all Are High-Tech Blood Pressure Monitors Really Worth It? By www.medicinenet.com Published On :: Tue, 16 Aug 2022 00:00:00 PDT Title: Are High-Tech Blood Pressure Monitors Really Worth It?Category: Health NewsCreated: 8/16/2022 12:00:00 AMLast Editorial Review: 8/16/2022 12:00:00 AM Full Article
all Stay Independent of Asthma, Allergies This July 4th By www.medicinenet.com Published On :: Fri, 1 Jul 2022 00:00:00 PDT Title: Stay Independent of Asthma, Allergies This July 4thCategory: Health NewsCreated: 7/1/2022 12:00:00 AMLast Editorial Review: 7/1/2022 12:00:00 AM Full Article
all The 8 Most Common Food Allergies By www.medicinenet.com Published On :: Wed, 13 Jul 2022 00:00:00 PDT Title: The 8 Most Common Food AllergiesCategory: Health and LivingCreated: 7/13/2022 12:00:00 AMLast Editorial Review: 7/13/2022 12:00:00 AM Full Article
all Health Care Plans Keep Allergy Rescue Injectors Pricey for Some By www.medicinenet.com Published On :: Fri, 15 Jul 2022 00:00:00 PDT Title: Health Care Plans Keep Allergy Rescue Injectors Pricey for SomeCategory: Health NewsCreated: 7/15/2022 12:00:00 AMLast Editorial Review: 7/15/2022 12:00:00 AM Full Article
all SIBO (Small Intestinal Bacterial Overgrowth) By www.medicinenet.com Published On :: Mon, 8 Aug 2022 00:00:00 PDT Title: SIBO (Small Intestinal Bacterial Overgrowth)Category: Diseases and ConditionsCreated: 10/28/2005 12:00:00 AMLast Editorial Review: 8/8/2022 12:00:00 AM Full Article
all CDC Panel Urges Seniors to Get New, More Potent Flu Shot This Fall By www.medicinenet.com Published On :: Thu, 23 Jun 2022 00:00:00 PDT Title: CDC Panel Urges Seniors to Get New, More Potent Flu Shot This FallCategory: Health NewsCreated: 6/23/2022 12:00:00 AMLast Editorial Review: 6/23/2022 12:00:00 AM Full Article
all Cold, Flu, Allergy Treatments By www.medicinenet.com Published On :: Fri, 15 Jul 2022 00:00:00 PDT Title: Cold, Flu, Allergy TreatmentsCategory: Diseases and ConditionsCreated: 9/24/1999 12:00:00 AMLast Editorial Review: 7/15/2022 12:00:00 AM Full Article
all Patient-managed interventions for adults with bronchiectasis: evidence, challenges and prospects By err.ersjournals.com Published On :: 2024-10-30T01:30:15-07:00 Bronchiectasis is a chronic lung condition which is characterised by recurrent chest infections, chronic sputum production and cough, and limited exercise tolerance. While bronchiectasis may be caused by various aetiologies, these features are shared by most patients with bronchiectasis regardless of the cause. This review consolidates the existing evidence on patient-managed interventions for adults with bronchiectasis, while also outlining areas for future research. Airway clearance techniques and hyperosmolar agents are key components of the bronchiectasis management and consistently recommended for clinical implementation. Questions around their prescription, such as optimal sequence of delivery, are still to be answered. Pulmonary rehabilitation and exercise are also recommended for patients with bronchiectasis. Relatively strong evidence underpins this recommendation during a clinically stable stage of the disease, although the role of pulmonary rehabilitation following an exacerbation is still unclear. Additionally, self-management programmes feature prominently in bronchiectasis treatment, yet the lack of consensus regarding their definition and outcomes presents hurdles to establishing a cohesive evidence base. Moreover, cough, a cardinal symptom of bronchiectasis, warrants closer examination. Although managing cough in bronchiectasis may initially appear risky, further research is necessary to ascertain whether strategies employed in other respiratory conditions can be safely and effectively adapted to bronchiectasis, particularly through identifying patient responder populations and criteria where cough may not enhance airway clearance efficacy and its control is needed. Overall, there is a growing recognition of the importance of patient-managed interventions in the bronchiectasis management. Efforts to improve research methodologies and increase research funding are needed to further advance our understanding of these interventions, and their role in optimising patient care and outcomes. Full Article
all Opioids for the palliation of symptoms in people with serious respiratory illness: a systematic review and meta-analysis By err.ersjournals.com Published On :: 2024-10-09T00:15:15-07:00 Background People living with serious respiratory illness experience a high burden of distressing symptoms. Although opioids are prescribed for symptom management, they generate adverse events, and their benefits are unclear. Methods We examined the efficacy and safety of opioids for symptom management in people with serious respiratory illness. Embase, MEDLINE and the Cochrane Central Register of Controlled Trials were searched up to 11 July 2022. Reports of randomised controlled trials administering opioids to treat symptoms in people with serious respiratory illness were included. Key exclusion criteria included <80% of participants having a nonmalignant lung disease. Data were extracted regarding study characteristics, outcomes of breathlessness, cough, health-related quality of life (HRQoL) and adverse events. Treatment effects were pooled using a generic inverse variance model with random effects. Risk of bias was assessed using the Cochrane Risk of Bias tool version 1. Results Out of 17 included trials, six were laboratory-based exercise trials (n=70), 10 were home studies measuring breathlessness in daily life (n=788) and one (n=18) was conducted in both settings. Overall certainty of evidence was "very low" to "low". Opioids reduced breathlessness intensity during laboratory exercise testing (standardised mean difference (SMD) –0.37, 95% CI –0.67– –0.07), but not breathlessness measured in daily life (SMD –0.10, 95% CI –0.64–0.44). No effects on HRQoL (SMD –0.42, 95% CI –0.98–0.13) or cough (SMD –1.42, 95% CI –3.99–1.16) were detected. In at-home studies, opioids led to increased frequency of nausea/vomiting (OR 3.32, 95% CI 1.70–6.51), constipation (OR 3.08, 95% CI 1.69–5.61) and drowsiness (OR 1.37, 95% CI 1.01–1.86), with serious adverse events including hospitalisation and death identified. Conclusions Opioids improved exertional breathlessness in laboratory exercise studies, but did not improve breathlessness, cough or HRQoL measured in daily life at home. There were significant adverse events, which may outweigh any benefits. Full Article
all The Challenge of Implementing Race-Neutral PFT Reference Equations By rc.rcjournal.com Published On :: 2024-10-25T05:44:13-07:00 Full Article
all Effect of Fasting Prior to Extubation on Prevalence of Empty Stomach in Enterally Fed and Mechanically Ventilated Patients By rc.rcjournal.com Published On :: 2024-10-25T05:44:12-07:00 BACKGROUND:Practice on fasting prior to extubation in critically ill patients is variable. Efficacy of fasting in reducing gastric volume has not been well established. The primary objective of this study was to assess the effect of 4 h of fasting on prevalence of empty stomach using gastric ultrasonography in critically ill subjects who are fasted for extubation. The secondary objectives were to evaluate the change in gastric volumes during 4 h of fasting and to determine factors associated with empty stomach after fasting.METHODS:This was a single-center, prospective, observational study on adult ICU subjects who were enterally fed for at least 6 h continuously and mechanically ventilated. Gastric ultrasound was performed immediately prior to commencement of fasting, after 4 h of fasting, and after nasogastric (NG) aspiration after 4 h of fasting. An empty stomach was defined as a gastric volume ≤ 1.5 mL/kg.RESULTS:Forty subjects were recruited, and 38 (95%) had images suitable for analysis. The prevalence of empty stomach increased after 4 h of fasting (25 [65.8%] vs 31 [81.6%], P = .041) and after 4 h of fasting with NG aspiration (25 [65.8%] vs 34 [89.5%], P = .008). There was a significant difference in median (interquartile range) gastric volume per body weight between before fasting and 4 h after fasting (1.0 [0.5–1.8] mL/kg vs 0.4 [0.2–1.0] mL/kg, P < .001). No patient factors were associated with higher prevalence of empty stomach after 4 h of fasting.CONCLUSIONS:Most mechanically ventilated subjects had empty stomachs prior to fasting for extubation. Fasting for 4 h further increased the prevalence of empty stomach at extubation to > 80%. Full Article
all Decoding biology with massively parallel reporter assays and machine learning [Reviews] By genesdev.cshlp.org Published On :: 2024-10-16T07:18:56-07:00 Massively parallel reporter assays (MPRAs) are powerful tools for quantifying the impacts of sequence variation on gene expression. Reading out molecular phenotypes with sequencing enables interrogating the impact of sequence variation beyond genome scale. Machine learning models integrate and codify information learned from MPRAs and enable generalization by predicting sequences outside the training data set. Models can provide a quantitative understanding of cis-regulatory codes controlling gene expression, enable variant stratification, and guide the design of synthetic regulatory elements for applications from synthetic biology to mRNA and gene therapy. This review focuses on cis-regulatory MPRAs, particularly those that interrogate cotranscriptional and post-transcriptional processes: alternative splicing, cleavage and polyadenylation, translation, and mRNA decay. Full Article
all The small noncoding RNA Vaultrc5 is dispensable to mouse development [ARTICLE] By rnajournal.cshlp.org Published On :: 2024-10-16T07:18:13-07:00 Vault RNAs (vtRNAs) are evolutionarily conserved small noncoding RNAs transcribed by RNA polymerase III. Vault RNAs were initially described as components of the vault particle, but have since been assigned multiple vault-independent functions, including regulation of PKR activity, apoptosis, autophagy, lysosome biogenesis, and viral particle trafficking. The full-length transcript has also been described as a noncanonical source of miRNAs, which are processed in a DICER-dependent manner. As central molecules in vault-dependent and independent processes, vtRNAs have been attributed numerous biological roles, including regulation of cell proliferation and survival, response to viral infections, drug resistance, and animal development. Yet, their impact to mammalian physiology remains largely unexplored. To study vault RNAs in vivo, we generated a mouse line with a conditional Vaultrc5 loss-of-function allele. Because Vaultrc5 is the sole murine vtRNA, this allele enables the characterization of the physiological requirements of this conserved class of small regulatory RNAs in mammals. Using this strain, we show that mice constitutively null for Vaultrc5 are viable and histologically normal but have a slight reduction in platelet counts, pointing to a potential role for vtRNAs in hematopoiesis. This work paves the way for further in vivo characterizations of this abundant but mysterious RNA molecule. Specifically, it enables the study of the biological consequences of constitutive or lineage-specific Vaultrc5 deletion and of the physiological requirements for an intact Vaultrc5 during normal hematopoiesis or in response to cellular stresses such as oncogene expression, viral infection, or drug treatment. Full Article
all CPAP recall and cancer risk: should we be concerned? By erj.ersjournals.com Published On :: 2024-11-07T00:35:56-08:00 Extract There is an expanding literature on the association between obstructive sleep apnoea (OSA) and cancer risk [1, 2]. Evidence is growing from population- and clinic-based cohort studies that the severity of OSA and sleep-related hypoxaemia may adversely affect both overall cancer risk and incidence of certain cancers [3–7]. These clinical findings are supported by the identification of the intermediate mechanisms by which intermittent hypoxia and sleep fragmentation, the hallmark features of OSA, might promote oncogenesis, tumour growth and metastasis [8]. Although studies have shown a relationship between OSA and cancer, few have evaluated whether the risk of cancer development or progression in patients with OSA is modified by continuous positive airway pressure (CPAP) therapy (the primary treatment for OSA) [1, 2]. Full Article
all Association between a recalled positive airway pressure device and incident cancer: a population-based study By erj.ersjournals.com Published On :: 2024-11-07T00:35:55-08:00 Background The real-world consequences of a Philips Respironics recall for positive airway pressure (PAP) devices distributed between 2009 and 2021 are unknown. Methods We conducted a retrospective population-based study using health administrative databases (Ontario, Canada) on all new adult PAP users identified through the provincial funding system, free of cancer at baseline, who initiated (claimed) PAP treatment between 2012 and 2018. Everyone was followed from the PAP claim date to the earliest of incident cancer diagnosis, death or end of follow-up (March 2022). We used inverse probability of treatment weighting to balance baseline characteristics between individuals on recalled devices and those on devices from other manufacturers. Weighted hazard ratios of incident cancer were compared between groups. Results Of 231 692 individuals identified, 58 204 (25.1%) claimed recalled devices and 173 488 (74.9%) claimed devices from other manufacturers. A meaningful baseline difference between groups (standardised difference ≥0.10) was noted only by location-relevant covariates; other variables were mostly equally distributed (standardised differences ≤0.06). Over a median (interquartile range) follow-up of 6.3 (4.9–8.0) years, 11 166 (4.8%) developed cancer: unadjusted rates per 10 000 person-years of 78.8 (95% CI 76.0–81.7) in the recall group versus 74.0 (95% CI 72.4–75.6) in others (p=0.0034). Propensity score weighting achieved excellent balance in baseline characteristics between groups (standardised differences ≤0.07). On a weighted sample, there was no statistical difference in the hazard of incident cancer between groups: cause-specific hazard ratio (recalled versus others) 0.97 (95% CI 0.89–1.06). Conclusion In our real-world population study, compared to other manufacturers and adjusting for confounders, recalled Philips Respironics PAP devices do not appear to be independently associated with developing cancer. Full Article
all Functional Characterization of Reduced Folate Carrier and Protein-Coupled Folate Transporter for Antifolates Accumulation in Non-Small Cell Lung Cancer Cells [Articles] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Antifolates are important for chemotherapy in non–small cell lung cancer (NSCLC). They mainly rely on reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) to enter cells. PCFT is supposed to be the dominant transporter of the two in tumors, as it operates optimally at acidic pH and has limited transport activity at physiological pH, whereas RFC operates optimally at neutral pH. In this study, we found RFC showed a slightly pH-dependent uptake of antifolates, with similar affinity values at pH 7.4 and 6.5. PCFT showed a highly pH-dependent uptake of antifolates, with an optimum pH of 6.0 for pemetrexed and 5.5 for methotrexate. The Michaelis-Menten constant (Km) value of PCFT for pemetrexed at pH 7.4 was more than 10 times higher than that at pH 6.5. Interestingly, we found that antifolate accumulations mediated by PCFT at acidic pH were significantly affected by the efflux transporter, breast cancer resistance protein (BCRP). The highest pemetrexed concentration was observed at pH 7.0–7.4 after a 60-minute accumulation in PCFT-expressing cells, which was further evidenced by the cytotoxicity of pemetrexed, with the IC50 value of pemetrexed at pH 7.4 being one-third of that at pH 6.5. In addition, the in vivo study indicated that increasing PCFT and RFC expression significantly enhanced the antitumor efficacy of pemetrexed despite the high expression of BCRP. These results suggest that both RFC and PCFT are important for antifolates accumulation in NSCLC, although there is an acidic microenvironment and high BCRP expression in tumors. SIGNIFICANCE STATEMENT Evaluating the role of reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) on antifolates accumulation in non–small cell lung cancer (NSCLC) is necessary for new drug designs. By using cell models, we found both RFC and PCFT were important for antifolates accumulation in NSCLC. Breast cancer resistance protein (BCRP) significantly affected PCFT-mediated antifolates accumulation at acidic pH but not RFC-mediated pemetrexed accumulation at physiological pH. High expression of PCFT or RFC enhanced the cytotoxicity and antitumor effect of pemetrexed. Full Article
all Quantitatively Predicting Effects of Exercise on Pharmacokinetics of Drugs Using a Physiologically Based Pharmacokinetic Model [Articles] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Exercise significantly alters human physiological functions, such as increasing cardiac output and muscle blood flow and decreasing glomerular filtration rate (GFR) and liver blood flow, thereby altering the absorption, distribution, metabolism, and excretion of drugs. In this study, we aimed to establish a database of human physiological parameters during exercise and to construct equations for the relationship between changes in each physiological parameter and exercise intensity, including cardiac output, organ blood flow (e.g., muscle blood flow and kidney blood flow), oxygen uptake, plasma pH and GFR, etc. The polynomial equation P = aiHRi was used for illustrating the relationship between the physiological parameters (P) and heart rate (HR), which served as an index of exercise intensity. The pharmacokinetics of midazolam, quinidine, digoxin, and lidocaine during exercise were predicted by a whole-body physiologically based pharmacokinetic (WB-PBPK) model and the developed database of physiological parameters following administration to 100 virtual subjects. The WB-PBPK model simulation results showed that most of the observed plasma drug concentrations fell within the 5th–95th percentiles of the simulations, and the estimated peak concentrations (Cmax) and area under the curve (AUC) of drugs were also within 0.5–2.0 folds of observations. Sensitivity analysis showed that exercise intensity, exercise duration, medication time, and alterations in physiological parameters significantly affected drug pharmacokinetics and the net effect depending on drug characteristics and exercise conditions. In conclusion, the pharmacokinetics of drugs during exercise could be quantitatively predicted using the developed WB-PBPK model and database of physiological parameters. SIGNIFICANCE STATEMENT This study simulated real-time changes of human physiological parameters during exercise in the WB-PBPK model and comprehensively investigated pharmacokinetic changes during exercise following oral and intravenous administration. Furthermore, the factors affecting pharmacokinetics during exercise were also revealed. Full Article
all Nonclinical Pharmacokinetics Study of OLX702A-075-16, N-Acetylgalactosamine Conjugated Asymmetric Small Interfering RNA (GalNAc-asiRNA) [Articles] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 In this study, the nonclinical pharmacokinetics of OLX702A-075-16, an RNA interference therapeutic currently in development, were investigated. OLX702A-075-16 is a novel N-acetylgalactosamine conjugated asymmetric small-interfering RNA (GalNAc-asiRNA) used for the treatment of an undisclosed liver disease. Its unique 16/21-mer asymmetric structure reduces nonspecific off-target effects without compromising efficacy. We investigated the plasma concentration, tissue distribution, metabolism, and renal excretion of OLX702A-075-16 following a subcutaneous administration in mice and rats. For bioanalysis, high-performance liquid chromatography with fluorescence detection was used. The results showed rapid clearance from plasma (0.5 to 1.5 hours of half-life) and predominant distribution to the liver and/or kidney. Less than 1% of the liver concentration of OLX702A-075-16 was detected in the other tissues. Metabolite profiling using liquid chromatography coupled with high-resolution mass spectrometry revealed that the intact duplex OLX702A-075-16 was the major compound in plasma. The GalNAc moiety was predominantly metabolized from the sense strand in the liver, with the unconjugated sense strand of OLX702A-075-16 accounting for more than 95% of the total exposure in the rat liver. Meanwhile, the antisense strand was metabolized by the sequential loss of nucleotides from the 3'-terminus by exonuclease, with the rat liver samples yielding the most diverse truncated forms of metabolites. Urinary excretion over 96 hours was less than 1% of the administered dose in rats. High plasma protein binding of OLX702A-075-16 likely inhibited its clearance through renal filtration. SIGNIFICANCE STATEMENT This study presents the first comprehensive characterization of the in vivo pharmacokinetics of GalNAc-asiRNA. The pharmacokinetic insights gained from this research will aid in understanding toxicology and efficacy, optimizing delivery platforms, and improving the predictive power of preclinical species data for human applications. Full Article
all Early Prediction and Impact Assessment of CYP3A4-Related Drug-Drug Interactions for Small-Molecule Anticancer Drugs Using Human-CYP3A4-Transgenic Mouse Models [Articles] By dmd.aspetjournals.org Published On :: 2024-10-16T09:02:03-07:00 Early detection of drug-drug interactions (DDIs) can facilitate timely drug development decisions, prevent unnecessary restrictions on patient enrollment, resulting in clinical study populations that are not representative of the indicated study population, and allow for appropriate dose adjustments to ensure safety in clinical trials. All of these factors contribute to a streamlined drug approval process and enhanced patient safety. Here we describe a new approach for early prediction of the magnitude of change in exposure for cytochrome P450 (P450) CYP3A4-related DDIs of small-molecule anticancer drugs based on the model-based extrapolation of human-CYP3A4-transgenic mice pharmacokinetics to humans. Victim drugs brigatinib and lorlatinib were evaluated with the new approach in combination with the perpetrator drugs itraconazole and rifampicin. Predictions of the magnitude of change in exposure deviated at most 0.99- to 1.31-fold from clinical trial results for inhibition with itraconazole, whereas exposure predictions for the induction with rifampicin were less accurate, with deviations of 0.22- to 0.48-fold. Results for the early prediction of DDIs and their clinical impact appear promising for CYP3A4 inhibition, but validation with more victim and perpetrator drugs is essential to evaluate the performance of the new method. SIGNIFICANCE STATEMENT The described method offers an alternative for the early detection and assessment of potential clinical impact of CYP3A4-related drug-drug interactions. The model was able to adequately describe the inhibition of CYP3A4 metabolism and the subsequent magnitude of change in exposure. However, it was unable to accurately predict the magnitude of change in exposure of victim drugs in combination with an inducer. Full Article
all Ketamine and Major Ketamine Metabolites Function as Allosteric Modulators of Opioid Receptors [Article] By molpharm.aspetjournals.org Published On :: 2024-10-17T05:12:59-07:00 Ketamine is a glutamate receptor antagonist that was developed over 50 years ago as an anesthetic agent. At subanesthetic doses, ketamine and some metabolites are analgesics and fast-acting antidepressants, presumably through targets other than glutamate receptors. We tested ketamine and its metabolites for activity as allosteric modulators of opioid receptors expressed as recombinant receptors in heterologous systems and with native receptors in rodent brain; signaling was examined by measuring GTP binding, β-arrestin recruitment, MAPK activation, and neurotransmitter release. Although micromolar concentrations of ketamine alone had weak agonist activity at μ opioid receptors, the combination of submicromolar concentrations of ketamine with endogenous opioid peptides produced robust synergistic responses with statistically significant increases in efficacies. All three opioid receptors (μ, , and ) showed synergism with submicromolar concentrations of ketamine and either methionine-enkephalin (Met-enk), leucine-enkephalin (Leu-enk), and/or dynorphin A17 (Dyn A17), albeit the extent of synergy was variable between receptors and peptides. S-ketamine exhibited higher modulatory effects compared with R-ketamine or racemic ketamine, with ~100% increase in efficacy. Importantly, the ketamine metabolite 6-hydroxynorketamine showed robust allosteric modulatory activity at μ opioid receptors; this metabolite is known to have analgesic and antidepressant activity but does not bind to glutamate receptors. Ketamine enhanced potency and efficacy of Met-enkephalin signaling both in mouse midbrain membranes and in rat ventral tegmental area neurons as determined by electrophysiology recordings in brain slices. Taken together, these findings support the hypothesis that some of the therapeutic effects of ketamine and its metabolites are mediated by directly engaging the endogenous opioid system. SIGNIFICANCE STATEMENT This study found that ketamine and its major biologically active metabolites function as potent allosteric modulators of μ, , and opioid receptors, with submicromolar concentrations of these compounds synergizing with endogenous opioid peptides, such as enkephalin and dynorphin. This allosteric activity may contribute to ketamine’s therapeutic effectiveness for treating acute and chronic pain and as a fast-acting antidepressant drug. Full Article
all Going Rogue: Mechanisms, Regulation, and Roles of Mutationally Activated G{alpha} in Human Cancer [Minireview] By molpharm.aspetjournals.org Published On :: 2024-10-17T05:12:59-07:00 G protein–coupled receptors (GPCRs) couple to heterotrimeric G proteins, comprised of α and β subunits, to convert extracellular signals into activation of intracellular signaling pathways. Canonically, GPCR-mediated activation results in the exchange of GDP for GTP on G protein α subunits (Gα) and the dissociation of Gα-GTP and G protein β subunits (Gβ), both of which can regulate a variety of signaling pathways. Hydrolysis of bound GTP by Gα returns the protein to Gα-GDP and allows reassociation with Gβ to reform the inactive heterotrimer. Naturally occurring mutations in Gα have been found at conserved glutamine and arginine amino acids that disrupt the canonical G protein cycle by inhibiting GTP hydrolysis, rendering these mutants constitutively active. Interestingly, these dysregulated Gα mutants are found in many different cancers due to their ability to sustain aberrant signaling without a need for activation by GPCRs. This review will highlight an increased recognition of the prevalence of such constitutively activating Gα mutations in cancers and the signaling pathways activated. In addition, we will discuss new knowledge regarding how these constitutively active Gα are regulated, how different mutations are biochemically distinct, and how mutationally activated Gα are unique compared with GPCR-activated Gα. Lastly, we will discuss recent progress in developing inhibitors directly targeting constitutively active Gα mutants. SIGNIFICANCE STATEMENT Constitutively activating mutations in G protein α subunits (Gα) widely occur in and contribute to the development of many human cancers. To develop ways to inhibit dysregulated, oncogenic signaling by these mutant Gα, it is crucial to better understand mechanisms that lead to constitutive Gα activation and unique mechanisms that regulate mutationally activated Gα in cells. The prevalence of activating mutations in Gα in various cancers makes Gα proteins compelling targets for the development of therapeutics. Full Article
all Delays in Cardiovascular Emergency Responses in Africa: Health System Failures or Cultural Challenges? By ghspjournal.org Published On :: 2024-10-29T12:28:39-07:00 Full Article
all {Delta}9-Tetrahydrocannabinol Alleviates Hyperalgesia in a Humanized Mouse Model of Sickle Cell Disease [Special Section: Cannabinoid Signaling in Human Health and Disease] By jpet.aspetjournals.org Published On :: 2024-10-18T07:04:15-07:00 People with sickle cell disease (SCD) often experience chronic pain as well as unpredictable episodes of acute pain, which significantly affects their quality of life and life expectancy. Current treatment strategies for SCD-associated pain primarily rely on opioid analgesics, which have limited efficacy and cause serious adverse effects. Cannabis has emerged as a potential alternative, yet its efficacy remains uncertain. In this study, we investigated the antinociceptive effects of 9-tetrahydrocannabinol (THC), cannabis’ intoxicating constituent, in male HbSS mice, which express >99% human sickle hemoglobin, and male HbAA mice, which express normal human hemoglobin A, as a control. Acute THC administration (0.1–3 mg/kg–1, i.p.) dose-dependently reduced mechanical and cold hypersensitivity in human sickle hemoglobin (HbSS) but not human normal hemoglobin A (HbAA) mice. In the tail-flick assay, THC (1 and 3 mg/kg–1, i.p.) produced substantial antinociceptive effects in HbSS mice. By contrast, THC (1 mg/kg–1, i.p.) did not alter anxiety-like behavior (elevated plus maze) or long-term memory (24-hour novel object recognition). Subchronic THC treatment (1 and 3 mg/kg–1, i.p.) provided sustained relief of mechanical hypersensitivity but led to tolerance in cold hypersensitivity in HbSS mice. Together, the findings identify THC as a possible therapeutic option for the management of chronic pain in SCD. Further research is warranted to elucidate its mechanism of action and possible interaction with other cannabis constituents. SIGNIFICANCE STATEMENT The study explores 9-tetrahydrocannabinol (THC)’s efficacy in alleviating pain in sickle cell disease (SCD) using a humanized mouse model. Findings indicate that acute THC administration reduces mechanical and cold hypersensitivity in SCD mice without impacting emotional and cognitive dysfunction. Subchronic THC treatment offers sustained relief of mechanical hypersensitivity but leads to cold hypersensitivity tolerance. These results offer insights into THC's potential as an alternative pain management option in SCD, highlighting both its benefits and limitations. Full Article
all Reimagining Biologically Adapted Somatostatin Receptor-Targeted Radionuclide Therapy: Perspectives Based on Personal Experience and Observations on Recent Trials By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 Full Article
all Is the Clinical Application of CXCR4 Imaging in the Diagnosis and Management of Primary Aldosteronism Really Happening? By jnm.snmjournals.org Published On :: 2024-11-01T04:25:31-07:00 Full Article
all Deep Learning-Based Reconstruction of 3D T1 SPACE Vessel Wall Imaging Provides Improved Image Quality with Reduced Scan Times: A Preliminary Study [ARTIFICIAL INTELLIGENCE] By www.ajnr.org Published On :: 2024-11-07T15:14:12-08:00 BACKGROUND AND PURPOSE: Intracranial vessel wall imaging is technically challenging to implement, given the simultaneous requirements of high spatial resolution, excellent blood and CSF signal suppression, and clinically acceptable gradient times. Herein, we present our preliminary findings on the evaluation of a deep learning–optimized sequence using T1-weighted imaging. MATERIALS AND METHODS: Clinical and optimized deep learning–based image reconstruction T1 3D Sampling Perfection with Application optimized Contrast using different flip angle Evolution (SPACE) were evaluated, comparing noncontrast sequences in 10 healthy controls and postcontrast sequences in 5 consecutive patients. Images were reviewed on a Likert-like scale by 4 fellowship-trained neuroradiologists. Scores (range, 1–4) were separately assigned for 11 vessel segments in terms of vessel wall and lumen delineation. Additionally, images were evaluated in terms of overall background noise, image sharpness, and homogeneous CSF signal. Segment-wise scores were compared using paired samples t tests. RESULTS: The scan time for the clinical and deep learning–based image reconstruction sequences were 7:26 minutes and 5:23 minutes respectively. Deep learning–based image reconstruction images showed consistently higher wall signal and lumen visualization scores, with the differences being statistically significant in most vessel segments on both pre- and postcontrast images. Deep learning–based image reconstruction had lower background noise, higher image sharpness, and uniform CSF signal. Depiction of intracranial pathologies was better or similar on the deep learning–based image reconstruction. CONCLUSIONS: Our preliminary findings suggest that deep learning–based image reconstruction–optimized intracranial vessel wall imaging sequences may be helpful in achieving shorter gradient times with improved vessel wall visualization and overall image quality. These improvements may help with wider adoption of intracranial vessel wall imaging in clinical practice and should be further validated on a larger cohort. Full Article
all All-Trans-Retinal (ATR, 100 mM) By cshprotocols.cshlp.org Published On :: 2024-11-01T06:46:10-07:00 Full Article
all Healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality: a longitudinal community-based study By bjgp.org Published On :: 2024-10-31T16:05:26-07:00 BackgroundDuring the COVID-19 pandemic, global trends of reduced healthcare-seeking behaviour were observed. This raises concerns about the consequences of healthcare avoidance for population health.AimTo determine the association between healthcare avoidance during the early stages of the COVID-19 pandemic and all-cause mortality.Design and settingThis was a 32-month follow-up within the population-based Rotterdam Study, after sending a COVID-19 questionnaire at the onset of the pandemic in April 2020 to all communty dwelling participants (n = 6241/8732, response rate 71.5%).MethodCox proportional hazards models assessed the risk of all-cause mortality among respondents who avoided health care because of the COVID-19 pandemic. Mortality status was collected through municipality registries and medical records.ResultsOf 5656 respondents, one-fifth avoided health care because of the COVID-19 pandemic (n = 1143). Compared with non-avoiders, those who avoided health care more often reported symptoms of depression (n = 357, 31.2% versus n = 554, 12.3%) and anxiety (n = 340, 29.7% versus n = 549, 12.2%), and more often rated their health as poor to fair (n = 336, 29.4% versus n = 457, 10.1%) . Those who avoided health care had an increased adjusted risk of all-cause mortality (hazard ratio [HR] 1.30, 95% confidence interval [CI] = 1.01 to 1.67), which remained nearly identical after adjustment for history of any non-communicable disease (HR 1.20, 95% CI = 0.93 to 1.54). However, this association attenuated after additional adjustment for mental and physical self-perceived health factors (HR 0.93, 95% CI = 0.71 to 1.20).ConclusionThis study found an increased risk of all-cause mortality among individuals who avoided health care during COVID-19. These individuals were characterised by poor mental and physical self-perceived health. Therefore, interventions should be targeted to these vulnerable individuals to safeguard their access to primary and specialist care to limit health disparities, inside and beyond healthcare crises. Full Article
all Can’t prescribe, can’t dispense: the challenge of medicine shortages By bjgp.org Published On :: 2024-10-31T16:05:26-07:00 Full Article
all Challenging the status quo: deprescribing antihypertensive medication in older adults in primary care By bjgp.org Published On :: 2024-10-31T16:05:26-07:00 Full Article
all Deep End Kawasaki/Yokohama: A New Challenge for GPs in Deprived Areas in Japan [Innovations in Primary Care] By www.annfammed.org Published On :: 2024-09-23T14:00:14-07:00 Full Article
all Face-to-Face Relationships Still Matter in a Digital Age: A Call for a 5th C in the Core Tenets of Primary Care [Reflections] By www.annfammed.org Published On :: 2024-09-23T14:00:14-07:00 We primary care clinicians, scholars, and leaders ascribe value to Barbara Starfield’s core tenets of primary care—the 4 Cs: first contact, comprehensiveness, coordination, and continuity. In today’s era of rapid technological advancements and dwindling resources, what are the implications for face-to-face interactions of patient-clinician relationships? We propose adding a 5th C: "Contiguity." Contiguity—or physical proximity and presence—is a key dimension that not only enables the necessary technical aspects of a physical exam but also authenticates the most human aspects of a relationship and occurs specifically when we are physically vulnerable and responsible for the other before us. This, in turn, may best enable us to bridge difference and nurture trust with our patients. We measure what we value and, thus, naming Contiguity as a core tenet assures that we will not lose sight of this keystone in a patient’s relationship with their personal physician. Full Article
all Challenges in Receiving Care for Long COVID: A Qualitative Interview Study Among Primary Care Patients About Expectations and Experiences [Original Research] By www.annfammed.org Published On :: 2024-09-23T14:00:14-07:00 BACKGROUND For many patients with post–COVID-19 condition (long COVID), primary care is the first point of interaction with the health care system. In principle, primary care is well situated to manage long COVID. Beyond expressions of disempowerment, however, the patient’s perspective regarding the quality of long COVID care is lacking. Therefore, this study aimed to analyze the expectations and experiences of primary care patients seeking treatment for long COVID. METHODS A phenomenological approach guided this analysis. Using purposive sampling, we conducted semistructured interviews with English-speaking, adult primary care patients describing symptoms of long COVID. We deidentified and transcribed the recorded interviews. Transcripts were analyzed using inductive qualitative content analysis. RESULTS This article reports results from 19 interviews (53% female, mean age = 54 years). Patients expected their primary care practitioners (PCPs) to be knowledgeable about long COVID, attentive to their individual condition, and to engage in collaborative processes for treatment. Patients described 2 areas of experiences. First, interactions with clinicians were perceived as positive when clinicians were honest and validating, and negative when patients felt dismissed or discouraged. Second, patients described challenges navigating the fragmented US health care system when coordinating care, treatment and testing, and payment. CONCLUSION Primary care patients’ experiences seeking care for long COVID are incongruent with their expectations. Patients must overcome barriers at each level of the health care system and are frustrated by the constant challenges. PCPs and other health care professionals might increase congruence with expectations and experiences through listening, validating, and advocating for patients with long COVID. Annals Early Access article Full Article
all Family Medicine Obstetrics: Answering the Call [Editorials] By www.annfammed.org Published On :: 2024-09-23T14:00:14-07:00 Full Article
all The CheckMate 816 trial: a milestone in neoadjuvant chemoimmunotherapy of nonsmall cell lung cancer By breathe.ersjournals.com Published On :: 2024-11-12T00:25:08-08:00 Advancements in immunotherapy in the perioperative setting have revolutionised the treatment of resectable nonsmall cell lung cancer (NSCLC). Here we present the methodology and results of the clinical trial CheckMate 816 demonstrating the benefit of neoadjuvant therapy with nivolumab plus chemotherapy compared with chemotherapy alone. Furthermore, this article discusses the implications for future practice in resectable NSCLC and the need for future research. Full Article
all Small cell lung cancer and neuroendocrine tumours By breathe.ersjournals.com Published On :: 2024-11-12T00:25:08-08:00 Lung cancer is one of the leading causes of death worldwide. It can broadly be divided into small cell lung cancer (SCLC) and nonsmall cell lung cancer. There have been many advances over the recent years in both fields. The purpose of this review is to provide a concise summary of SCLC for the general respiratory readership. Full Article
all Palliative care in lung cancer: tumour- and treatment-related complications in lung cancer and their management By breathe.ersjournals.com Published On :: 2024-11-12T00:25:08-08:00 Palliative care pertains to the holistic multidimensional concept of "patient-centred" care. It is an interprofessional specialty, primarily aiming to improve quality of care for cancer patients and their families, from the time of diagnosis of malignant disease, over the continuum of cancer care, and extending after the patient's death to the period of bereavement to support the patient's family. There are various complex and frequently unmet needs of lung cancer patients and their families/caregivers, not only physical but also psychological, social, spiritual and cultural. Systematic monitoring of patients’ symptoms using validated questionnaires and patient-reported outcomes (PROs), on a regular basis, is highly encouraged and recommended in recent guidelines on the role of PRO measures in the continuum of cancer clinical care. It improves patient–physician communication, physician awareness of symptoms, symptom control, patient satisfaction, health-related quality of life and cost-effectiveness. This implies that all treating physicians should improve their skills in communication with lung cancer patients/relatives and become more familiar with this multidimensional assessment, repeatedly screening patients for palliative care needs. Therefore, they should receive education and training to develop palliative care knowledge, skills and attitudes. This review is dedicated to lung cancer palliative care essentials that should be within the competences of treating physicians, i.e. pneumologists/thoracic oncologists. Full Article
all Can You Really Save a Life? Study Reveals the Impact of Bystander CPR By gizmodo.com Published On :: Tue, 12 Nov 2024 21:50:16 +0000 New research shows that bystander CPR can substantially improve a person's odds of surviving a cardiac arrest while avoiding major brain damage, especially if given immediately. Full Article Health cardiac arrest CPR heart health
all Squid Game Season 2 Will Be All About Divisions—and the Fight to Overcome Them By gizmodo.com Published On :: Wed, 13 Nov 2024 01:00:24 +0000 Netflix's mega-violent mega-hit series returns December 26. Full Article Television Netflix Squid Game
all Column: Why reporting from South Sudan is so difficult — and critically needed By www.pbs.org Published On :: Sun, 15 Oct 2017 14:27:40 +0000 Simona Foltyn walks down a mountain slope shortly after crossing into South Sudan. Photo by Jason Patinkin In August, fellow reporter Jason Patinkin and I crossed on foot from northern Uganda into rebel-held South Sudan. Over the course of four days, we walked more than 40 miles through the bush, escorted by rebel soldiers, to shed light on one of the world’s most underreported conflicts. Reporting on South Sudan’s war, which began in 2013, has always been a challenge due to the risk and logistical hurdles associated with accessing remote areas where fighting takes place. But over the past year, covering the war and its humanitarian fallout has become particularly difficult. Since the beginning of this year, South Sudan’s government has banned at least 20 foreign journalists in an apparent effort to silence reporters who had a track record of critically reporting on the government. The war has had a devastating impact on South Sudanese communities, but much of it has remained out of the limelight of international media. This systematic crackdown on the foreign press (South Sudanese journalists have long risked imprisonment and death for doing their work) coincided with two important developments. In November 2016, the United Nations warned that the violence being committed against civilians in the southern region of Equatoria risked spiraling into genocide. Then, in February, the UN declared a man-made famine, warning that 100,000 people were at risk of starving to death as a result of civil war. Journalists seeking to cover these events were left with two equally unsavory options: self-censorship or a risky trip to rebel-held parts of the country. Only a handful of journalists have attempted the latter since fighting escalated in July last year. For us, this was our second embed with the rebels this year. Martin Abucha (second from right) rests with his troops in rebel-held South Sudan. Photo by Jason Patinkin We set off from a town in northern Uganda at five in the morning, bouncing along a bumpy dirt track towards the South Sudan border. Crammed into our four-wheel drive were rebel commander Martin Abucha, a dual American and South Sudanese citizen who we planned to profile for our PBS NewsHour Weekend segment, a couple of guides, and several duffle bags stuffed with our tents, sleeping bags, emergency medical kits and provisions to last us four days. Just as the sun began to rise above a distant range of hills that we aimed to cross later that day, our car came to a halt in front of a stream. Because of the rainy reason, it carried more water than usual. It was time to disembark and start walking, or “footing,” as South Sudanese tend to call it. We took off our shoes and waded through the stream’s chilly waters. This was the first of a many rivers we’d have to cross along the way, either on foot or in small flimsy canoes dug out from tree trunks. Each time, we dreaded the idea of falling in with our camera gear. The first part of our journey in northern Uganda felt very much like a hike through a national park. Passing beautiful landscapes and idyllic farming villages, one could almost forget we were headed into a war zone — but we were about to get a reality check. We had just crossed into South Sudan when out of nowhere, two dozen armed men popped out of the tall grass and surrounded us at gunpoint. “Stop! Who are you and where are you going?” a soldier called out in Juba Arabic from his hideout no more than 20 yards away, pointing his AK47 at us. Another one next to him had a rocket-propelled grenade propped on his shoulder, also unequivocally aiming it in our direction. Instinctively, we threw our hands in the air and exchanged a baffled glance. Had we accidentally bumped into government soldiers? Or perhaps we had come onto the “wrong” rebels? Abucha’s group, called the Sudan People’s Liberation Army In Opposition, is the biggest but not the only armed group in Equatoria, an area rife with rival militia and bandits who exploit the security vacuum left by war. To our relief, and only after Abucha answered a series of questions, this routine security check quickly gave way to a warm welcome. The platoon would be our escort for the next four days as we trekked to their base and to Loa, Abucha’s hometown. Keeping up with the rebels was no easy task. Given the country’s pervasive lack of basic infrastructure, South Sudanese grow up walking for dozens of miles just to go about their daily lives. For sedentary Westerners, keeping the target pace of “two meters per second” (around five miles an hour) proved challenging amid 90-degree temperatures, all while filming and plowing our way through dense, itchy elephant grass. The upside of the cumbersome terrain was that it kept us safe. During our four-day trip, we didn’t cross a single road, instead walking along a dizzying network of narrow bush paths the rebels seemed to know like the backs of their hands. An unwanted encounter with government troops, who tended to stick to roads and move around in vehicles as opposed to on foot, was highly unlikely. The closest we got to government-controlled area was a visit to Loa, located just two kilometers away from a main road frequently patrolled by government soldiers. We couldn’t stay long, but the hour we spent on the ground offered us a glimpse into what villages must look like in many parts of Equatoria: burned mud huts, looted schools and clinics, fallow fields and – most strikingly – no civilians. The war has had a devastating impact on South Sudanese communities like the one in Loa, but much of it has remained out of the limelight of international media. Our four-day venture into rebel-held South Sudan offered us a rare opportunity to report ground truths, and we are thankful for that. The post Column: Why reporting from South Sudan is so difficult — and critically needed appeared first on PBS NewsHour. Full Article NewsHour Weekend Reporter's Notebook South Sudan
all Turnbull calls for electronic voting By www.dailytelegraph.com.au Published On :: Sun, 10 Jul 2016 07:39:00 GMT ROLLING UPDATES: Australia waited eight days for Malcolm Turnbull to claim election victory and now the PM and Bill Shorten have united in their push for online voting. Full Article
all Two thirds of Celtic fans want fan board put in place as 'poor' engagement called out By www.heraldscotland.com Published On :: Mon, 11 Nov 2024 16:35:51 +0000 Two thirds of Celtic fans believe the club should have an independently elected Fan Advisory Board according to new research from the University of Glasgow. Full Article
all Treasury stake in NatWest falls to 11.4% on £1bn shares buyback By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 04:31:00 +0000 NATWEST has moved to reduce the UK Government’s stake in the bank after buying back a significant tranche of shares from the Treasury in what it described as a “another important milestone”, it was announced this morning. Full Article
all Nordic-style Open Kindergarten to be trialled in Scotland ahead of potential roll-out By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 00:01:00 +0000 A new Nordic-style Open Kindergarten will be trialled in part of Scotland ahead of a potential roll-out across the country. Full Article
all Limogate: Neil Gray to address use of ministerial car for football trips By www.heraldscotland.com Published On :: Tue, 12 Nov 2024 16:02:34 +0000 Health Secretary Neil Gray will address concerns around his use of a ministerial car to attend football games at Hampden. Full Article
all RPG Cast – Episode 580: “Marshmallow Is Canon” By rpgamer.com Published On :: Sat, 10 Apr 2021 18:45:26 +0000 It's just the core trio this week, as Chris tosses a coin to his hunting horn partner Kelley, and Anna Marie rolls her eyes as Chris cracks terrible jokes about what the Vita really means. We all consider MiHoYo's bottom line, as well as whether we're classified as normies. The post RPG Cast – Episode 580: “Marshmallow Is Canon” appeared first on RPGamer. Full Article News Podcasts RPG Cast Bravely Default II Monster Hunter Rise Rainbow Skies Regalia: Of Men and Monarchs Yakuza: Like a Dragon
all RPG Cast – Episode 611: “All the Bidoofs I Released Before” By rpgamer.com Published On :: Sat, 11 Dec 2021 20:58:56 +0000 Robert tells us who the babby daddy is. Kelley plays Dark Souls Tetris. Chris designs a very special bidet. And you get to breed with a ditto. Have fun! The post RPG Cast – Episode 611: “All the Bidoofs I Released Before” appeared first on RPGamer. Full Article News Podcasts RPG Cast Final Fantasy V Final Fantasy XIV: Endwalker Pokémon Brilliant Diamond / Shining Pearl Pokémon Sword / Shield Shin Megami Tensei V Yakuza 6
all RPG Cast – Episode 629: “Legally Distinct Ghost Rider” By rpgamer.com Published On :: Sat, 30 Apr 2022 19:00:34 +0000 Kelley goes down the Sega Strategy Game Rabbit Hole. Chris becomes a doily shill. And Josh wants Sega to release Valkyria Chronicles as many times as it takes until people like it! The post RPG Cast – Episode 629: “Legally Distinct Ghost Rider” appeared first on RPGamer. Full Article News Podcasts RPG Cast Final Fantasy XIV: Endwalker Rune Factory 5 Valkyria Chronicles
all RPG Cast – Episode 653: “What Really Sank Sega?” By rpgamer.com Published On :: Sat, 29 Oct 2022 18:26:57 +0000 Tragedy strikes Kelley on the Beetle core. Phil doesn't expect the balloon inquisition. Chris brings his standard issue cat. And you all get to just sit there and wonder when the next Persona will come out. The post RPG Cast – Episode 653: “What Really Sank Sega?” appeared first on RPGamer. Full Article News Podcasts RPG Cast Baldur's Gate Monster Hunter Rise New World Shining Force III The Legend of Heroes: Trails in the Sky World of Warcraft: Shadowlands
all RPG Cast – Episode 669: “The 1 of 1 Ring to Rule Them All” By rpgamer.com Published On :: Sat, 25 Mar 2023 18:57:31 +0000 Chris walks in on Anna playing Tactics Ogre. Alex is head of the elemental winds. And Kelley's cat stole a banana. The post RPG Cast – Episode 669: “The 1 of 1 Ring to Rule Them All” appeared first on RPGamer. Full Article News Podcasts RPG Cast Diablo III Diablo IV Path of Exile The Outer Worlds Valkyrie Profile: Silmeria