Changes in arterial pH do not explain the reductions in ionised calcium observed during COVID-19 infection.

BACKGROUND: Hypocalcaemia predicts coronavirus disease 2019 (COVID-19) severity and mortality. We hypothesized an association between respiratory alkalosis secondary to hypoxia and low ionised calcium (iCa) concentration in patients with COVID-19. METHODS: Arterial blood gas samples taken from January 2019 to March 2021 were retrospectively matched with infection status. Principal components regression was undertaken to determine the correlation between pH, partial pressure arterial oxygen (PaO2), partial pressure arterial carbon dioxide (PaCO2), and iCa. RESULTS: We included 4056 patients (300 COVID-19 detected, 19 influenza detected), corresponding to 5960 arterial blood samples. The COVID-19 detected group had a statistically significantly lower iCa, PaO2 and PaCO2, and more alkalotic pH than infection-free groups. The influenza group had a lower iCa and PaCO2, higher PaO2, and a more alkalotic pH than infection-free groups, but these differences were non-significant. Principal components regression revealed that pH, PaCO2, and PaO2 explain just 2.72 % of the variance in iCa. An increase in pH by 1 unit was associated with an iCa reduction of 0.141 â€‹mmol/L (p â€‹< â€‹0.0001). CONCLUSION: Reduction in iCa concentration in patients with COVID-19 is not associated with pH derangement. Influenza infection was associated with a minor reduction in iCa in our small sample, a hitherto unreported finding, although statistical significance was not demonstrated.

Trends in medication use at the onset of and during the COVID-19 pandemic in the Republic of Ireland: An interrupted time series study.

The COVID-19 pandemic had a substantial impact on healthcare delivery, particularly in general practice. This study aimed to evaluate how dispensing of medications in primary care in Ireland changed following the COVID-19 pandemic's onset compared to expected trends. This interrupted time series study used data on medications prescribed in general practice 2016-2022 to patient eligible for state health cover, approximately one third of the population. Dispensing volumes for all therapeutic subgroups (ATC2 codes) and commonly dispensed medications were summarized. Pre-pandemic data were used to forecast expected trends (with 99% prediction intervals) using the Holt-Winters method, and these were compared to observed dispensing from March 2020 onwards. Many (31/77) therapeutic subgroups had dispensing significantly different from forecast in March 2020. Drugs for obstructive airway disease had the largest difference, with dispensing 26.2% (99%CI 19.5%-33.6%) higher than forecasted. Only two subgroups were significantly lower than forecasted, other gynaecologicals (17.7% lower, 99%CI 6.3%-26.6%) and dressings (11.6%, 99%CI 9.4%-41.6%). Dispensing of amoxicillin products and oral prednisolone were lower than forecasted in the months following the pandemic's onset, particularly during winter 2020/2021. There was a spike in dispensing for many long-term medications in March 2020, while pandemic restrictions likely contributed to reductions for other medications.

A Case of Acute Intermittent Porphyria Leading to Severe Disability in a Young 21-Year-Old Female.

Acute intermittent porphyria (AIP) is a rare metabolic disorder that is challenging to diagnose and treat. Symptoms are nonspecific and severe acute attacks may be life-threatening. This is a case of a previously healthy 21-year-old woman diagnosed with an acute attack of AIP following recurrent hospitalizations with undiagnosed abdominal pain over a 12-month period with gradual onset of motor neuropathy which resulted in complete paralysis and respiratory failure. Through our case, we will highlight the challenges in AIP diagnosis and management, its potential severity, and how an early diagnosis could have prevented severe disability.

Analysis of primary care prescription trends in England during the COVID-19 pandemic compared against a predictive model.

OBJECTIVES: The COVID-19 pandemic has had an unprecedented impact across primary care. Primary care services have seen an upheaval, and more and more patients are engaging in telephone consultations in order to maintain social distancing. In the present study, we seek to quantify the effect of the pandemic on primary care prescribing. DESIGN: We conducted a retrospective analysis of the English Prescribing Dataset from January 2014 to November 2020, totalling 7 542 293 921 prescriptions. Data were separated into prepandemic and pandemic sets. A Holt-Winters predictive model was used to forecast individual drug prescribing based on historic trends. Observed data were compared with the forecast quantitatively and qualitatively. SETTING: All prescriptions signed in England and dispensed during the years 2014-2020. PARTICIPANTS: All residents of England who received a prescription from primary care facilities during 2014-2020. RESULTS: Prescribing of numerous health-critical medications was above predicted in March 2020, including salbutamol (53.0% (99% CI (41.2% to 66.9%))), insulin aspart (26.9% (99% CI (18.5% to 36.6%))) and tacrolimus (18.6% (99% CI (8.3% to 31.1%))). Medications for end-of-life symptom control increased in April, including levomepromazine hydrochloride (94.7% (99% CI (54.6% to 163.0%))). Medications requiring face-to-face visits decreased, including the local anaesthetic bupivacaine hydrochloride (86.6% (99% CI (89.3% to 82.0%))). There was no observed change in medications relating to type 2 diabetes, hypertension or mental health conditions. CONCLUSIONS: Significantly increased prescribing of several medications was observed, especially among those critical for health. A dramatic spike in end-of-life prescribing highlights the adversity faced by community practitioners during 2020. Medications involving face-to-face consultations declined, as did contraceptives, travel-related vaccines and drugs used in dementia and Parkinson's disease. Drugs relating to type 2 diabetes, hypertension and mental health were unchanged.

Novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines as potent and selective agonists of the 5-HT2C receptor.

A series of novel (R)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines were identified as potent and selective agonists of the 5-HT2C receptor. Optimizations performed on a previously reported series of racemic tetrahydroquinoline-based tricyclic amines, delivered an advanced drug lead, (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine, which displayed excellent in vitro and in vivo pharmacological profiles.

Development of locally relevant clinical guidelines for procedure-related neonatal analgesic practice in Kenya: a systematic review and meta-analysis.

Background Increasing numbers of neonates are undergoing painful procedures in low-income and middle-income countries, with adequate analgesia seldom used. In collaboration with a multi-disciplinary team in Kenya, we aimed to establish the first evidence-based guidelines for the management of routine procedure-related neonatal pain that consider low-resource hospital settings. METHODS: We did a systematic review by searching MEDLINE, Embase, CINAHL, and CENTRAL databases for studies published from Jan 1, 1953, to March 31, 2019. We included data from randomised controlled trials using heart rate, oxygen saturation (SpO2), premature infant pain profile (PIPP) score, neonatal infant pain scale (NIPS) score, neonatal facial coding system score, and douleur aiguë du nouveau-né scale score as pain outcome measures. We excluded studies in which neonates were undergoing circumcision or were intubated, studies from which data were unextractable, or when pain was scored by non-trained individuals. We did a narrative synthesis of all studies, and meta-analysis when data were available from multiple studies comparing the same analgesics and controls and using the same outcome measures. 17 Kenyan health-care professionals formed our clinical guideline development panel, and we used the Grading of Recommendations, Assessment, Development and Evaluation framework and the panel's knowledge of the local health-care context to guide the guideline development process. This study is registered with PROSPERO, CRD42019126620. FINDINGS: Of 2782 studies assessed for eligibility, data from 149 (5%) were analysed, with 80 (3%) of these further contributing to our meta-analysis. We found a high level of certainty for the superiority of breastfeeding over placebo or no intervention (standardised mean differences [SMDs] were -1·40 [95% CI -1·96 to -0·84] in PIPP score and -2·20 [-2·91 to -1·48] in NIPS score), and the superiority of oral sugar solutions over placebo or no intervention (SMDs were -0·38 [-0·61 to -0·16] in heart rate and 0·23 [0·04 to 0·42] in SpO2). We found a moderate level of certainty for the superiority for expressed breastmilk over placebo or no intervention (SMDs were -0·46 [95% CI -0·87 to -0·05] in heart rate and 0·48 [0·20 to 0·75] in SpO2). Therefore, the panel recommended that breastfeeding should be given as first-line analgesic treatment, initiated at least 2 min pre-procedure. Given contextual factors, for neonates who are unable to breastfeed, 1-2 mL of expressed breastmilk should be given as first-line analgesic, or 1-2 mL of oral sugar (≥10% concentration) as second-line analgesic. The panel also recommended parental presence during procedures with adjunctive provision of skin-to-skin care, or non-nutritive sucking when possible. INTERPRETATION: We have generated Kenya's first neonatal analgesic guidelines for routine procedures, which have been adopted by the Kenyan Ministry of Health, and have shown a framework for clinical guideline development that is applicable to other low-income and middle-income health-care settings. FUNDING: Wellcome Trust Research Programme, and the Africa-Oxford Initiative.

GP prescribing in Northern Ireland by deprivation index: retrospective analysis.

OBJECTIVE: In the present study, we sought to explore the relationship between socioeconomic status and prescribing magnitude and cost in primary care throughout Northern Ireland. DESIGN: We performed a retrospective data analysis of general practitioner (GP) prescribing using open-source databases with data collected from May to October 2019 to determine the number of prescriptions and cost of drugs and drug classes by area, ranking these by deprivation index. We used Kendall's tau to quantify the relationship between prescribing and deprivation. SETTING: We analysed open-source data collected from 325 GP practices in Northern Ireland during the period from May to October 2019. PARTICIPANTS: We analysed a total of 2 764 303 prescriptions signed during our study period. RESULTS: Our study indicates a clear trend of increased overall spending per patient (r=-0.1232, p=0.02) and number of prescriptions per patient (r=-0.3440, p<0.001) in areas of higher deprivation. The mean cost per item was higher in less deprived areas (r=0.3809, p<0.001). Overall, £13.79 more was spent and 3.5 more items were prescribed per patient in the most compared with the least deprived decile, although more expensive items tended to be prescribed in areas with lower socioeconomic deprivation (£11.27 per item vs £9.20 per item). We found a statistically significant correlation of prescribing of key drug classes, such as bronchodilators, antidepressants and drugs used to treat diabetes, among others, with greater deprivation. Prescribing of vaccines and drugs used in the treatment of glaucoma was correlated with lower deprivation. CONCLUSION: We provide an exploration of the correlation of prescribing with deprivation by analysing all prescriptions signed within a 6-month period in Northern Ireland. Our study broadly agrees with published literature, although a few notable exceptions are highlighted. We provide evidence of discrepancies in medication cost between areas of differing deprivation and suggest possible explanations for these trends. This information will be valuable for future investigation of disease prevalence, as well as targeting of patient education and future funding.

Involvement of the open-source community in combating the worldwide COVID-19 pandemic: a review.

The ongoing COVID-19 pandemic is unprecedented in the modern age both due to its scale and its disruption to daily life throughout the world. Widespread social isolation and restrictions in the age of modern communicative technology, coupled with some early successes for makers, have united the open-source community towards a common goal in a way not previously seen. Local hospitals and care facilities are turning to makers to print essential consumable parts, such as simple visors, while in the hardest hit areas, critical pieces of medical technology are being fabricated. While important and effective innovations are appearing almost daily, there are also some worrying trends towards hobbyists attempting manufacture of complex medical devices with little understanding of the clinical or scientific rationale behind their design. The nature of the open-source community, an area of intensive innovation, fluidity, and experimentation, jars with the exacting standards of medical device regulation. Here, we review the involvement of rapid prototyping and the open-source community in the key areas of personal protective equipment (PPE), diagnostics, critical care technology, and information acquisition and sharing, highlighting where makers and hackers have clashed with medical device regulations, and areas where the system has worked well to facilitate change.

Discovery of a lead series of potent benzodiazepine 5-HT2C receptor agonists with high selectivity in functional and binding assays.

A series of potential new 5-HT2 receptor scaffolds based on a simplification of the clinically studied, 5-HT2CR agonist vabicaserin, were designed. An in vivo feeding assay early in our screening process played an instrumental part in the lead identification process, leading us to focus on a 6,5,7-tricyclic scaffold. A subsequent early SAR investigation provided potent agonists of the 5-HT2C receptor that were highly selective in both functional and binding assays, had good rat PK properties and that significantly reduced acute food intake in the rat.

Emerging patterns of hypercoagulability associated with critical COVID-19: A review.

While the COVID-19 pandemic sweeps the world, much evidence is being gathered regarding its novel pathological mechanisms. It is the authors' clinical experience that patients in the intensive care unit suffering from COVID-19 are extremely pro-coagulable, with venous and arterial thromboembolism frequently observed, and losses of vascular access lines and filtration circuits to thrombosis now commonplace. Here, we explore the evidence for hypercoagulability in this group, presenting evidence of both a localised pulmonary hypercoagulability, and a systemic hypercoagulability resulting in thrombosis distant to the pulmonary vasculature. Furthermore, we discuss the possible risk factors exacerbated by, or selected for in COVID-19. We review the available evidence for use of plasma D-dimer as a prognostic marker, exploring the possibility that it acts as a marker of a COVID-19-associated hypercoagulability. We review the evidence for a pro-coagulant subtype of disseminated intravascular coagulation, discussing its clinical significance. Finally, we discuss the current evidence surrounding treatment of COVID-19 hypercoagulability, including prophylactic and treatment-dose heparin, thrombolytic agents, antiplatelet agents, and direct thrombin inhibitors, among others. We suggest areas in which further investigation is urgently needed to reduce the startling incidence of thrombosis in this group, a complication no doubt contributing to morbidity and mortality.

Evaluating the effects of switching from cigarette smoking to using a heated tobacco product on health effect indicators in healthy subjects: study protocol for a randomized controlled trial.

Tobacco heating products (THPs) are a potentially safer alternative to combustible cigarette smoking. Through continued use, THPs may reduce smoking-related disease risk, whilst maintaining the sensorial experience and nicotine delivery sought by smokers. While literature evidence of the biological effects of THP aerosol exposure is increasing, there remains a knowledge gap with respect to substantiation of THP reduced risk potential in longer term real-life use. This randomized, multi-centre, controlled clinical study will test the hypotheses that following a switch from combustible cigarettes to a THP for 1 year, participants will experience a sustained reduction in exposure to tobacco-related toxicants that will lead to favourable changes in health effect indicators associated with smoking-related disease development. Changes in such indicators will be contextualized against smoking cessation and never-smoker cohorts. Up to 280 participants who do not intend to quit smoking will be randomized to continued combustible smoking (arm A, up to n = 80) or a commercially available THP (arm B n = 200). Furthermore, up to 190 participants with a high intent to quit smoking will undergo smoking cessation (arm D), and 40 never smokers will serve as a control group (arm E). Recruitment numbers were determined to be sufficient to achieve n = 50 in arms A, B and D, at study end. Enrolment started in March 2018 and the trial is scheduled to be completed in March 2020. Data from this study will be a valuable addition to the growing body of evidence in the field of understanding the individual and public health impact of THPs.Clinical Trial Registration: https://www.isrctn.com/ISRCTN81075760.

Angiotensin (1-7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor.

Angiotensin (1-7) has been reported to be a ligand for the GPCR MAS1. Small molecule MAS1 modulators have also been recently characterized. Aside from convincing evidence for MAS1 activation of Gq signaling, little is known about MAS1 mediated signaling pathways initiated by these ligands, especially Ang (1-7). We performed a comprehensive characterization of recombinant MAS1 signaling induced by Ang (1-7) and small molecule ligands through numerous G protein-dependent and independent pathways, and in a signaling pathway agnostic approach. We find that small molecule ligands modulate numerous G protein-dependent and independent pathways through MAS1, including Gq and Gi pathways, GTPγS binding, ß-arrestin recruitment, Erk1/2 and Akt phosphorylation, arachidonic acid release, and receptor internalization. Moreover, in dynamic mass redistribution (DMR) assays that provide a pathway-agnostic readout of cellular responses, small molecule agonists produced robust responses. In contrast, Ang (1-7) failed to induce or block signaling in any of these assay platforms. We detected specific binding of radiolabeled Ang (1-7) to rat aortic endothelial cell (RAEC) membranes, but not to recombinant MAS1. Biphasic, concentration-dependent biased signaling responses to Ang II were detected in RAEC. These phases were associated with vastly different DMR characteristics and this likely provides a molecular basis for previously observed concentration-dependent divergent physiological actions of Ang II. Both phases of Ang II signaling in RAECs were potently inhibited by Ang (1-7), providing a plausible molecular mechanism for Ang (1-7) as counter regulator of the Ang II- AT1 axis, responsible at least in part for Ang (1-7) physiological activities.

Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children's Oncology Group Report.

Children and adolescents with Burkitt Lymphoma (BL) and combined central nervous system (CNS) and bone marrow involvement still have a poor prognosis with chemotherapy alone. We therefore investigated in children and adolescents with bone marrow (≥25% blasts) and/or CNS-positive Burkitt lymphoma the chemoimmunotherapy combination of rituximab (375 mg/m(2) ) and the standard chemotherapy arm of our previously reported French-American-British (FAB) Lymphome Malins de Burkitt (LMB) 96 trial. Central pathological and cytogenetic characterization was also performed. There were 40 evaluable patients with Burkitt histology (25 with leukaemia and 15 with CNS disease ± leukaemia). The chemoimmunotherapy regimen was well tolerated. The incidence of grade III/IV mucositis during induction cycles with combined chemotherapy and rituximab was 31% and 26%, respectively. The 3-year event-free survival (EFS)/overall survival (OS) was 90% (95% confidence interval [CI], 76-96%) in the entire cohort and 93% (95% CI, 61-99%) in patients with CNS disease. Based on the results of this trial, an international randomized study of FAB/LMB 96 chemotherapy ± rituximab for high-risk patients is currently under investigation.

Kinetics of 5-HT2B receptor signaling: profound agonist-dependent effects on signaling onset and duration.

The kinetics of drug-receptor interactions can profoundly influence in vivo and in vitro pharmacology. In vitro, the potencies of slowly associating agonists may be underestimated in assays capturing transient signaling events. When divergent receptor-mediated signaling pathways are evaluated using combinations of equilibrium and transient assays, potency differences driven by kinetics may be erroneously interpreted as biased signaling. In vivo, drugs with slow dissociation rates may display prolonged physiologic effects inconsistent with their pharmacokinetic profiles. We evaluated a panel of 5-hydroxytryptamine2B (5-HT2B) receptor agonists in kinetic radioligand binding assays and in transient, calcium flux assays, and inositol phosphate accumulation assays; two functional readouts emanating from Gαq-mediated activation of phospholipase C. In binding studies, ergot derivatives demonstrated slow receptor association and dissociation rates, resulting in significantly reduced potency in calcium assays relative to inositol phosphate accumulation assays. Ergot potencies for activation of extracellular signal-regulated kinases 1 and 2 were also highly time-dependent. A number of ergots produced wash-resistant 5-HT2B signaling that persisted for many hours without appreciable loss of potency, which was not explained simply by slow receptor-dissociation kinetics. Mechanistic studies indicated that persistent signaling originated from internalized or sequestered receptors. This study provides a mechanistic basis for the long durations of action in vivo and wash-resistant effects in ex vivo tissue models often observed for ergots. The 5-HT2B agonist activity of a number of ergot-derived therapeutics has been implicated in development of cardiac valvulopathy in man. The novel, sustained nature of ergot signaling reported here may represent an additional mechanism contributing to the valvulopathic potential of these compounds.

Identification of fused bicyclic heterocycles as potent and selective 5-HT(2A) receptor antagonists for the treatment of insomnia.

A series of fused bicyclic heterocycles was identified as potent and selective 5-HT(2A) receptor antagonists. Optimization of the series resulted in compounds that had improved PK properties, favorable CNS partitioning, good pharmacokinetic properties, and significant improvements on deep sleep (delta power) and sleep consolidation.

Identification of biaryl sulfone derivatives as antagonists of the histamine H3 receptor: discovery of (R)-1-(2-(4'-(3-methoxypropylsulfonyl)biphenyl-4-yl)ethyl)-2-methylpyrrolidine (APD916).

The design of a new clinical candidate histamine-H(3) receptor antagonist for the potential treatment of excessive daytime sleepiness (EDS) is described. Phenethyl-R-2-methylpyrrolidine containing biphenylsulfonamide compounds were modified by replacement of the sulfonamide linkage with a sulfone. One compound from this series, 2j (APD916) increased wakefulness in rodents as measured by polysomnography with a duration of effect consistent with its pharmacokinetic properties. The identification of a suitable salt form of 2j allowed it to be selected for further development.

A pediatric B lineage leukemia with coincident MYC and MLL translocations.

Translocations are key oncogenic events, and many rearrangements are characteristic for a specific malignancy. We present here a case of phenotypic precursor-B acute lymphoblastic leukemia (ALL), subsequently found to have both MYC and MLL translocations. Owing to the potential prognostic impact of these translocations, a novel treatment strategy was applied which merged precursor-B ALL, Burkitt-ALL, and "MLL-adapted" rationales. With the advent of expanding diagnostic panels and molecular therapeutic options, use of such adapted therapies for individualized treatment will undoubtedly continue to increase as we move toward pharmacogenomic-based approaches.

Synthesis and in vivo evaluation of phenethylpiperazine amides: selective 5-hydroxytryptamine(2A) receptor antagonists for the treatment of insomnia.

Recent developments in sleep research suggest that antagonism of the serotonin 5-HT(2A) receptor may improve sleep maintenance insomnia. We herein report the discovery of a series of potent and selective serotonin 5-HT(2A) receptor antagonists based on a phenethylpiperazine amide core structure. When tested in a rat sleep pharmacology model, these compounds increased both sleep consolidation and deep sleep. Within this series of compounds, an improvement in the metabolic stability of early leads was achieved by introducing a carbonyl group into the phenethylpiperazine linker. Of note, compounds 14 and 27 exhibited potent 5-HT(2A) receptor binding affinity, high selectivity over the 5-HT(2C) receptor, favorable CNS partitioning, and good pharmacokinetic and early safety profiles. In vivo, these two compounds showed dose-dependent, statistically significant improvements on deep sleep (delta power) and sleep consolidation at doses as low as 0.1 mg/kg.

Discovery and structure-activity relationship of 3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): a highly selective 5-hydroxytryptamine2A receptor inverse agonist for the treatment of arterial thrombosis.

Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT(2A) receptor. 5-HT(2A) receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT(2A) receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC(50) = 8.7 nM and had negligible binding affinity for the closely related 5-HT(2B) and 5-HT(2C) receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.