate pressure product (RPP) was calculated at baseline, at laryngoscopy and then at 1, 3, 5, 10 & 15 minutes after laryngoscopy and endotracheal intubation. RESULTS In Group G there was significant attenuation of HR, SBP, DBP, MAP at 1, 3 and 5 minutes after laryngoscopy and endotracheal intubation as compared to Group C. Hence, in Group G there was significant attenuation of RPP at 1 minute (12673.60 ± 1691.25, 11769.08 ± 1146.02, P = 0.01), 3 minutes (12546.85 ± 1123.78, 11759.98 ± 1358.02, P = 0.01) and 5 minutes (12411.68 ± 1270.04, 11537.03 ± 1230.06, P = 0.002) after laryngoscopy and endotracheal intubation as compared to Group C. No statistical difference was seen at 10 and 15 minutes. CONCLUSIONS Oral gabapentin 800 mg given preoperatively can attenuate haemodynamic responses to laryngoscopy and endotracheal intubation without significant side effects. KEY WORDS Oral Gabapentin, Laryngoscopy, Endotracheal Intubation, Haemodynamic Changes, Attenuation, Pressor Responses

Medical disinformation and the unviable nature of COVID-19 conspiracy theories

The coronavirus pandemic has seen a marked rise in medical disinformation across social media. A variety of claims have garnered considerable traction, including the assertion that COVID is a hoax or deliberately manufactured, that 5G frequency radiation causes coronavirus, and that the pandemic is a ruse by big pharmaceutical companies to profiteer off a vaccine. An estimated 30% of some populations subscribe some form of COVID medico-scientific conspiracy narratives, with detrimental impacts for themselves and others. Consequently, exposing the lack of veracity of these claims is of considerable importance. Previous work has demonstrated that historical medical and scientific conspiracies are highly unlikely to be sustainable. In this article, an expanded model for a hypothetical en masse COVID conspiracy is derived. Analysis suggests that even under ideal circumstances for conspirators, commonly encountered conspiratorial claims are highly unlikely to endure, and would quickly be exposed. This work also explores the spectrum of medico-scientific acceptance, motivations behind propagation of falsehoods, and the urgent need for the medical and scientific community to anticipate and counter the emergence of falsehoods.

Immunodominant B cell epitope in SARS-CoV-2 RBD comprises a B.1.351 and P.1 mutation hotspot: implications for viral spread and antibody escape

Recent SARS-CoV-2 variants pose important concerns due to their higher transmissibility (1) and escape (2) from previous infections or vaccine-induced neutralizing antibodies (nAb). The receptor binding domain (RBD) of the Spike protein is a major nAb target (3), but data on its B cell epitopes are still lacking. Using a peptide microarray, we identified an immunodominant epitope (S415-429) recognized by 68% of sera from 71 convalescent Brazilians infected with the ancestral variant. In contrast with previous studies, we have identified a linear IgG and IgA antibody binding epitope within the RBD. IgG and IgA antibody levels for this epitope positively correlated with nAb titers, suggesting a potential target of antibody neutralizing activity. Interestingly, this immunodominant RBD region harbors the mutation hotspot site K417 present in P.1 (K417T) and B.1.351 (K417N) variants. In silico simulation analyses indicate impaired RBD binding to nAb in both variants and that a glycosylation in the B.1.351 417N could further hinder antibody binding as compared to the K417T mutation in P.1. This is in line with published data showing that nAb from either convalescents or anti-CoV-2 vaccinees are less effective towards B.1.351 than for P.1. Our data support the occurrence of immune pressure and selection involving this immunodominant epitope that may have critically contributed to the recent COVID-19 marked rise in Brazil and South Africa, and pinpoint a potential additional immune escape mechanism for SARS-CoV-2.

The use of Lactobacillus reuteri DSM 17938 and ATCC PTA 5289 on oral health indexes in a school population: A pilot randomized clinical trial

To assess the effects of a probiotic upon oral health indices in adolescents and to establish relationships between these indices and dietary habits and oral hygiene. Twenty-seven adolescents between 12 and 18 years of age were randomized into two groups. The study group received tablets containing Lactobacillus reuteri DSM 17938/ ATCC 5289 for 28 days, while the control group received tablets without any bacteria. Streptococcus mutans, Lactobacillus sp., and salivary pH were assessed at baseline and at 7, 14, 21, 28, and 45 days. The plaque, gingivitis, and bleeding indices were recorded at baseline and at 14, 28, and 45 days. Dietary and oral hygiene habits were also evaluated by means of a questionnaire. A less marked rise in S. mutans was recorded in the study group. Improvements were observed in terms of plaque, gingivitis, and bleeding, though statistical significance was not reached. Oral pH increased in the study group, though not to a significant degree. Poorer eating habits were significantly correlated to increased plaque. The study parameters decreased with the two strains of L. reuteri DSM 17938 and ATCC PTA 5289, though the results failed to reach statistical.