Adherence to antihypertensive drugs (AHDs) is crucial for controlling blood pressure (BP). We aimed to determine the effectiveness of measuring AHD concentrations using a dried blood spot (DBS) ...sampling method to identify nonadherence, combined with personalized feedback, in reducing resistant hypertension.
We conducted a multicenter, randomized, controlled trial (RHYME-RCT, ICTRP NTR6914) in patients with established resistant hypertension. Patients were randomized to receive either an intervention with standard of care (SoC) or SoC alone. SoC consisted of BP measurement and DBS sampling at baseline, 3 months (t3), 6 months (t6), and 12 months (t12); AHD concentrations were measured but not reported in this arm. In the intervention arm, results on AHD concentrations were discussed during a personalized feedback conversation at baseline and t3. Study endpoints included the proportion of patients with RH and AHD adherence at t12.
Forty-nine patients were randomized to receive the intervention+SoC, and 51 were randomized to receive SoC alone. The proportion of adherent patients improved from 70.0 to 92.5% in the intervention+SoC arm ( P = 0.008, n = 40) and remained the same in the SoC arm (71.4%, n = 42). The difference in adherence between the arms was statistically significant ( P = 0.014). The prevalence of resistant hypertension decreased to 75.0% in the intervention+SoC arm ( P < 0.001, n = 40) and 59.5% in the SoC arm ( P < 0.001, n = 42) at t12; the difference between the arms was statistically nonsignificant ( P = 0.14).
Personalized feedback conversations based on DBS-derived AHD concentrations improved AHD adherence but did not reduce the prevalence of RH.
Blowfly strike and the methods used to combat blowfly strike were recorded on 33 properties in the Rûens area of South Africa during 2003/2004. Data were recorded on Merino and Dohne Merino hoggets ...(n = 4951) with at least 3 months' wool growth. The following data were captured: presence or absence of strike, site of the strike (body or breech), presence or absence of dermatophilosis as well as subjective scores for wool quality and wool colour. Control measures recorded include: chemical treatment (preventative and spot treatment), crutching, mulesing and the use of the Lucitrap® system. Blowfly strike was not significantly influenced by gender or breed. Hoggets suffering from dermatophilosis were more likely to be struck, compared with contemporaries not suffering from the skin disorder (0.057 vs 0.027; P < 0.05). Merino hoggets generally had higher scores than their Dohne Merino contemporaries for wool quality (32.6 vs 27.4; P<0.05) and wool colour (29.0 vs 27.2; P<0.05). There was an indication that the Lucitrap® system may have reduced flystrike, but the effect was not statistically significant (P = 0.19 for overall strikes and P = 0.12 for body strike). The Mules operation benefited overall flystrike (0.013 vs 0.110; P < 0.05); mainly through an effect on breech strike (0.010 vs 0.109; P < 0.05). The proportion of fly strikes increased with wool length, and declined with an increase in farm size in wool colour score. None of the ethically acceptable control measures assessed could substantially reduce blowfly strike on their own, and an integrated pest management programme was proposed.
Organoids are self‐organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long‐term‐expanding ...human airway organoids from broncho‐alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi‐ciliated cells, mucus‐producing secretory cells, and CC10‐secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non‐structural viral NS2 protein, and preferentially recruits neutrophils upon co‐culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.
Synopsis
To date, persistent in vitro culture of adult human lung epithelium remains elusive. In this methods resource article, culture conditions to maintain three‐dimensional pulmonary tissue long‐term are reported and applied to recapitulate related diseases.
Culture conditions for long‐term expansion of healthy, hereditary disease and malignant human airway epithelial organoids.
Airway organoids are amenable for medium‐throughput drug screening.
Airway organoids readily allow modelng of viral infection.
Three‐dimensional human pulmonary tissue culture allows for investigation of hereditary diseases.
Divergent selection resulted in Merino lines that differ markedly for reproduction. These lines were selected from the same base population from 1986 to 2009. Selection was initially based on ...maternal ranking values for reproduction in both ewe and ram progeny. The maternal ranking scores were augmented by breeding values from a single-trait repeatability model since 2003. The site and severity of flystrike were recorded for mature breeding ewes in the flock from 2007 to 2009. The following details were captured: animal number, site of the strike (body or breech) and the severity of the strike (1 = mild to 5 = severe). Breech strikes amounted to 92.1% of all strikes and this trend was consistent across years. High-line ewes were less likely (P 20 years were less likely to be affected by breech strike than contemporaries selected for low reproduction.
Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard treatment for locally advanced oesophageal cancer. With this treatment, 29% of patients have a pathologically complete response in the ...resection specimen. This provides the rationale for investigating an active surveillance approach. The aim of this study is to assess the (cost-)effectiveness of active surveillance vs. standard oesophagectomy after nCRT for oesophageal cancer.
This is a phase-III multi-centre, stepped-wedge cluster randomised controlled trial. A total of 300 patients with clinically complete response (cCR, i.e. no local or disseminated disease proven by histology) after nCRT will be randomised to show non-inferiority of active surveillance to standard oesophagectomy (non-inferiority margin 15%, intra-correlation coefficient 0.02, power 80%, 2-sided α 0.05, 12% drop-out). Patients will undergo a first clinical response evaluation (CRE-I) 4-6 weeks after nCRT, consisting of endoscopy with bite-on-bite biopsies of the primary tumour site and other suspected lesions. Clinically complete responders will undergo a second CRE (CRE-II), 6-8 weeks after CRE-I. CRE-II will include 18F-FDG-PET-CT, followed by endoscopy with bite-on-bite biopsies and ultra-endosonography plus fine needle aspiration of suspected lymph nodes and/or PET- positive lesions. Patients with cCR at CRE-II will be assigned to oesophagectomy (first phase) or active surveillance (second phase of the study). The duration of the first phase is determined randomly over the 12 centres, i.e., stepped-wedge cluster design. Patients in the active surveillance arm will undergo diagnostic evaluations similar to CRE-II at 6/9/12/16/20/24/30/36/48 and 60 months after nCRT. In this arm, oesophagectomy will be offered only to patients in whom locoregional regrowth is highly suspected or proven, without distant dissemination. The main study parameter is overall survival; secondary endpoints include percentage of patients who do not undergo surgery, quality of life, clinical irresectability (cT4b) rate, radical resection rate, postoperative complications, progression-free survival, distant dissemination rate, and cost-effectiveness. We hypothesise that active surveillance leads to non-inferior survival, improved quality of life and a reduction in costs, compared to standard oesophagectomy.
If active surveillance and surgery as needed after nCRT leads to non-inferior survival compared to standard oesophagectomy, this organ-sparing approach can be implemented as a standard of care.
Abstract Lack of fragile X mental retardation protein (FMRP) causes Fragile X Syndrome, the most common form of inherited mental retardation. FMRP is an RNA-binding protein and is a component of ...messenger ribonucleoprotein complexes, associated with brain polyribosomes, including dendritic polysomes. FMRP is therefore thought to be involved in translational control of specific mRNAs at synaptic sites. In mice lacking FMRP, protein synthesis-dependent synaptic plasticity is altered and structural malformations of dendritic protrusions occur. One hypothesized cause of the disease mechanism is based on exaggerated group I mGluR receptor activation. In this study, we examined the effect of the mGluR5 antagonist MPEP on Fragile X related behavior in Fmr1 KO mice. Our results demonstrate a clear defect in prepulse inhibition of startle in Fmr1 KO mice, that could be rescued by MPEP. Moreover, we show for the first time a structural rescue of Fragile X related protrusion morphology with two independent mGluR5 antagonists.
Background
The Stent‐In 2 trial randomized patients with malignant colonic obstruction to emergency surgery or stent placement as a bridge to elective surgery. The aim of this study was to compare ...the oncological outcomes.
Methods
Disease recurrence, and disease‐free, disease‐specific and overall survival were evaluated, including a subgroup analysis of patients with a stent‐ or guidewire‐related perforation.
Results
Of 98 patients included in the original Stent‐In 2 trial, patients with benign (16) or incurable (23) disease were excluded from this study, along with a patient who had withdrawn from the trial. Of the remaining 58 patients, 32 were randomized to emergency surgery (31 resection, 1 stoma only) and 26 to stenting. Unsuccessful stenting required emergency surgery in six patients owing to wire or stent perforation. Locoregional or distant disease recurrence developed in nine of 32 patients in the emergency surgery group and 13 of 26 in the stent group. Disease‐free survival was worse in the subgroup with stent‐ or guidewire‐related perforation. Five of six patients in this subgroup developed a recurrence, compared with nine of 32 in the emergency surgery group and eight of 20 who had unperforated stenting.
Conclusion
Stent placement for malignant colonic obstruction was associated with a risk of recurrence in this trial, but the numbers are small. There is not enough evidence to refute the approach strongly. Registration number: ISRCTN46462267 (
http://www.controlled‐trials.com).
A cautionary note
Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 ...individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential
UDP
-
glucose pyrophosphorylase
(
UGP2
) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in
UGP2
as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies.
Multidisciplinary cardiac rehabilitation (CR) reduces morbidity and mortality and increases quality of life in cardiac patients. However, CR utilisation rates are low, and targets for secondary ...prevention of cardiovascular disease are not met in the majority of patients, indicating that secondary prevention programmes such as CR leave room for improvement. Cardiac telerehabilitation (CTR) may resolve several barriers that impede CR utilisation and sustainability of its effects. In CTR, one or more modules of CR are delivered outside the environment of the hospital or CR centre, using monitoring devices and remote communication with patients. Multidisciplinary CTR is a safe and at least equally (cost-)effective alternative to centre-based CR, and is therefore recommended in a recent addendum to the Dutch multidisciplinary CR guidelines. In this article, we describe the background and core components of this addendum on CTR, and discuss its implications for clinical practice and future perspectives.
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