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Journal of Korean Medical Science Mar 2024As the prevalence of hypertension increases with age and the proportion of the older population is also on the rise, research on the characteristics of older... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
As the prevalence of hypertension increases with age and the proportion of the older population is also on the rise, research on the characteristics of older hypertensive patients and the importance of frailty is necessary. This study aimed to identify clinical characteristics of older hypertension in Korea and to investigate these characteristics based on frailty status.
METHODS
The HOW to Optimize eLDerly systolic BP (HOWOLD-BP) is a prospective, multicenter, open-label, randomized clinical trial that aims to compare intensive (target systolic blood pressure [SBP] ≤ 130 mmHg) with standard (target SBP ≤ 140 mmHg) treatment to reduce cardiovascular events in older hypertensive Korean patients aged ≥ 65 years. Data were analyzed through a screening assessment of 2,085 patients recruited from 11 university hospitals. Demographic, functional (physical and cognitive), medical history, laboratory data, quality of life, and medication history of antihypertensive drugs were assessed.
RESULTS
The mean age was 73.2 years (standard deviation ± 5.60), and 48.0% (n = 1,001) were male. Prevalent conditions included dyslipidemia (66.5%), obesity (body mass index ≥ 25 kg/m², 53.6%), and diabetes (28.9%). Dizziness and orthostatic hypotension were self-reported by 1.6% (n = 33) and 1.2% (n = 24), respectively. The majority of patients were on two antihypertensive drugs (48.4%), while 27.5% (n = 574) and 20.8% (n = 433) were on 1 and 3 antihypertensive medications, respectively. Frail to pre-frail patients were older and also tended to have dependent instrumental activities of daily living, slower gait speed, weaker grip strength, lower quality of life, and lower cognitive function. The frail to pre-frail group reported more dizziness (2.6% vs. 1.2%, < 0.001) and had concerning clinical factors, including lower glomerular filtration rate, more comorbidities such as diabetes, stroke, and a history of admission. Frail to pre-frail older hypertensive patients used slightly more antihypertensive medications than robust older hypertensive patients (1.95 vs. 2.06, = 0.003). Pre-frail to frail patients often chose beta-blockers as a third medication over diuretics.
CONCLUSION
This study described the general clinical characteristics of older hypertensive patients in Korea. Frail hypertensive patients face challenges in achieving positive clinical outcomes because of multifactorial causes: they are older, have more morbidities, decreased function, lower quality of life and cognitive function, and take more antihypertensive medications. Therefore, it is essential to comprehensively evaluate and monitor disease-related or drug-related adverse events more frequently during regular check-ups, which is necessary for pre-frail to frail older patients with hypertension.
TRIAL REGISTRATION
Clinical Research Information Service Identifier: KCT0003787.
Topics: Aged; Humans; Male; Female; Antihypertensive Agents; Frailty; Quality of Life; Activities of Daily Living; Prospective Studies; Dizziness; Hypertension; Blood Pressure; Diabetes Mellitus; Republic of Korea
PubMed: 38501181
DOI: 10.3346/jkms.2024.39.e84 -
Molecular Therapy : the Journal of the... Aug 2023Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is...
Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.
Topics: Animals; Humans; Adipose Tissue; AMP-Activated Protein Kinases; Cachexia; Neoplasms; Peptides; Pharmaceutical Preparations; Quality of Life
PubMed: 37408309
DOI: 10.1016/j.ymthe.2023.06.020 -
Pharmacy (Basel, Switzerland) Aug 2023There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous...
BACKGROUND
There is a paucity of evidence to inform the value of pharmacogenomic (PGx) results in patients after kidney transplant and how these results differ between Indigenous Americans and Whites. This study aims to identify the frequency of recommended medication changes based on PGx results and compare the pharmacogenomic (PGx) results and patients' perceptions of the findings between a cohort of Indigenous American and White kidney transplant recipients.
METHODS
Thirty-one Indigenous Americans and fifty White kidney transplant recipients were studied prospectively. Genetic variants were identified using the OneOme RightMed PGx test of 27 genes. PGx pharmacist generated a report of the genetic variation and recommended changes. Pre- and post-qualitative patient surveys were obtained.
RESULTS
White and Indigenous American subjects had a similar mean number of medications at the time of PGx testing (mean 13 (SD 4.5)). In the entire cohort, 53% received beta blockers, 30% received antidepressants, 16% anticoagulation, 47% pain medication, and 25% statin therapy. Drug-gene interactions that warranted a clinical action were present in 21.5% of patients. In 12.7%, monitoring was recommended. Compared to the Whites, the Indigenous American patients had more normal CYP2C19 ( = 0.012) and CYP2D6 ( = 0.012) activities. The Indigenous American patients had more normal CYP4F2 ( = 0.004) and lower VKORC ( = 0.041) activities, phenotypes for warfarin drug dosing, and efficacy compared to the Whites. SLC6A4, which affects antidepressant metabolism, showed statistical differences between the two cohorts ( = 0.017); specifically, SLC6A4 had reduced expression in 45% of the Indigenous American patients compared to 20% of the White patients. There was no significant difference in patient perception before and after PGx.
CONCLUSIONS
Kidney transplant recipients had several drug-gene interactions that were clinically actionable; over one-third of patients were likely to benefit from changes in medications or drug doses based on the PGx results. The Indigenous American patients differed in the expression of drug-metabolizing enzymes and drug transporters from the White patients.
PubMed: 37624080
DOI: 10.3390/pharmacy11040125 -
CNS Drugs Nov 2023Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The...
Trends and Differences in Status Epilepticus Treatment of Children and Adults Over 10 Years: A Comparative Study of Medical Records (2012-2021) from a University Hospital in Germany.
BACKGROUND AND OBJECTIVES
Over the last decade, significant advancements have been made in status epilepticus (SE) management, influenced by landmark trials such as ESETT and RAMPART. The objectives of this study were to explore the evolution of drug treatments for patients with SE, to investigate its association with outcomes and mortality, and to evaluate differences in treatment patterns between adults and children for a potential shift in medication trends due to the above mentioned trials.
METHODS
The medical records of patients with SE treated at University Hospital Frankfurt between 2012 and 2021 were evaluated for medication trends and outcomes. Children and adults were analyzed separately and jointly.
RESULTS
This study included 1151 SE episodes in 1021 patients (mean age = 53.3 ± 28.3 years; 52.5 % female [n = 533]). The overall percentage of patients with SE treated prehospital was stable over the last decade. More than half (53.6 %) of children were treated prehospital, compared with less than one-third (26.7 %) of adults. Prehospital midazolam use increased over time, while diazepam use decreased. Lorazepam was the most commonly used benzodiazepine in hospitals in 2012-2013, used in 40.8 % of all episodes. However, its use declined to 27.2 % in 2020-2021, while midazolam use increased to 44.0 %. While the use of older antiseizure medications (ASMs) such as phenobarbital (p = 0.02), phenytoin (p < 0.001), and valproate (p < 0.001) decreased, the use of newer ASMs such as levetiracetam and lacosamide significantly increased (p < 0.001). Propofol and continuous midazolam infusion remained the most used third-line therapy drugs. Overall mortality was 16.5 % at discharge and 18.9 % at 30 days. Mortality rates did not change between 2012 and 2021.
CONCLUSION
Midazolam has become the preferred benzodiazepine in pre- and in-hospital settings, both in children and adults. The same applies to the increased use of levetiracetam and lacosamide over time in children and adults, while phenobarbital, phenytoin, and valproate use decreased. Continuous midazolam infusion and propofol remain the most frequently used anesthetic drugs. Mortality and outcome remain stable despite changes in medication patterns.
Topics: Humans; Child; Adult; Female; Middle Aged; Aged; Aged, 80 and over; Male; Anticonvulsants; Phenytoin; Midazolam; Levetiracetam; Valproic Acid; Propofol; Lacosamide; Hospitals, University; Status Epilepticus; Phenobarbital; Benzodiazepines; Medical Records
PubMed: 37979095
DOI: 10.1007/s40263-023-01049-w -
Journal of Controlled Release :... Nov 2023Although cationic liposomes are efficient carriers for nucleic acid delivery, their toxicity often hampers the clinical translation. Polyethylene glycol (PEG) coating...
Although cationic liposomes are efficient carriers for nucleic acid delivery, their toxicity often hampers the clinical translation. Polyethylene glycol (PEG) coating has been largely used to improve their stability and reduce toxicity. Nevertheless, it has been found to decrease the transfection process. In order to exploit the advantages of cationic liposomes and PEG decoration for nucleic acid delivery, liposomes decorated with tetraArg-[G-1]-distearoyl glycerol (Arg-DAG) dendronic oligo-cationic lipid enhancer (OCE) and PEG-lipid have been investigated. Non decorated or OCE-decorated lipoplexes (OCE-LPX and OCE-LPX, respectively) were obtained by lipid film hydration using oligonucleotide (ON) solutions. PEG and OCE/PEG decorated lipoplexes (PEG-OCE-LPX and PEG-OCE-LPX, respectively) were obtained by post-insertion of 2 or 5 kDa PEG-DSPE on preformed lipoplexes. The OCE decoration yielded lipoplexes with size of about 240 nm, 84% loading efficiency at 10 N/P ratio, ten times higher than OCE-LPX, and prevented the ON release when incubated with physiological heparin concentration or with plasma. The PEG decoration reduced the zeta potential, enhanced the lipoplex stability in serum and decreased both hemolysis and cytotoxicity, while it did not affect the lipoplex size and ON loading. With respect to OCE-LPX, the OCE-LPX remarkably associated with cells and were taken up by different cancer cell lines (HeLa and MDA-MB-231). Interestingly, 2 or 5 kDa PEG decoration did not reduce either the cell interaction or the cell up-take of the cationic lipoplexes. With siRNA as a payload, OCE enabled efficient internalization, but endosomal release was hampered. Post-transfection treatment with the lysosomotropic drug chloroquine allowed to identify the optimal time point for endosomal escape. Chloroquine treatment after 12 to 20 h of LPX pre-incubation enabled siRNA mediated target knockdown indicating that this is the time window of endo-lysosomal processing. This indicates that OCE can protect siRNA from lysosomal degradation for up to 20 h, as shown by these rescue experiments.
Topics: Humans; RNA, Small Interfering; Liposomes; Transfection; HeLa Cells; Polyethylene Glycols; Lipids; Chloroquine
PubMed: 37722420
DOI: 10.1016/j.jconrel.2023.09.022 -
Current Heart Failure Reports Dec 2023Cardiac tissue regenerative strategies have gained much traction over the years, in particular those utilizing hydrogels. With our review, and with special focus on... (Review)
Review
PURPOSE OF REVIEW
Cardiac tissue regenerative strategies have gained much traction over the years, in particular those utilizing hydrogels. With our review, and with special focus on supporting post-myocardial infarcted tissue, we aim to provide insights in determining crucial design considerations of a hydrogel and the implications these could have for future clinical use.
RECENT FINDINGS
To date, two hydrogel delivery strategies are being explored, cardiac injection or patch, to treat myocardial infarction. Recent advances have demonstrated that the mechanism by which a hydrogel is gelated (i.e., physically or chemically cross-linked) not only impacts the biocompatibility, mechanical properties, and chemical structure, but also the route of delivery of the hydrogel and thus its effect on cardiac repair. With regard to cardiac regeneration, various hydrogels have been developed with the ability to function as a delivery system for therapeutic strategies (e.g., drug and stem cells treatments), as well as a scaffold to guide cardiac tissue regeneration following myocardial infarction. However, these developments remain within the experimental and pre-clinical realm and have yet to transition towards the clinical setting.
Topics: Humans; Hydrogels; Prospective Studies; Heart Failure; Myocardial Infarction; Myocardium
PubMed: 37812347
DOI: 10.1007/s11897-023-00630-0 -
Journal of Clinical Medicine May 2024Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication... (Review)
Review
Patients with neuromuscular diseases are particularly vulnerable in the perioperative period to the development of pulmonary and cardiac complications, or medication side effects. These risks could include hypoventilation, aspiration pneumonia, exacerbation of underlying cardiomyopathy, arrhythmias, adrenal insufficiency, prolonged neuromuscular blockade, issues related to thermoregulation, rhabdomyolysis, malignant hyperthermia, or prolonged mechanical ventilation. Interventions at each of the perioperative stages can be implemented to mitigate these risks. A careful pre-operative evaluation may help identify risk factors so that appropriate interventions are initiated, including cardiology consultation, pulmonary function tests, initiation of noninvasive ventilation, or implementation of preventive measures. Important intraoperative issues include positioning, airway and anesthetic management, and adequate ventilation. The postoperative period may require correction of electrolyte abnormalities, control of secretions with medications, manual or mechanical cough assistance, avoiding the risk of reintubation, judicious pain control, and appropriate medication management. The aim of this review is to increase awareness of the particular surgical challenges in this vulnerable population, and guide the clinician on the various evaluations and interventions that may result in a favorable surgical outcome.
PubMed: 38792504
DOI: 10.3390/jcm13102963 -
Nature Communications Jan 2024The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in...
The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment.
Topics: Humans; Female; Animals; Mice; Cell Line, Tumor; Endothelial Cells; Drug Carriers; Cell Proliferation; Neoplasms; Hyaluronan Receptors; Aminopeptidases; Minor Histocompatibility Antigens; Membrane Proteins
PubMed: 38177179
DOI: 10.1038/s41467-023-44572-6 -
BMC Psychiatry Nov 2023Somatic symptom disorder (SSD) presents challenges to the healthcare system, including frequent medical visits, lack of symptom relief experienced by individuals with...
BACKGROUND
Somatic symptom disorder (SSD) presents challenges to the healthcare system, including frequent medical visits, lack of symptom relief experienced by individuals with this condition, high associated medical costs, and patient dissatisfaction. This study examined the utility of a novel, low-barrier, brief cognitive behavioural therapy (CBT) group intervention for individuals with SSD.
METHODS
Participants were referred by their mental health providers or self-referral. Each participant underwent a telephone screen and in-person psychological and neuropsychological screen. Two cycles of the CBT-based group (n = 30), each consisting of six weekly two-hour sessions, were facilitated at a large outpatient mental healthcare facility in Ontario, Canada. The final sample consisted of 13 individuals of whom 11 completed the treatment. Clinical outcome measures were administered pre-, mid- and post-group, including the Generalized Anxiety Disorder-7, Perceived Stress Scale-4, Pain Self-Efficacy Questionnaire, Pain Disability Index, Revised Illness Perception Questionnaire, and sections of the Patient Health Questionnaire. Six healthcare utilization metrics were collected from electronic medical records at six months pre- and post-group. Paired samples t-tests were used to examine pre- to post-group differences in participants' somatic symptoms, psychological functioning, health, and degree of healthcare utilization.
RESULTS
When comparing pre- and post- group, we observed reductions in the mean scores for somatic symptom severity, depressive symptomatology, anxiety, perceived stress, and perceived disability related to pain. The change in depressive symptomatology yielded a small effect size (d = 0.30). Further, we observed downward trends across participants' pre- to post-group healthcare utilization, with small effect sizes observed for hospital admission (d = 0.36), days admitted to hospital (d = 0.47), and inpatient consults (d = 0.42). Differences between pre- and post-group measures of somatic symptom severity, psychological functioning, health, or healthcare utilization did not reach significance.
CONCLUSIONS
Current findings provide support for the potential effectiveness of an abbreviated CBT group for individuals with SSD in reducing psychiatric symptomatology. Further research is recommended, including randomized control trials, cost-benefit analyses, and comparisons between abbreviated versus longer-duration treatment programs for SSD.
TRIAL REGISTRATION
Not applicable.
Topics: Humans; Medically Unexplained Symptoms; Pilot Projects; Cognitive Behavioral Therapy; Pain; Cognition; Ontario
PubMed: 38037036
DOI: 10.1186/s12888-023-05141-9 -
Frontiers in Neurology 2023For drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option....
INTRODUCTION
For drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option. Neuromodulatory approaches include responsive neurostimulation (RNS), deep brain stimulation (DBS), and vagal nerve stimulation (VNS). Thalamocortical circuits are involved in both generalized and focal onset seizures. This paper explores the use of RNS in the centromedian nucleus of the thalamus (CMN) and in the anterior thalamic nucleus (ANT) of patients with drug resistant epilepsy.
METHODS
This is a retrospective multicenter study from seven different epilepsy centers in the United States. Patients that had unilateral or bilateral thalamic RNS leads implanted in the CMN or ANT for at least 6 months were included. Primary objectives were to describe the implant location and determine changes in the frequency of disabling seizures at 6 months, 1 year, 2 years, and > 2 years. Secondary objectives included documenting seizure free periods, anti-seizure medication regimen changes, stimulation side effects, and serious adverse events. In addition, the global clinical impression scale was completed.
RESULTS
Twelve patients had at least one lead placed in the CMN, and 13 had at least one lead placed in the ANT. The median baseline seizure frequency was 15 per month. Overall, the median seizure reduction was 33% at 6 months, 55% at 1 year, 65% at 2 years, and 74% at >2 years. Seizure free intervals of at least 3 months occurred in nine patients. Most patients (60%, 15/25) did not have a change in anti-seizure medications post RNS placement. Two serious adverse events were recorded, one related to RNS implantation. Lastly, overall functioning seemed to improve with 88% showing improvement on the global clinical impression scale.
DISCUSSION
Meaningful seizure reduction was observed in patients who suffer from drug resistant epilepsy with unilateral or bilateral RNS in either the ANT or CMN of the thalamus. Most patients remained on their pre-operative anti-seizure medication regimen. The device was well tolerated with few side effects. There were rare serious adverse events. Most patients showed an improvement in global clinical impression scores.
PubMed: 37745648
DOI: 10.3389/fneur.2023.1202631