Hazardous alcohol use increases the risk of hypertension but is underdetected in primary healthcare (PHC) patients. Use of the biomarker phosphatidylethanol (PEth), which reflects the last 2-3 weeks ...of alcohol consumption, is increasing in Swedish PHC, but studies exploring its use for hypertension are scarce or missing.
To explore GPs' experiences of using PEth to identify hazardous alcohol use in the context of managing hypertension.
A qualitative study of GPs (
= 12) experienced in using PEth in hypertension management who were recruited at Swedish primary healthcare centres (PHCC) in 2021.
The GPs participated in five focus group interviews. A questioning route was used. The interviews were audio-recorded, transcribed verbatim, and analysed with inductive qualitative content analysis.
was the overall theme, which reflected both the disappearance of GPs' fear that the PEth result might upset the patient, as this rarely occurred, and that the positive effects of PEth predominated in the findings. The theme is underpinned by the following four sub-themes: serving as an eye-opener; improving the dialogue; using with care; and learning by doing.
PEth is a useful tool that changed GPs' routines for addressing alcohol and identifying hazardous alcohol use in patients with hypertension managed in PHC. The GPs advocated adopting PEth as a routine test in the treatment of hypertension. However, PEth needs to be used with care to maximise benefit and minimise harm.
The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT
4
receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal ...pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT
4
receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The majority of patients who seek help for insomnia do so in primary health care. Nurse-led group treatment in primary care based on cognitive behavioral therapy for insomnia (CBT-I) can lead to ...improvements in both day- and nighttime symptoms. This study aimed to explore patients' experiences of nurse-led group treatment for insomnia in primary health care.
Seventeen patients who had participated in the group treatment program were interviewed in five focus groups. Interview transcriptions were analyzed with qualitative content analysis.
Four themes emerged that described patients' experiences of the group treatment program. Involvement and trust open the door for change: Motivation to engage in treatment arose from patients' own desire for change, from being together with others who shared or understood their struggles, and from feeling emotionally affirmed and trustful. Competence arising from deeper understanding: Patients obtained knowledge and made it their own, which enabled them to develop functional sleep habits and let go of sleep performance and worry. The ability to impact their insomnia increased patients' trust in their own efficacy and helped them persist in behavioral change. Struggling with vulnerability and failure: Treatment was tough, and patients could feel challenged by external circumstances. Moreover, they could distrust their own efficacy. Tailoring treatment to individual needs: Patients experienced different life circumstances and adapted the techniques to their needs and abilities by focusing on what felt right for them.
Patients went through a process of motivation, change, and challenges. They experienced certain aspects of treatment as essential to changing behavior and achieving improvements. Examples included being in a group with others who shared similar experiences, gaining knowledge about sleep, keeping a sleep diary, and practicing the sleep restriction technique. The study provides insights into patients' struggles during treatment, both those related to external circumstances and those related to feelings of vulnerability and failure. It also highlights the importance of adapting treatment to patients' differing needs, underscoring the value of person-centered care.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The in vivo preclinical pharmacodynamic profile of TD-5108, a selective 5-HT(4) receptor agonist with high intrinsic activity, was compared to that of the clinically studied gastrointestinal ...pro-kinetic agents, tegaserod, cisapride and mosapride. The activity of TD-5108 was evaluated in guinea pig colonic transit, rat oesophageal relaxation and dog gastrointestinal smooth muscle contractility models. Subcutaneous administration of TD-5108, tegaserod, cisapride and mosapride increased guinea pig colonic transit (rank order of potencies: TD-5108 > tegaserod > cisapride > mosapride). Following intravenous and intraduodenal dosing, TD-5108, tegaserod, cisapride and mosapride produced dose-dependent relaxation of the rat oesophagus. On a molar basis, TD-5108 was approximately twofold less potent than tegaserod following intravenous dosing but 6- or 86-fold more potent than cisapride or mosapride, respectively, and 9- or 18-fold more potent than tegaserod or cisapride, respectively, after intraduodenal administration. Orally dosed TD-5108 increased the contractility of the canine antrum, duodenum and jejunum with higher potency than tegaserod. The selective 5-HT(4) receptor agonist, TD-5108, demonstrates robust in vivo activity in the guinea pig, rat and dog gastrointestinal tracts.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Diets rich in saturated fatty acids (SFAs) produce a form of tissue inflammation driven by “metabolically activated” macrophages. We show that SFAs, when in excess, induce a unique transcriptional ...signature in both mouse and human macrophages that is enriched by a subset of ER stress markers, particularly IRE1α and many adaptive downstream target genes. SFAs also activate the NLRP3 inflammasome in macrophages, resulting in IL-1β secretion. We found that IRE1α mediates SFA-induced IL-1β secretion by macrophages and that its activation by SFAs does not rely on unfolded protein sensing. We show instead that the ability of SFAs to stimulate either IRE1α activation or IL-1β secretion can be specifically reduced by preventing their flux into phosphatidylcholine (PC) or by increasing unsaturated PC levels. Thus, IRE1α is an unrecognized intracellular PC sensor critical to the process by which SFAs stimulate macrophages to secrete IL-1β, a driver of diet-induced tissue inflammation.
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•Saturated fatty acids induce an ER stress transcriptional signature in macrophages•Flux of saturated fatty acids into phospholipids activates the ER stress sensor IRE1α•IRE1α mediates saturated fatty-acid-induced activation of the NLRP3 inflammasome
Excessive saturated fat consumption promotes tissue inflammation driven by “metabolically activated” macrophages. Here, Robblee et al. use transcriptomic profiling to identify the ER stress sensor IRE1α as a key component of metabolic activation that senses phospholipid saturation to mediate inflammatory activation in macrophages exposed to saturated fat.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hypersensitivity to asparaginase is common, but the differential diagnosis can be challenging and the diagnostic utility of antibody tests is unclear. We studied allergic reactions and serum ...antibodies to E. coli asparaginase (Elspar) in 410 children treated on St. Jude Total XV protocol for acute lymphoblastic leukemia. Of 169 patients (41.2%) with clinical allergy, 147 (87.0%) were positive for anti-Elspar antibody. Of 241 patients without allergy, 89 (36.9%) had detectable antibody. Allergies (P=0.0002) and antibodies (P=6.6 × 10(-6)) were higher among patients treated on the low-risk arm than among those treated on the standard/high-risk arm. Among those positive for antibody, the antibody titers were higher in those who developed allergy than in those who did not (P<1 × 10(-15)). Antibody measures at week 7 of continuation therapy had a sensitivity of 87-88% and a specificity of 68-69% for predicting or confirming clinical reactions. The level of antibodies was inversely associated with serum asparaginase activity (P=7.0 × 10(-6)). High antibody levels were associated with a lower risk of osteonecrosis (odds ratio=0.83; 95% confidence interval, 0.78-0.89; P=0.007). Antibodies were related to clinical allergy and to low systemic exposure to asparaginase, leading to lower risk of some adverse effects of therapy.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.
We evaluated infection-related complications that were grade ...≥3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.
Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n= 389), followed by ear (n= 151), bloodstream (n= 147), and gastrointestinal tract (n= 145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n= 4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1–9.9 years at diagnosis was associated with febrile neutropenia (P= 0.002) during induction and febrile neutropenia and documented infection (both P< 0.001) during later continuation. White race was associated with documented infection (P= 0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P< 0.001) and documented infections (P= 0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P< 0.001).
The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We analyzed the long-term outcome of 1011 patients treated in five successive clinical trials (Total Therapy Studies 11, 12, 13A, 13B, and 14) between 1984 and 1999. The event-free survival improved ...significantly (P=0.003) from the first two trials conducted in the 1980s to the three more recent trials conducted in the 1990s. Approximately 75% of patients treated in the 1980s and 80% in the 1990s were cured. Early intensive triple intrathecal therapy, together with more effective systemic therapy, including consolidation and reinduction treatment (Studies 13A and 13B) as well as dexamethasone (Study 13B), resulted in a very low rate of isolated central nervous system (CNS) relapse rate (<2%), despite the reduced use of cranial irradiation. Factors consistently associated with treatment outcome were age, leukocyte count, immunophenotype, DNA index, and minimal residual disease level after remission induction treatment. Owing to concerns about therapy-related secondary myeloid leukemia and brain tumors, in our current trials we reserve the use of etoposide for patients with refractory or relapsed leukemia undergoing hematopoietic stem cell transplantation, and cranial irradiation for those with CNS relapse. The next main challenge is to further increase cure rates while improving quality of life for all patients.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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