Purpose: Hypertension should be confirmed with the use of home BP measurement (HBPM) or 24h ambulatory BP measurement (ABPM). The aim of our study was to compare measurements obtained by OBPM, HBPM and ABPM in individuals with elevated OBPM participating in the population-based Swiss Longitudinal Cohort Study (SWICOS). Material and methods: Participants with OBPM ≥140/90 mmHg assessed their BP using HBPM and ABPM. The cut-off for hypertension was ≥135/85 mmHg for HBPM, ≥130/80 mmHg for ABPM. White-coat hypertension (WCH) was defined as normal HPBM and ABPM in participants not taking antihypertensive drugs. Uncontrolled hypertension was defined as hypertension in HBPM or ABPM despite antihypertensive treatment. Results: Of 72 hypertensive subjects with office BP ≥140/90 mmHg and valid measurements of HBPM and ABPM, 39 were males (aged 62.8 ± 11.8y), 33 were females (aged 57.4 ± 14.2y). Hypertension was confirmed with HBPM and ABPM in 17 participants (24%), with ABPM only in 24 further participants (33%), and with HBPM only in 2 further participants (3%). Participants who had hypertension according to ABPM but not HBPM were younger (59 ± 11 y versus 67 ± 16 y; p < 0.001) and more frequently still working (83% versus 23%; p < 0.001). The prevalence of WCH was 28%. Among the 32 subjects taking antihypertensive drugs, uncontrolled hypertension was found in 49%. Conclusion: This population-based study found a high prevalence of WCH and potential uncontrolled hypertension among individuals with elevated OBPM. This study, therefore, supports the ESH recommendations of complementing OBPM by ABPM or HBPM. The use of HBPM instead of ABPM for the confirmation of hypertension in individuals with elevated OBPM might lead to underdiagnosis and uncontrolled hypertension, in particular in the younger working population. In these individuals, this study suggests using ABPM instead of HBPM.
Site-directed Enzyme Enhancement Therapy (SEE-Tx®) technology is a disease-agnostic drug discovery tool that can be applied to any protein target of interest with a known three-dimensional structure. We used this proprietary technology to identify and characterize the therapeutic potential of structurally targeted allosteric regulators (STARs) of the lysosomal hydrolase β-galactosidase (β-Gal), which is deficient due to gene mutations in galactosidase beta 1 (GLB1)-related lysosomal storage disorders (LSDs). The biochemical HaloTag cleavage assay was used to monitor the delivery of wildtype (WT) β-Gal and four disease-related β-Gal variants (p.Ile51Thr, p.Arg59His, p.Arg201Cys and p.Trp273Leu) in the presence and absence of two identified STAR compounds. In addition, the ability of STARs to reduce toxic substrate was assessed in a canine fibroblast cell model. In contrast to the competitive pharmacological chaperone N-nonyl-deoxygalactonojirimycin (NN-DGJ), the two identified STAR compounds stabilized and substantially enhanced the lysosomal transport of wildtype enzyme and disease-causing β-Gal variants. In addition, the two STAR compounds reduced the intracellular accumulation of exogenous GM1 ganglioside, an effect not observed with the competitive chaperone NN-DGJ. This proof-of-concept study demonstrates that the SEE-Tx® platform is a rapid and cost-effective drug discovery tool for identifying STARs for the treatment of LSDs. In addition, the HaloTag assay developed in our lab has proved valuable in investigating the effect of STARs in promoting enzyme transport and lysosomal delivery. Automatization and upscaling of this assay would be beneficial for screening STARs as part of the drug discovery process.
Advances in information technology have increased the availability of time-stamped relational data, such as those produced by email exchanges or interaction through social media. Whereas the associated information flows could be aggregated into cross-sectional panels, the temporal ordering of the events frequently contains information that requires new models for the analysis of continuous-time interactions, subject to both endogenous and exogenous influences. The introduction of the relational event model (REM) has been a major development that has stimulated new questions and led to further methodological developments. In this review, we track the intellectual history of the REM, define its core properties, and discuss why and how it has been considered useful in empirical research. We describe how the demands of novel applications have stimulated methodological, computational, and inferential advancements. Expected final online publication date for the Annual Review of Statistics and Its Application, Volume 11 is March 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Our purposes were: 1) to estimate the prediction performance (PP) of cytology in identifying papillary thyroid carcinoma (PTC) subtypes; 2) to explore how the PTC subtypes distribute among the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) categories. Nodules were included if both the histology with the PTC subtype report and the cytology report with the possible PTC subtype were available. The PP was calculated by making the proportion of True positives/False positives+false negatives. 309 cytologically “suspicious for malignancy” and “malignant” thyroid nodules with PTC histology were evaluated. ACR TI-RADS categorization for classical PTC was significantly different from non-classical PTC (p-value 0.02). For the whole cohort the PP of cytologically classical cases was 0.74, while that of cytologically non classical cases was 0.41. ACR TI-RADS categorization was not significantly different for aggressive vs non-aggressive PTC subtypes (p-value 0.1). When considering only aggressive or non-aggressive PTC subtypes, the PP of cytologically classical cases was respectively 0.86 and 0.87, while that of cytologically non classical cases was respectively 0.27 and 0.22. The PP of cytologically classical cases was 0.73 and 0.79, respectively for macroPTCs and microPTCs, while that of cytologically non classical cases was 0.55 and 0.33, respectively for macroPTCs and microPTCs. Cytology examination reliably performed in predicting classical PTC versus non classical PTC subtypes. ACR TI-RADS categorization was significantly different among classical PTC versus non classical PTC subtypes.
Current treatments for modulating the glial‐mediated inflammatory response after spinal cord injury (SCI) have limited ability to improve recovery. This is quite likely due to the lack of a selective therapeutic approach acting on microgliosis and astrocytosis, the glia components most involved after trauma, while maximizing efficacy and minimizing side effects. We have developed and characterized a new nanogel that can selectively release active compounds in microglial cells and astrocytes. We evaluated the degree of selectivity and subcellular distribution of the nanogel by applying an innovative super‐resolution microscopy technique, expansion microscopy. We then tested two different administration schemes in a SCI mouse model: in an early phase, the nanogel loaded with Rolipram, an anti‐inflammatory drug, achieved significant improvement in the animal's motor performance due to the increased recruitment of microglia and macrophages that were able to localize the lesion. Treatment in the late phase, however, gave opposite results, with worse motor recovery because of the widespread degeneration. These findings demonstrate that the nanovector can be selective and functional in the treatment of the glial component in different phases of SCI. They also open a new therapeutic scenario for tackling glia‐mediated inflammation after neurodegenerative events in the central nervous system. This article is protected by copyright. All rights reserved
Importance Abbreviated dual antiplatelet therapy (DAPT) reduces bleeding with no increase in ischemic events in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI). Objectives To evaluate the association of sex with the comparative effectiveness of abbreviated vs standard DAPT in patients with HBR. Design, Setting, and Patients This prespecified subgroup comparative effectiveness analysis followed the Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated vs Standard DAPT Regimen (MASTER DAPT) trial, a multicenter, randomized, open-label clinical trial conducted at 140 sites in 30 countries and performed from February 28, 2017, to December 5, 2019. A total of 4579 patients with HBR were randomized at 1 month after PCI to abbreviated or standard DAPT. Data were analyzed from July 1 to October 31, 2022. Interventions Abbreviated (immediate DAPT discontinuation, followed by single APT for ≥6 months) or standard (DAPT for ≥2 additional months, followed by single APT for 11 months) treatment groups. Main Outcomes and Measures One-year net adverse clinical events (NACEs) (a composite of death due to any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (MACCEs) (a composite of death due to any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding (MCB). Results Of the 4579 patients included in the analysis, 1408 (30.7%) were women and 3171 (69.3%) were men (mean [SD] age, 76.0 [8.7] years). Ischemic and bleeding events were similar between sexes. Abbreviated DAPT was associated with comparable NACE rates in men (hazard ratio [HR], 0.97 [95% CI, 0.75-1.24]) and women (HR, 0.87 [95% CI, 0.60-1.26]; P = .65 for interaction). There was evidence of heterogeneity of treatment effect by sex for MACCEs, with a trend toward benefit in women (HR, 0.68 [95% CI, 0.44-1.05]) but not in men (HR, 1.17 [95% CI, 0.88-1.55]; P = .04 for interaction). There was no significant interaction for MCB across sex, although the benefit with abbreviated DAPT was relatively greater in men (HR, 0.65 [95% CI, 0.50-0.84]) than in women (HR, 0.77 [95% CI, 0.53-1.12]; P = .46 for interaction). Results remained consistent in patients with acute coronary syndrome and/or complex PCI. Conclusions and Relevance These findings suggest that women with HBR did not experience higher rates of ischemic or bleeding events compared with men and may derive particular benefit from abbreviated compared with standard DAPT owing to these numerically lower rates of events. Trial Registration ClinicalTrials.gov Identifier: NCT03023020
Basement membranes are among the most widespread, non‐cellular functional materials in metazoan organisms. Despite this ubiquity, the links between their compositional and biophysical properties are often difficult to establish due to their thin and delicate nature. In this article, we examine these features on a molecular level by combining results from proteomics, elastic and nanomechanical analyses across a selection of human basement membranes. Comparing results between these different membranes links certain compositional attributes to distinct nanomechanical signatures, and further demonstrate to what extent water defines these properties. In all, these data underline BMs as stiff yet highly elastic connective tissue layers, and highlight how the interplay between composition, mechanics and hydration yields such exceptionally adaptable materials.
In rural sub-Saharan Africa, knowledge of non-communicable diseases such as high blood pressure (BP) is rather limited. This report provides information about a BP screening in Mata Sector, a rural region in Southern Province of Rwanda. Community-based, house-to-house screening was performed between February and July 2020 on more than 7,000 inhabitants. The screening was conducted by a local team composed by 20 community health care workers, five community health care supervisors, and one nurse with hypertension surveillance training. BP and heart rate were recorded after 5 minutes of resting, using a validated automated oscillometric OMRON M6 IT-HEM-7322-E monitor with Intelli Wrap Cuff (HEM-FL31-E) technology. The mean of the second and third value was retained. BP was normal (< 140/90 mm Hg) in 6,340 (88%) and elevated in 863 (12%) participants with 95% of unawareness. Grade 1 (140–159/90–99 mm Hg) hypertensive BP readings were detected in 697 (81%), grade 2 (160–179/100–109 mm Hg) in 134 (16%), and grade 3 (≥ 180/≥110 mm Hg) in 32 (3.7%) individuals. The prevalence of hypertensive readings was significantly age-dependent. Additionally, a slightly greater proportion of participants with high BP (14% versus 11%) had a body mass index (BMI) ≥ 25.0 kg/m². Also resting heart rate was higher in individuals with high BP (82 versus 77 beats/min). Although individuals identified with occasionally elevated BP values need further confirmatory measurements to establish the diagnosis of hypertension, these data suggest that high BP represents an escalating concern within sub-Saharan Africa.
Background and purpose Lower urinary tract symptoms (LUTS) significantly affect quality of life (QoL) of multiple sclerosis (MS) patients, and pharmacotherapy has limited efficacy. We investigated efficacy and safety of the implantable StimRouter neuromodulation system for treating refractory LUTS in MS. Methods This prospective, single‐center, clinical trial was conducted at the Multiple Sclerosis Center of Lugano, Switzerland, involving MS patients treated with self‐administered percutaneous tibial nerve stimulation delivered by StimRouter over 24 weeks. Changes in video‐urodynamic parameters as well as LUTS severity were measured by Overactive Bladder Questionnaire (OAB‐q), QoL using the Multiple Sclerosis Quality of Life (MSQoL‐54), and treatment satisfaction using a 1–10 visual analogue scale. Adverse events were also recorded. Results Of 23 MS patients recruited, six had neurogenic detrusor overactivity (NDO), five had detrusor sphincter dyssynergia (DSD), and 12 had both NDO and DSD. Of patients with NDO, median bladder volume at first uninhibited contraction significantly increased from baseline to week 24 (median = 136 mL, interquartile range [IQR] = 101–244 mL vs. 343 mL, IQR = 237–391 mL; β = 138.2, p = 0.001). No significant changes of urodynamic parameters were found in patients with DSD. OAB‐q symptom scores progressively decreased, and OAB‐q quality of life scores increased ( β = −0.50, p < 0.001 and β = 0.47, p < 0.001, respectively), whereas MSQoL‐54 scores did not significantly change ( β = 0.24, p = 0.084) in the overall population. Treatment satisfaction was overall high (median = 8, IQR = 6–9). No serious adverse events were recorded. Conclusions StimRouter represents a minimally invasive, magnetic resonance imaging‐compatible, self‐administered neuromodulation device leading to objective and subjective improvements of OAB symptoms and related QoL in MS patients with refractory LUTS.
The number of elderly patients with a diagnosis of colorectal cancer (CRC) is increasing. Considering short life expectancy and multiple comorbidities, surgery may not always be the best treatment option. We included all consecutive patients aged 80 years and older who underwent elective resection for CRC following Enhanced Recovery after Surgery (ERAS) protocol between January 2011 and May 2021. The primary endpoint was overall survival, secondary endpoints were 30-day morbidity, and the rate of return to pre-operative living conditions 3 months after surgery. Ninety-four patients were included. Mean age was 84.6 ± 3.6 years, 49 patients (52%) were female. Most patients (77.6%) were ASA score ≥ 3. Laparoscopic resections were performed in 85 patients (90.4%), involving 69 (73.4%) colonic and 25 (26.6%) rectal resections. A stoma was constructed in 22 patients (23%), and reversed in 12 (54.5%). Twenty-two patients (23.4%) experienced a Clavien-Dindo ≥ 3 complication, and 2 patients (2.1%) died. The median length of hospital stay was 8 (interquartiles: 6–15) days. Sixty-six patients (70.2%) were discharged home directly and 26 (27.7%) to rehabilitation or postacute care institutes. At three months after surgery, eighty-two patients (96.5%) returned to their pre-operative living conditions directly or after short-term rehabilitation. Mean follow-up was 53 ± 33 months, estimated 5-year overall survival was 60.3% (95%CI 49.5–71.1%), and disease-free survival was 86.3% (95%CI 78.1–94.4%). Our study suggests that elderly patients undergoing elective surgery have a high potential to return to preoperative living conditions and good overall- and disease-free survivals, despite significant postoperative morbidity.
Receiving the diagnosis of a severe disease may present a traumatic event for patients and their families. To cope with the related challenges, digital interventions can be combined with traditional psychological support to help meet respective needs. We aimed to 1) discuss the most common consequences and challenges for resilience in Neuro Muscular Disease patients and family members and 2) elicit practical needs, concerns, and opportunities for digital platform use. We draw from findings of a transdisciplinary workshop and conference with participants ranging from the fields of clinical practice to patient representatives. Reported consequences of the severe diseases were related to psychosocial challenges, living in the nexus between physical development and disease progression, social exclusion, care-related challenges, structural and financial challenges, and non-inclusive urban design. Practical needs and concerns regarding digital platform use included social and professional support through these platforms, credibility and trust in online information, and concerns about privacy and informed consent. Furthermore, the need for safe, reliable, and expert-guided information on digital platforms and psychosocial and relationship-based digital interventions was expressed. There is a need to focus on a family-centered approach in digital health and social care and a further need in researching the suitability of digital platforms to promote resilience in the affected population. Our results can also inform city councils regarding investments in inclusive urban design allowing for disability affected groups to enjoy a better quality of life.
Introduction The prevalence of type 2 diabetes mellitus (T2DM) and associated morbidity and mortality are increasing in sub-Saharan Africa (SSA). To facilitate access to quality care and improve treatment outcomes, there is a need for innovative community care models and optimized use of non-physician healthcare workers bringing diagnosis and care closer to patients’ homes. Aim We aimed to describe with a scoping review different models of community-based care for non-pregnant adults with T2DM in SSA, and to synthesize the outcomes in terms of engagement in care, blood sugar control, acceptability, and end-organ damage. We further aimed to critically appraise the different models of care and compare community-based to facility-based care if data were available. Methods We searched Medline, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Scopus, supplemented with backward and forward citation searches. We included cohort studies, randomized trials and case-control studies that reported on non-pregnant individuals diagnosed with T2DM in SSA, who received a substantial part of care in the community. Only studies which reported at least one of our outcomes of interest were included. A narrative analysis was done, and comparisons made between community-based and facility-based models, where within-study comparison was reported. Results We retrieved 5,335 unique studies, four of which met our inclusion criteria. Most studies were excluded because interventions were facility-based; community care interventions described in the studies were only add-on features of a primarily facility-based care; and studies did not report outcomes of interest. The included studies reported on a total of 383 individuals with T2DM. Three different community care models were identified. 1) A community-initiated model where diagnosis, treatment and monitoring occurred primarily in the community. This model reported a higher linkage and engagement in care at 9 months compared to the corresponding facility model, but only slight reductions of average blood glucose levels at six months compared to baseline. 2) A facility-originated community model where after treatment initiation, a substantial part of follow-up was offered at community level. Two studies reported such a model of care, both had as core component home-delivery of medication. Acceptability of this approach was high. But neither study found improved T2DM control when compared to facility care 3) An eHealth model with high acceptability scores for both patients and care providers, and an absolute 1.76% reduction in average HbA1c levels at two months compared to baseline. There were no reported outcomes on end-organ damage. All four studies were rated as being at high risk for bias. Conclusion Evidence on models of care for persons with T2DM in SSA where a substantial part of care is shifted to the community is scant. Whereas available literature indicates high acceptability of community-based care, we found no conclusive data on their effectiveness in controlling blood sugar and preventing complications. Evidence from larger scale studies, ideally randomized trials with clinically relevant endpoints is needed before roll-out of community-based T2DM care can be recommended in SSA.
Chronic mesenteric ischemia (CMI) arises from the inability to achieve adequate intestinal blood flow after meals, leading to an imbalance between oxygen and metabolite supply and demand. The true incidence of CMI remains uncertain. However, the occurrence of mesenteric artery occlusive disease (MAOD) is relatively common among the elderly population. Delays in diagnosing CMI can often be attributed to several factors, including the variability in patient symptoms and the range of potential causes for chronic abdominal pain with weight loss. Mikkelson pioneered the introduction of a surgical treatment for occlusive lesions of the superior mesenteric artery (SMA) in 1957. The inaugural performance of endovascular revascularization (ER) for visceral vessels took place in 1980. The literature has documented two types of endovascular revascularization (ER) methods: percutaneous transluminal angioplasty (PTA) and primary stenting (PMAS). Despite the limited quality of available evidence, the consensus among experts is strongly in favor of PMAS over PTA alone for the treatment of atherosclerotic mesenteric artery stenosis. There are several key areas of focus for chronic mesenteric ischemia (CMI) treatment. Randomized controlled trials comparing different stent types, such as covered stents versus bare metal stents, are needed to evaluate efficacy, patency rates, and long-term outcomes in CMI patients.
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