Patterns of initial and first-intensifying antidiabetic drug utilization among patients with type 2 diabetes mellitus in Scotland, 2010-2020: A retrospective population-based cohort study.

AIM: To evaluate the utilization and prescribing patterns of antidiabetic drugs (ADDs) for patients with type 2 diabetes mellitus (T2DM) at treatment initiation and first intensification. METHODS: A retrospective cohort study was performed using linked routinely collected data of patients with T2DM who received ADDs between January 2010 and December 2020 in Scotland. The prescribing patterns were quantified using frequency/percentages, absolute/relative change, and trend tests. RESULTS: Overall, 145 909 new ADD users were identified, with approximately 91% (N = 132 382) of patients receiving a single ADD at first treatment initiation. Metformin was the most often prescribed monotherapy (N = 118 737, 89.69%). A total of 50 731 patients (39.40%) who were started on metformin (N = 46 730/118 737, 39.36%) or sulphonylurea (SU; N = 4001/10 029, 39.89%) monotherapy had their treatment intensified with one or more additional ADD. Most initial-metformin (45 963/46 730; 98.36%) and initial-SU users (3894/4001; 97.33%) who added further drugs were intensified with single ADDs. SUs (22 197/45 963; 48.29%) were the most common first-intensifying monotherapy after initial metformin use, but these were replaced by sodium-glucose cotransporter-2 (SGLT2) inhibitors in 2019 (SGLT2 inhibitors: 2039/6065, 33.62% vs. SUs: 1924/6065, 31.72%). Metformin was the most frequently added monotherapy to initial SU use (2924/3894, 75.09%). Although the majority of patients received a single ADD, the use of combination therapy significantly increased over time. Nevertheless, there was a significant increasing trend towards prescribing the newer ADD classes (SGLT2 inhibitors, dipeptidyl peptidase-4 inhibitors) as monotherapy or in combination compared with the older ones (SUs, insulin, thiazolidinediones) at both drug initiation and first intensification. CONCLUSIONS: An overall increasing trend in prescribing the newer ADD classes compared to older ADDs was observed. However, metformin remained the most commonly prescribed first-line ADD, while SGLT2 inhibitors replaced SUs as the most common add-on therapy to initial metformin use in 2019.

Peri-ictal activation of dorsomedial dorsal raphe serotonin neurons reduces mortality associated with maximal electroshock seizures.

Over one-third of patients with epilepsy will develop refractory epilepsy and continue to experience seizures despite medical treatment. These patients are at the greatest risk for sudden unexpected death in epilepsy. The precise mechanisms underlying sudden unexpected death in epilepsy are unknown, but cardiorespiratory dysfunction and arousal impairment have been implicated. Substantial circumstantial evidence suggests serotonin is relevant to sudden unexpected death in epilepsy as it modulates sleep/wake regulation, breathing and arousal. The dorsal raphe nucleus is a major serotonergic center and a component of the ascending arousal system. Seizures disrupt the firing of dorsal raphe neurons, which may contribute to reduced responsiveness. However, the relevance of the dorsal raphe nucleus and its subnuclei to sudden unexpected death in epilepsy remains unclear. The dorsomedial dorsal raphe may be a salient target due to its role in stress and its connections with structures implicated in sudden unexpected death in epilepsy. We hypothesized that optogenetic activation of dorsomedial dorsal raphe serotonin neurons in TPH2-ChR2-YFP (n = 26) mice and wild-type (n = 27) littermates before induction of a maximal electroshock seizure would reduce mortality. In this study, pre-seizure activation of dorsal raphe nucleus serotonin neurons reduced mortality in TPH2-ChR2-YFP mice with implants aimed at the dorsomedial dorsal raphe. These results implicate the dorsomedial dorsal raphe in this novel circuit influencing seizure-induced mortality. It is our hope that these results and future experiments will define circuit mechanisms that could ultimately reduce sudden unexpected death in epilepsy.

Unearthing opportunity amid declining plant-beneficial bacteria.

Plant-associated microbiomes maintain biodiversity and ecosystem productivity amid global change. Under projected climate change scenarios, the abundance of plant-beneficial bacteria is expected to decrease. Altered plant-associated microbiomes may affect plant tolerance to stress and (agro-)ecosystem productivity. Forward-thinking approaches, like microbiome breeding, offer biotechnological opportunities to understand and mine plant-microbe interactions.

N-glycosylation of the SARS-CoV-2 spike protein at Asn331 and Asn343 is involved in spike-ACE2 binding, virus entry, and regulation of IL-6.

The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global public health crisis. The causative agent, the SARS-CoV-2 virus, enters host cells via molecular interactions between the viral spike protein and the host cell ACE2 surface protein. The SARS-CoV-2 spike protein is extensively decorated with up to 66 N-linked glycans. Glycosylation of viral proteins is known to function in immune evasion strategies but may also function in the molecular events of viral entry into host cells. Here, we show that N-glycosylation at Asn331 and Asn343 of SARS-CoV-2 spike protein is required for it to bind to ACE2 and for the entry of pseudovirus harboring the SARS-CoV-2 spike protein into cells. Interestingly, high-content glycan binding screening data have shown that N-glycosylation of Asn331 and Asn343 of the RBD is important for binding to the specific glycan molecule G4GN (Galß-1,4 GlcNAc), which is critical for spike-RBD-ACE2 binding. Furthermore, IL-6 was identified through antibody array analysis of conditioned media of the corresponding pseudovirus assay. Mutation of N-glycosylation of Asn331 and Asn343 sites of the spike receptor-binding domain (RBD) significantly reduced the transcriptional upregulation of pro-inflammatory signaling molecule IL-6. In addition, IL-6 levels correlated with spike protein levels in COVID-19 patients' serum. These findings establish the importance of RBD glycosylation in SARS-CoV-2 pathogenesis, which can be exploited for the development of novel therapeutics for COVID-19.

Unbiased high-dimensional flow cytometry identified NK and DC immune cell signature in Luminal A-type and triple negative breast cancer.

Breast cancer is the most common malignancy in women worldwide and a highly heterogeneous disease. Four different subtypes are described that differ in the expression of hormone receptors as well as the growth factor receptor HER2. Treatment modalities and survival rate depend on the subtype of breast cancer. However, it is still not clear which patients benefit from immunotherapeutic approaches such as checkpoint blockade. Thus, we aimed to decipher the immune cell signature of the different breast cancer subtypes based on high-dimensional flow cytometry followed by unbiased approaches. Here, we show that the frequency of NK cells is reduced in Luminal A and B as well as triple negative breast cancer and that the phenotype of residual NK cells is changed toward regulatory CD11b-CD16- NK cells. Further, we found higher frequencies of PD-1+ CD4+ and CD8+ T cells in triple negative breast cancer. Moreover, while Luminal A-type breast cancer was enriched for CD14+ cDC2 (named type 3 DC (DC3)), CD14- cDC2 (named DC2) were more frequent in triple negative breast cancer. In contrast, HER2-enriched breast cancer did not show major alterations in the composition of the immune cell compartment in the tumor microenvironment. These findings suggest that patients with Luminal A- and B-type as well as triple negative breast cancer might benefit from immunotherapeutic approaches targeting NK cells.

Toward an integrative framework for microbial community coalescence.

Community coalescence is defined as the mixing of intact ecological communities. From river confluences to fecal microbiota transplantation, community coalescence constitutes a common ecological occurrence affecting natural and engineered microbial systems. In this opinion article, we propose an integrative framework for microbial community coalescence to guide advances in our understanding of this important - yet underexplored - ecological phenomenon. We start by aligning community coalescence with the unified framework of biological invasion and enumerate commonalities and idiosyncrasies between these two analogous processes. Then, we discuss how organismal interactions and cohesive establishment affect coalescence outcomes with direct implications for community functioning. Last, we propose the use of ecological null modeling to study the interplay of ecological processes structuring community reassembly following coalescence.

Soil microbiome analysis supports claims of ineffectiveness of Pseudomonas fluorescens D7 as a biocontrol agent of Bromus tectorum.

IMPORTANCE: Cheatgrass is one of North America's most problematic invasive species. Invasion by this annual grass alters ecosystem structure and function and has proven very challenging to remove with traditional approaches. Commercially available bioherbicides, like P. fluorescens D7, are applied with the goal of providing lasting control from a single application. However, experimental results suggest that this bioherbicide has limited efficacy under field conditions. Potential explanations for variable efficacy include a failure of this bioherbicide to establish in the soil microbiome. However, to our knowledge, no data exist to support or refute this hypothesis. Here, we use a deep-sequencing approach to better understand the effects of this bioherbicide on the soil microbiome and screen for P. fluorescens at 18 months post-application.

BIOLOGICAL ANTIARRHYTHMICS-SODIUM CHANNEL INTERACTING PROTEINS.

Voltage gated Na channels (NaV) are essential for excitation of tissues. Mutations in NaVs cause a spectrum of human disease from autism and epilepsy to cardiac arrhythmias to skeletal myotonias. The carboxyl termini (CT) of NaV channels are hotspots for disease-causing mutations and are richly invested with protein interaction sites. We have focused on the regulation of NaV by two proteins that bind in this region: calmodulin (CaM) and non-secreted fibroblast growth factors (iFGF or FHF). CaM regulates NaV gating, mediating Ca2+-dependent inactivation (CDI) in a channel isoform-specific manner, while Ca2+-free CaM (apo-CaM) binding broadly regulates NaV opening and suppresses the arrhythmogenic late Na current (INa-L). FHFs inhibit CDI, in NaV isoforms that exhibit this property, and potently suppress INa-L, the latter requiring the amino terminus of the FHF. A peptide comprised of the first 39 amino acids of FHF1A is sufficient to inhibit INa-L, constituting a credible specific antiarrhythmic.

Validación de la ecografía Point-of-Care para el diagnóstico de hernia diafragmática: a propósito de un caso / Validation of Point-of-Care ultrasound in the diagnosis of a diaphragmatic hernia

La ecografía Point-of-Care (POCUS) es una herramienta sensible y específica para diagnosticar de manera precoz la patología del diafragma en pacientes críticos. Presentamos un caso clínico de un paciente con antecedentes de hernia diafragmática iatrogénica que ingresó en la unidad de reanimación tras una laparotomía exploradora de emergencia. Aprovechando el diagnóstico conocido de hernia diafragmática, describimos los signos clínicos que debemos encontrar en la evaluación POCUS para establecer el diagnóstico de hernia diafragmática: 1)fracción de acortamiento diafragmático normal bilateral; 2)excursión diafragmática reducida, y 3)posición cefálica de la cúpula diafragmática 4)mayor en supino que en sedestación. Igualmente, proponemos una sistemática de exploración ecográfica del diafragma y una clasificación diferencial de la disfunción diafragmática evaluada mediante POCUS en función de la correcta integridad y el buen funcionamiento del músculo periférico y del tendón central diafragmáticos en el paciente crítico.(AU)

Point-of-care ultrasound (POCUS) is a sensitive, specific tool for early diagnosis of diaphragm pathology in critically ill patients. We report the case of a patient with a history of iatrogenic diaphragmatic hernia who was admitted to the Resuscitation Unit after an emergency exploratory laparotomy. As the diagnosis of diaphragmatic hernia had already been confirmed, we determined the POCUS features that establish the diagnosis of diaphragmatic hernia: (1)normal bilateral diaphragmatic shortening fraction; (2)decreased diaphragmatic excursion, and (3)cephalic position of the diaphragmatic dome (4)greater in supine than in sitting position. We also outline a systematic ultrasound examination of the diaphragm and a POCUS-based differential classification of diaphragmatic dysfunction based on the functional integrity of the peripheral muscle and central diaphragmatic tendon in critically ill patients.(AU)

Risk of Arrhythmic Death in Patients With Nonischemic Cardiomyopathy: JACC Review Topic of the Week.

Nonischemic cardiomyopathy (NICM) is common and patients are at significant risk for early mortality secondary to ventricular arrhythmias. Current guidelines recommend implantable cardioverter-defibrillator (ICD) therapy to decrease sudden cardiac death (SCD) in patients with heart failure and reduced left ventricular ejection fraction. However, in randomized clinical trials comprised solely of patients with NICM, primary prevention ICDs did not confer significant mortality benefit. Moreover, left ventricular ejection fraction has limited sensitivity and specificity for predicting SCD. Therefore, precise risk stratification algorithms are needed to define those at the highest risk of SCD. This review examines mechanisms of sudden arrhythmic death in patients with NICM, discusses the role of ICD therapy and treatment of heart failure for prevention of SCD in patients with NICM, examines the role of cardiac magnetic resonance imaging and computational modeling for SCD risk stratification, and proposes new strategies to guide future clinical trials on SCD risk assessment in patients with NICM.

Validation of Point-of-Care ultrasound in the diagnosis of a diaphragmatic hernia.

Point-of-care ultrasound (POCUS) is a sensitive, specific tool for early diagnosis of diaphragm pathology in critically ill patients. We report the case of a patient with a history of iatrogenic diaphragmatic hernia who was admitted to the Resuscitation Unit after an emergency exploratory laparotomy. As the diagnosis of diaphragmatic hernia had already been confirmed, we determined the POCUS features that establish the diagnosis of diaphragmatic hernia: (1) normal bilateral diaphragmatic shortening fraction; (2) decreased diaphragmatic excursion; and (3) cephalic position of the diaphragmatic dome (4) greater in supine than in sitting position. We also outline a systematic ultrasound examination of the diaphragm and a POCUS-based differential classification of diaphragmatic dysfunction based on the functional integrity of the peripheral muscle and central diaphragmatic tendon in critically ill patients.

New patient privacy curtains to provide passive infection prevention.

Background: Cloth privacy curtains represent a potentially overlooked high touch surface. Inconsistent cleaning schedules paired with frequent contact allow curtains to provide a surface for the transmission of healthcare associated pathogens. Privacy curtains integrated with antimicrobial and sporicidal agents are shown to reduce the number of bacteria found on the surface of the curtains. The purpose of this initiative is to utilize antimicrobial and sporicidal privacy curtains to mitigate the transmission of healthcare associated pathogens from curtains to patients. Methods: The pre/post-test study design compared the bacterial and sporicidal burden of cloth curtains to the bacterial and sporicidal burden of Endurocide curtains following 20-weeks of use within the inpatient setting of a large military medical hospital. The Endurocide curtains were installed on two inpatient units in the organization. We also compared the overall costs associated with the two different types of curtains. Results: The antimicrobial and sporicidal curtains had a significant reduction in bacterial contamination (32.6 CFUs vs 0.56 CFUs, P < 0.05) after instillation on both units. There were no additional hospital associated infections during the study period. In addition, the direct cost savings of replacing the antimicrobial and sporicidal curtains is estimated to be $20,079.38 annually with a reduction of 66.95 hours in environmental services workload. Conclusion: These curtains represent a cost-effective intervention effective at reducing CFUs with the potential to mitigate the transmission of hospital associated pathogens to patients.

Ecological principles of fecal microbiota transplantation.

Fecal microbiota transplantation (FMT) is a procedure used to treat diseases related to microbiome imbalances. We discuss how ecological principles can inform the design of FMT clinical trials and contribute to data interpretation. This effort will promote a better understanding of microbiome engraftment and assist the development of clinical protocols.

A systematic review of the germicidal effectiveness of ultraviolet disinfection across high-touch surfaces in the immediate patient environment.

Background: There is not yet a consensus regarding the in-use effectiveness of ultraviolet irradiation (UV-C) as a supplementary tool for terminal room disinfection. Aims and Objectives: To summarize and evaluate literature detailing the germicidal effectiveness of UV-C disinfection on high-touch surfaces in the patient environment. Methods: A literature search was carried out utilizing PRISMA guidelines. Studies were included if intervention included UV-C after standard room disinfection in hospital rooms evaluated microbiologically by surface type. Findings/Results: Twelve records met our criteria for inclusion. Studies predominantly focused on terminal disinfection of patient rooms, including five reports carried out in isolation rooms and three studies including operating room (OR) surfaces. Bedrails, remote controls, phones, tray tables, assist rails, floors, and toilets were the most commonly reported surfaces. Across study designs, surfaces, and room types, flat surfaces tended to showcase UV-C effectiveness best, particularly isolation room floors. In contrast, handheld surfaces (i.e., bed controls and assist bars) tended to show reduced efficacies (81-93%). In the OR, complex surfaces similarly demonstrated reduced UV-C effectiveness. Bathroom surfaces demonstrated 83% UV-C effectiveness overall, with surface characteristics uniquely impacted depending on the room type. Isolation room studies tended to include effectiveness comparison with standard treatment, reporting UV-C superiority most of the time. Discussion: This review highlights the enhanced effectiveness of UV-C surface disinfection over standard protocols across various study designs and surfaces. However, surface and room characteristics do appear to play a role in the level of bacterial reduction.

Meta-analysis of factors associated with antidiabetic drug prescribing for type 2 diabetes mellitus.

BACKGROUND: There is a lack of consensus on prescribing alternatives to initial metformin therapy and intensification therapy for type 2 diabetes mellitus (T2DM) management. This review aimed to identify/quantify factors associated with prescribing of specific antidiabetic drug classes for T2DM. METHODS: Five databases (Medline/PubMed, Embase, Scopus, Web of Science) were searched using the synonyms of each concept (patients with T2DM, antidiabetic drugs and factors influencing prescribing) in both free text and Medical Subject Heading (MeSH) forms. Quantitative observational studies evaluating factors associated with antidiabetic prescribing of metformin, sulfonylurea, thiazolidinedione, Dipeptidyl-peptidase 4 inhibitors (DPP4-I), sodium glucose transporter 2 inhibitors (SGLT2-I), Glucagon-Like peptide receptor agonist (GLP1-RA) and insulin in outpatient settings and published from January 2009 to January 2021 were included. Quality assessment was performed using a Newcastle-Ottawa scale. The validation was done for 20% of identified studies. The pooled estimate was measured using a three-level random-effect meta-analysis model based on odds ratio [95% confidence interval]. Age, sex, body mass index (BMI), glycaemic control (HbA1c) and kidney-related problems were quantified. RESULTS: Of 2331 identified studies, 40 met the selection criteria. Of which, 36 and 31 studies included sex and age, respectively, while 20 studies examined baseline BMI, HbA1c and kidney-related problems. The majority of studies (77.5%, 31/40) were rated as good and despite that the overall heterogeneity for each studied factor was more than 75%, it is mostly related to within-study variance. Older age was significantly associated with higher sulfonylurea prescription (1.51 [1.29-1.76]), yet lower prescribing of metformin (0.70 [0.60-0.82]), SGLT2-I (0.57 [0.42-0.79]) and GLP1-RA (0.52 [0.40-0.69]); while higher baseline BMI showed opposite significant results (sulfonylurea: 0.76 [0.62-0.93], metformin: 1.22 [1.08-1.37], SGLT2-I: 1.88 [1.33-2.68], and GLP1-RA: 2.35 [1.54-3.59]). Both higher baseline HbA1c and having kidney-related problems were significantly associated with lower metformin prescription (0.74 [0.57-0.97], 0.39 [0.25-0.61]), but more insulin prescriptions (2.41 [1.87-3.10], 1.52 [1.10-2.10]). Also, DPP4-I prescriptions were higher for patients with kidney-related problems (1.37 [1.06-1.79]) yet lower among patients with higher HbA1c (0.82 [0.68-0.99]). Sex was significantly associated with GLP1-RA and thiazolidinedione prescribing (F:M; 1.38 [1.19-1.60] and 0.91 [0.84-0.98]). CONCLUSION: Several factors were identified as potential determinants of antidiabetic drug prescribing. The magnitude and significance of each factor differed by antidiabetic class. Patient's age and baseline BMI had the most significant association with the choice of four out of the seven studied antidiabetic drugs followed by the baseline HbA1c and kidney-related problems which had an impact on three studied antidiabetic drugs, whereas sex had the least impact on prescribing decision as it was associated with GLP1-RA and thiazolidinedione only.

Investigations into hydrogen sulfide-induced suppression of neuronal activity in vivo and calcium dysregulation in vitro.

Acute exposure to high concentrations of hydrogen sulfide (H2S) leads to sudden death and, if survived, lingering neurological disorders. Clinical signs include seizures, loss of consciousness, and dyspnea. The proximate mechanisms underlying H2S-induced acute toxicity and death have not been clearly elucidated. We investigated electrocerebral, cardiac and respiratory activity during H2S exposure using electroencephalogram (EEG), electrocardiogram (EKG) and plethysmography. H2S suppressed electrocerebral activity and disrupted breathing. Cardiac activity was comparatively less affected. To test whether Ca2+ dysregulation contributes to H2S-induced EEG suppression, we developed an in vitro real-time rapid throughput assay measuring patterns of spontaneous synchronized Ca2+ oscillations in cultured primary cortical neuronal networks loaded with the indicator Fluo-4 using the fluorescent imaging plate reader (FLIPR-Tetra®). Sulfide >5 ppm dysregulated synchronous calcium oscillation (SCO) patterns in a dose-dependent manner. Inhibitors of NMDA and AMPA receptors magnified H2S-induced SCO suppression. Inhibitors of L-type voltage gated Ca2+ channels and transient receptor potential channels prevented H2S-induced SCO suppression. Inhibitors of T-type voltage gated Ca2+ channels, ryanodine receptors, and sodium channels had no measurable influence on H2S-induced SCO suppression. Exposures to > 5 ppm sulfide also suppressed neuronal electrical activity in primary cortical neurons measured by multi-electrode array (MEA), an effect alleviated by pretreatment with the nonselective transient receptor potential channel inhibitor, 2-APB. 2-APB also reduced primary cortical neuronal cell death from sulfide exposure. These results improve our understanding of the role of different Ca2+ channels in acute H2S-induced neurotoxicity and identify transient receptor potential channel modulators as novel structures with potential therapeutic benefits.