Insight into the complex pathophysiology of sickle cell anaemia and possible treatment

Sickle cell anaemia (SCA) is the consequence of abnormal haemoglobin production due to an inherited point mutation in the β‐globin gene. The resulting haemoglobin tetramer is poorly soluble when deoxygenated, and when this is prolonged, intracellular gelation of sickle haemoglobin occurs, followed by haemoglobin polymerisation. If many cycles of sickling and unsickling occur, the red cell membrane will be disrupted leading to haemolysis and vaso‐occlusive events. Recent studies have also shown that leucocyte adhesion molecules and nitric oxide (NO) depletion are involved in endothelial damage. New insights in SCA pathophysiology and vascular biology have shown that cell‐derived microparticle (MP) generation is also involved in the vaso‐occlusion. Endothelial damage is perpetuated by impaired production or increased consumption of protective modulators such as protein C, protein S and NO. New therapeutic interventions should address these aspects of SCA pathogenesis. To date, the only US‐FDA‐approved therapy to prevent painful vaso‐occulsive episodes is hydroxyurea that reduces haemoglobin polymerisation in sickle cells by increasing the production of foetal haemoglobin and L‐glutamine. However, several new drugs have been tested in the last years in randomised clinical trials. We here report an update on the current status of knowledge on SCA.     

Relationship between saliva and plasma rufinamide concentrations in patients with epilepsy

The assay of saliva samples provides a valuable alternative to the use of blood samples for therapeutic drug monitoring (TDM), at least for certain categories of patients. To determine the feasibility of using saliva sampling for the TDM of rufinamide, we compared rufinamide concentrations in paired samples of saliva and plasma collected from 26 patients with epilepsy at steady state. Within-patient relationships between plasma rufinamide concentrations and dose, and the influence of comedication were also investigated. Assay results in the two tested fluids showed a good correlation (r² = .78, P < .0001), but concentrations in saliva were moderately lower than those in plasma (mean saliva to plasma ratio = 0.7 ± 0.2). In eight patients evaluated at three different dose levels, plasma rufinamide concentrations increased linearly with increasing dose. Patients receiving valproic acid comedication had higher dose-normalized plasma rufinamide levels than patients comedicated with drugs devoid of strong enzyme-inducing or enzyme-inhibiting activity. Overall, these findings indicate that use of saliva represents a feasible option for the application of TDM in patients treated with rufinamide. Because rufinamide concentrations are lower in saliva than in plasma, a correction factor is needed if measurements made in saliva are used as a surrogate for plasma concentrations.     

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One‐hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥ 1 abnormal CART) and confirmed CAN (≥ 2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns—COMPASS 31+ESC and COMPASS 31 and/or ESC—were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality.     

Treating insomnia in Swiss primary care practices: A survey study based on case vignettes

Guidelines recommend cognitive behavioural therapy for insomnia (CBT‐I) as first‐line treatment for chronic insomnia, but it is not clear how many primary care physicians (PCPs) in Switzerland prescribe this treatment. We created a survey that asked PCPs how they would treat chronic insomnia and how much they knew about CBT‐I. The survey included two case vignettes that described patients with chronic insomnia, one with and one without comorbid depression. PCPs also answered general questions about treating chronic insomnia and about CBT‐I and CBT‐I providers. Of the 820 Swiss PCPs we invited, 395 (48%) completed the survey (mean age 54 years; 70% male); 87% of PCPs prescribed sleep hygiene and 65% phytopharmaceuticals for the patient who had only chronic insomnia; 95% prescribed antidepressants for the patient who had comorbid depression. In each case, 20% of PCPs prescribed benzodiazepines or benzodiazepine receptor agonists, 8% prescribed CBT‐I, 68% said they knew little about CBT‐I, and 78% did not know a CBT‐I provider. In the clinical case vignettes, most PCPs treated chronic insomnia with phytopharmaceuticals and sleep hygiene despite their lack of efficacy, but PCPs rarely prescribed CBT‐I, felt they knew little about it, and usually knew no CBT‐I providers. PCPs need more information about the benefits of CBT‐I and local CBT‐I providers and dedicated initiatives to implement CBT‐I in order to reduce the number of patients who are prescribed ineffective or potentially harmful medications.     

Mesenchymal stromal cell secretome in liver failure: Perspectives on COVID-19 infection treatment

Due to their immunomodulatory potential and release of trophic factors that promote healing, mesenchymal stromal cells (MSCs) are considered important players in tissue homeostasis and regeneration. MSCs have been widely used in clinical trials to treat multiple conditions associated with inflammation and tissue damage. Recent evidence suggests that most of the MSC therapeutic effects are derived from their secretome, including the extracellular vesicles, representing a promising approach in regenerative medicine application to treat organ failure as a result of inflammation/fibrosis. The recent outbreak of respiratory syndrome coronavirus, caused by the newly identified agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has forced scientists worldwide to use all available instruments to fight the infection, including the inflammatory cascade caused by this pandemic disease. The use of MSCs is a valid approach to combat organ inflammation in different compartments. In addition to the lungs, which are considered the main inflammatory target for this virus, other organs are compromised by the infection. In particular, the liver is involved in the inflammatory response to SARS-CoV-2 infection, which causes organ failure, leading to death in coronavirus disease 2019 (COVID-19) patients. We herein summarize the current implications derived from the use of MSCs and their soluble derivatives in COVID-19 treatment, and emphasize the potential of MSC-based therapy in this clinical setting.     

Immunogenicity of two doses of BNT162b2 and mRNA-1273 vaccines for solid cancer patients on treatment with or without a previous SARS-CoV-2 infection

Previous studies on the immunogenicity of SARS-CoV-2 mRNA vaccines showed a reduced seroconversion in cancer patients. The aim of our study is to evaluate the immunogenicity of two doses of mRNA vaccines in solid cancer patients with or without a previous exposure to the virus. This is a single-institution, prospective, nonrandomized study. Patients in active treatment and a control cohort of healthy people received two doses of BNT162b2 (Comirnaty, BioNTech/Pfizer, The United States) or mRNA-1273 (Spikevax, Moderna). Vaccine was administered before starting anticancer therapy or on the first day of the treatment cycle. SARS-CoV-2 antibody levels against S1, RBD (to evaluate vaccine response) and N proteins (to evaluate previous infection) were measured in plasma before the first dose and 30 days after the second one. From January to June 2021, 195 consecutive cancer patients and 20 healthy controls were enrolled. Thirty-one cancer patients had a previous exposure to SARS-CoV-2. Cancer patients previously exposed to the virus had significantly higher median levels of anti-S1 and anti-RBD IgG, compared to healthy controls (P = .0349) and to cancer patients without a previous infection (P < .001). Vaccine type (anti-S1: P < .0001; anti-RBD: P = .0045), comorbidities (anti-S1: P = .0274; anti-RBD: P = .0048) and the use of G-CSF (anti-S1: P = .0151) negatively affected the antibody response. Conversely, previous exposure to SARS-CoV-2 significantly enhanced the response to vaccination (anti-S1: P < .0001; anti-RBD: P = .0026). Vaccine immunogenicity in cancer patients with a previous exposure to SARS-CoV-2 seems comparable to that of healthy subjects. On the other hand, clinical variables of immune frailty negatively affect humoral immune response to vaccination.     

Wound repair during arm regeneration in the red starfish Echinaster sepositus

Starfish can regenerate entire arms following their loss by both autotomic and traumatic amputation. Although the overall regenerative process has been studied several times in different asteroid species, there is still a considerable gap of knowledge as far as the detailed aspects of the repair phase at tissue and cellular level are concerned, particularly in post‐traumatic regeneration. The present work is focused on the arm regeneration model in the Mediterranean red starfish Echinaster sepositus; to describe the early cellular mechanisms of arm regeneration following traumatic amputation, different microscopy techniques were employed. In E. sepositus, the repair phase was characterized by prompt wound healing by a syncytial network of phagocytes and re‐epithelialisation followed by a localized subepidermal oedematous area formation. Scattered and apparently undifferentiated cells, intermixed with numerous phagocytes, were frequently found in the wound area during these first stages of regeneration and extensive dedifferentiation phenomena were seen at the level of the stump, particularly in the muscle bundles. A true localized blastema did not form. Our results confirm that regeneration in asteroids mainly relies on morphallactic processes, consisting in extensive rearrangement of the existing tissues which contribute to the new tissues through cell dedifferentiation, redifferentiation, and/or migration.