Treatment Goals Research Articles

A retrospective analysis of patients with very HIGH level of LDL-C and the predictors of mortality (HIGH-LDL-PM Registry)

Abstract Introduction Elevated levels of LDL cholesterol (LDL-C) significantly contribute to the development and progression of cardiovascular diseases (CVDs). In HIGH-LDL-PM Registry, we aimed to investigate the demographics and clinical characteristics of patients with very high level of LDL-C and the predictors of mortality, retrospectively. Methods We retrospectively searched the electronic database of Istanbul University-Cerrahpasa Institute of Cardiology and included patients with very high level of LDL-C (>190 mg/dl) in HIGH-LDL-PM registry. The study group were classified as patients with high probability of familial hypercholesterolemia (FH) and low probability of FH according to Dutch Lipid Clinic Network Score (DLCNS). Results The study group were consisted of 1127 patients and almost two thirds (61.5%) were female. The mean age was 56.5 12.2 years. Hypertension, diabetes, chronic kidney disease (CKD) were seen in 55.8%, 23.5% and 3.7%, respectively. One third of study group (31.1%) had coronary artery disease (CAD) and rest of them were primary prevention patients. the main rhythm was sinus in most of the patients (92,2) and 7.8% patients had atrial fibrillation (AF). Only minority of patients (3.9%) had stigmata for elevated cholesterol levels. While 41.8% of patients had high clinical probability for FH, 58.2% of them had low probability according to DLCNS. While 69% of patients were using lipid lowering treatments (LLTs), 42% of them had drug adherence. High dose (HD) statins (atorvastatin 40-80 and rosuvastatin 20-40 mg) were prescribed in more than half (55.2%) of patients with LLTs. Ezetimibe was the preferred agent as combination therapy in 6.9% and PCSK-9is were prescribed only in 2.5% of patients with LLTs. In 38.8% of study population, ASA was prescribed. 50% decrease in LDL-C levels or decreasing LDL-C below 70 or 100 mg/dl as a treatment goal were achieved in 37.1% and 15% of study population. MACE (MI, stroke, PCI or peripheral revascularization) was recorded in 21% of study population and the mortality rate was 10.4% at 12-years FU (6-145 months). Patients with low probability of FH had better survival than patient with high probability (91.4% vs 88.4%). The age, low dose statin use and higher level of LDL-C at FU were predictors of mortality in Cox-regression analysis. Conclusion Our retrospective analysis of patients with very high levels of LDL-C underscores the multifaceted nature of dyslipidemia management and its impact on cardiovascular outcomes. Despite advancements in pharmacotherapy, suboptimal adherence to lipid-lowering treatments remains a significant challenge, contributing to a notable burden of major adverse cardiovascular events and mortality. Identification of predictors of mortality, such as age, statin dosage, and LDL-C levels, highlights the importance of individualized risk assessment and tailored treatment approaches in this high-risk population.

Improvement of endorgan function following tricuspid edge-to-edge repair

Abstract Background/Introduction Subjects with severe tricuspid regurgitation (TR) often suffer from impaired endorgan function. The potential to improve endorgan function is an important goal of treatment. Purpose To assess baseline endorgan function and changes in organ function following transcatheter edge-to-edge repair with the TriClip device in subjects with severe TR from the TRILUMINATE Pivotal randomized controlled trial. Methods Right heart catheterization was required prior to enrollment; medication history was collected. Changes in biomarkers, including MELD-XI, GGT, eGFR, BUN, and TR and KCCQ overall summary score were assessed at baseline and 12-month follow-up for all enrolled subjects. A 15% improvement in biomarker levels was considered clinically relevant. The odds of achieving a 15% improvement in biomarkers between baseline and 12-month follow-up was compared between the Device and Control groups (presented as OR [95% CI]). Results A total of 572 subjects were enrolled and randomized. At baseline, subjects had elevated levels of GGT (83.0±87.7 U/L) and MELD-XI score (10.3±5.2), low eGFR (56.7±21.0 mL/min/1.73m2), and elevated BUN (29.5±16.7 mg/dL). Nearly 90% of subjects were on loop diuretics, with approximately 50% taking these in combination with a thiazide or potassium-sparing diuretic. The average diuretic dosage was 71 mg (furosemide equivalent). Most subjects had normal left ventricle ejection fraction (only 5% with LVEF <40%). Subjects had well-managed blood pressure (systolic: 122±13 mmHg, diastolic: 69±10), slightly elevated central venous pressures (12±6 mmHg), systolic pulmonary artery pressures (40±10 mmHg) and pulmonary capillary wedge pressures (15±4 mmHg), and normal transpulmonary gradients (11±4 mmHg). The odds of achieving a 15% improvement in liver and renal function was higher in TriClip patients compared to control: MELD-XI score (1.79 [1.22, 2.63]), GGT (1.83 [1.21, 2.77]), and eGFR (1.81 [1.18, 2.77]) - Fig 1. The favorable changes in organ function observed were also reflected when stratifying subjects by residual TR severity: The odds of a 15% biomarker improvement favored subjects with moderate or less residual TR for MELD-XI score (2.05 [1.39, 3.00]), GGT (1.91 [1.26, 2.90]), and eGFR (1.83 [1.20, 2.80]) compared with subjects who had severe or worse residual TR. Lastly, improvement in these biomarkers also favored subjects with a 15-point or greater improvement in KCCQ compared with subjects with less than a 15-point KCCQ improvement. Conclusions Use of TriClip in subjects with severe tricuspid regurgitation was associated with improvement in kidney and liver function, and this improvement was associated with reduction in the severity of TR. These data provide the first objective evidence of the physiologic impact of TR reduction obtained in a randomized clinical trial.

Impact of coronary revascularization on clinical outcomes of post-acute myocardial infarction patients with left ventricular thrombus

Abstract Background Left ventricular thrombus (LVT) is an uncommon, but dangerous complication seen in post-acute myocardial infarction (AMI). With advances in percutaneous coronary intervention (PCI) techniques, the incidence of post-AMI LVT has declined in the contemporary era. However, a minority of patients do not undergo coronary revascularisation due to medical contraindications or patient preference. This study aimed to evaluate the clinical characteristics and outcomes of post-AMI LVT patients treated with and without coronary revascularisation. Methods This was a retrospective study of 263 consecutive post-AMI patients diagnosed with LVT from November 2012 to January 2021, retrieved from a echocardiography database. Patients were stratified by the presence or absence of revascularisation treatment. Baseline clinical characteristics, treatment and outcomes data were collected and analysed. Results The median follow-up duration was 2.9 years (IQR: 0.9 – 4.7). A majority of post-AMI LVT patients underwent revascularisation via PCI (71.5%, n = 188), CABG (4.2%, n = 11) or thrombolysis (0.4%, n = 1). Unrevascularised patients (24.0%, n = 63) were older (p <0.001), more likely to be female (p <0.001), and had more co-morbidities such as previous stroke (p <0.001), heart failure (p = 0.001), chronic kidney disease (p = 0.020), and malignancy (p = 0.021). More unrevascularised patient had NSTEMI (p < 0.001), and significantly fewer were treated with triple therapy (p < 0.001). Incidence of LVT resolution was lower (p < 0.001) while all-cause mortality was higher (p < 0.001) for unrevascularised patients on univariate survival analyses. On multivariable Cox regression, revascularisation status was not an independent predictor of LVT resolution, bleeding, stroke, or all-cause mortality outcomes. Conclusion While unrevascularised post-AMI LVT patients had poorer outcomes compared to revascularised patients overall, revascularisation status itself was not independently associated with poorer clinical outcomes. Optimising medical therapy such as triple therapy remains a key treatment goal for post-AMI LVT patients.

Failure of primary prophylaxis: statin use, risk profile, and outcomes in contemporary patients treated with PCI for first atherosclerotic event

Abstract Background Atherosclerosis and coronary artery disease (CAD) are potentially preventable through lifestyle modifications and the use of medical cholesterol-lowering drugs in individuals at risk. However, guidelines for optimal use of statins are debated, and not enough is known about the real-world barriers to effective CAD-prevention. Understanding the mechanisms of prophylactic treatment failure in patients who undergo PCI for their first atherosclerotic event could help improve primary prevention strategies. Purpose To 1) examine the relative contribution of failure mechanisms of medical prophylaxis in patients undergoing PCI for their first atherosclerotic event, 2) examine how clinical characteristics differ between patients with different failure mechanisms, and 3) examine whether long-term outcomes after PCI differ depending on the mechanism of prophylactic failure. Methods A retrospective study was conducted to study electronic healthcare records for all patients ≥18 years treated with PCI at Gentofte Hospital, Denmark in 2019. Data was extracted from electronic health care records. Patients with first atherosclerotic event were divided into cardiovascular risk groups based on the ESC/EAS guidelines and further into four different prophylactic failure mechanism groups based on cardiovascular risk, statin indication, statin use and whether the risk-based LDL-C treatment goals were reached. Results 507 patients were treated with PCI for their first atherosclerotic event. 54% were categorized as low-moderate cardiovascular risk. 41% were not on statin and did not have class I indication for statin treatment (strategy failure). 26% were not on statin treatment despite class I indication for statin treatment (implementation failure). 18% were on statin treatment but had not reached their LDL-C target (efficiency failure), and 16% were on statin treatment, and had reached the LDL-C target (efficacy failure). Patients with strategy failure, were more likely to be younger, mostly males, and often had a smoking history. Patients with implementation failure, were typically elderly, with relatively few comorbidities. The frequency of death, myocardial infarction, stroke, or repeat revascularization over 4 years was 15.3%, with no statistically difference between the groups (p =0.3). Conclusion In this cohort study, patients treated with PCI for first atherosclerotic event were often classified as low or intermediate risk, and a majority had not been on statin treatment before. Improved primary prevention should focus on at-risk groups that are either not included in current recommendation for statin treatment, especially young smokers, or patients not receiving treatment despite recommendations, especially older patients with few medical contacts.Cardiovascular risk & failure mechanismKaplan-Meier MACE

LDL-C target attainment and statin use in patients with ASCVD, familial hypercholesterolaemia, and those otherwise at moderate/high-risk of ASCVD in australian general practice (SCOPE-GP)

Abstract Background The proportion of Australian general practice patients not attaining low-density lipoprotein cholesterol (LDL-C) goals is not well described. The SCOPE-GP study evaluated duration of LDL-C exceeding treatment goals, statin use and discontinuation rates in patients with atherosclerotic cardiovascular disease (ASCVD), without ASCVD events but at moderate/high-risk, and familial hypercholesterolemia (FH). Methods This population-based retrospective cohort study used de-identified medical records of adult patients captured in the IQVIA GP-EMR database. Patients were indexed at the earliest date of ASCVD, FH, or hyperlipidemia diagnosis from January 1, 2010 to June 30, 2022, with a variable follow-up period from index to June 30, 2022. Ascertainment of study cohort was based on the 2021 ESC/EAS guidelines and Framingham Risk Equation. LDL-C test result levels were extracted per patient, summarised and analysed. Patients were stratified based on their test results at latest results/closest to censor date. Average time above target levels is the proportion of number of days above LDL-C target levels over total number of follow-up days for each patient. A Poisson distribution was fitted to estimate 95% confidence interval. Lipid lowering therapies (LLT) were stratified by (ASCVD, FH and moderate/high risk of CVD) at last visit/censor date. Combination of LLT were defined as prescriptions for fixed dose combinations or ≥2 separate scripts of LLT from different classes within 180 days from last visit/censor date (look back period). Discontinuation is defined as no statins were prescribed again after the last script for 270 days or more, limited to the first occurrence. Results The average time with LDL-C levels above target was 1077.5 days in ASCVD patients (n=2,688), 938.6 days in moderate-risk ASCVD (n=37,003), 980.9 days in high-risk ASCVD (n=85,199), and 900.8 days in FH (n=279). The proportion of days above target level for all four cohorts is described in Figure 1. Among 107,552 patients with recorded LDL-C levels ≥1.8mmol/L at their last visit/censor date, 30.9% were on statin monotherapy and 1.0% were on statin+ezetimibe. Statin use was highest in ASCVD patients (65.4%), followed by FH (49.5%), high risk (40.0%) and moderate risk subjects (29.5%) (Table 1). Statin discontinuation rates were 60.3%, 76.3, 66.1%, and 65.8% in these groups, respectively. The predominant reason for statin discontinuation was non-specific adverse drug reactions (12.2% ASCVD, 11.7% moderate-risk, 13.2% high-risk and 17.9% FH). The proportion of subjects contraindicated to statins was highest in moderate risk subjects (0.05%). Conclusions Prolonged periods of elevated LDL-C and high statin discontinuation rates were prevalent among at-risk individuals in Australian primary care. This underscores a significant ASCVD burden that could be prevented with more active lipid management.

Prognostic impact of symptom relief under low and normal physical performance in patients hospitalized for worsening heart failure

Abstract Background Subjective symptoms, represented by the New York Heart Association (NYHA) class, are well-established prognostic indicators and treatment goals of heart failure (HF). However, older patients may be less likely to develop subjective symptoms due to an impaired physical performance. Purpose To evaluate the prognostic impact of symptom relief under low and normal physical performance in patients hospitalized for worsening HF. Methods We carried out a sub-analysis of FRAGILE-HF, a prospective multicenter study, including 1272 consecutive older (>=65 years) hospitalized patients with HF (median age 80; 57.2% male; left ventricular ejection fraction 46±17%). NYHA class and gait speed were documented before discharge. The patients were prospectively followed-up for two years after discharge. Results At the time of discharge, 715 patients (56%) remained symptomatic (NYHA2-4) whereas 557 patients (44%) were asymptomatic (NYHA1). Patients were classified into 4 groups according to symptom relief and physical performance represented by slow (<0.8 m/s) or normal (>=0.8 m/s) gait speed: 279 slow-asymptomatic, 278 normal-asymptomatic, 402 slow-symptomatic, and 313 normal-symptomatic patients, respectively. During the follow-up period, 266 patients (20.9%) died. Slow-asymptomatic (hazard ratio (HR) 1.72[1.09-2.72], p=0.019 in comparison with normal-asymptomatic patients as a reference) and slow-symptomatic (HR 1.85[1.21-2.82], p=0.004) status was associated with high mortality in a Cox regression analysis adjusted for the Meta-analysis Global Group in Chronic Heart Failure score and B-type natriuretic peptide level (Figure). Furthermore, the combined endpoint of HF rehospitalization and all-cause death within 90 days were more frequently observed in slow-asymptomatic (HR 1.94[1.05-3.60], p=0.034), normal-symptomatic (HR 1.89[1.06-3.36], p=0.031), and slow-symptomatic (HR 1.97[1.10-3.52], p=0.022) patients than normal-asymptomatic patients (Figure). Conclusions Symptom relief achieved at the time of discharge was not associated with a lower mortality in patients with low physical performance, for whom careful follow-up may be needed especially in the early period after discharge because the symptoms may be masked due to low physical performance.

An epigenetic editor targeting human PCSK9 efficiently and durably lowers Low Density Lipoprotein Cholesterol (LDL-C) in non-human primates

Abstract Background Reducing the risk of atherosclerotic cardiovascular disease is dependent on both the magnitude and cumulative duration of LDL-C lowering. However, in clinical practice achieving treatment goals is often hampered by low adherence to standard of care. Although PCSK9 inhibitors represent an effective option for LDL-C lowering, they require chronic life-long treatment. Epigenetic editing is a new therapeutic approach designed to durably silence genes by leveraging nature’s endogenous cellular mechanism for gene regulation via CpG methylation without the inherent genotoxic risks of genome editing approaches that nick or cut the DNA. We are developing a PCSK9 epigenetic editor (PCSK9-EE) to durably silence PCSK9, with the promise of lifelong reduction in LDL-C. Methods Here, we describe the development of an epigenetic editor targeting human PCSK9. This epigenetic editor consists of a DNA targeting component fused to a transcriptional repressor domain and a DNA methyltransferase domain. PCSK9-EE was first screened and evaluated for specificity and efficacy in primary human hepatocytes (PHH). In vivo efficacy and durability were then evaluated in a transgenic mouse carrying the human PCSK9 genomic locus (hPCSK9-Tg mouse) and non-human primates (NHP). Results Our initial screen of PCSK9-EEs identified several hits that efficiently suppressed secreted PCSK9 levels in immortalized liver cells. We confirmed that our top PCSK9-EE candidates robustly decreased PCSK9 secretion in PHH and were found to be highly specific at targeting PCSK9 as assessed by RNA-seq, methylation array, and whole-genome methylation sequencing. To examine in vivo activity, we treated hPCSK9-Tg mice with a single administration of a lipid nanoparticle delivering mRNA encoding our PCSK9-EE and observed >97% reduction in liver PCSK9 mRNA, and >98% reduction in plasma PCSK9 for the duration of the study (one year). We then delivered PCSK9-EE in NHP and observed a robust reduction in plasma PCSK9 with a concomitant reduction in LDL-C. These effects were found to be durable for at least 6 months following a single administration of PCSK9-EE in NHP. To establish a mechanistic relationship between PCSK9-EE’s molecular action and durable PCSK9 silencing, we performed serial liver biopsies in each NHP approximately 2 months apart. Robust CpG methylation at the PCSK9 genomic locus was observed in the first liver biopsy and was comparable to that observed in the second liver biopsy suggesting that PCSK9-EE induced stable CpG methylation in NHP livers. Conclusions We believe PCSK9-EE may offer an effective, safe, and durable approach to suppress hepatic PCSK9 expression and achieve long-lasting reduction in LDL-C. Furthermore, epigenetic editing may hold promise for one-and-done approaches for the treatment of atherosclerotic cardiovascular disease without cutting, nicking, or altering the DNA sequence.

Management of children with heterozygous familial hypercholesterolemia worldwide: a meta-analysis

Abstract Background HeFH is one of the most frequent monogenic disorders in the world, leading to premature ASCVD. Purpose The aim of this meta-analysis was to evaluate the efficacy and safety of lipid lowering therapy (LLT) and achievement of LDL-C goal in heFH children. Methods The main endpoint was efficacy of goal achievement for LDL-C and other lipid parameters: total cholesterol [TC], triglycerides [TG], high density lipoprotein cholesterol [HDL-C], apolipoprotein B [apo B] and lipoprotein(a) [Lp(a)]), and the LLT safety (adverse events [AEs], including endocrine function, and growth indices). The secondary endpoint was an effect of LLT on attainment of LDL-C goal treatment (<3.5 mmol/L/130 mg/dL). Results A total of 41 studies with 4667 pediatric patients at mean age 12.08±2.4 years were included. At median follow-up of 18.8 months, the group on LLT had significantly higher mean reductions of TC, LDL-C, TG, and increased HDL-C compared to control (-1.75 [-67,7 mg/dl], -1.84 [-71.2 mg/dl], -0.11 [-9.74 mg/dl], 0.08 mmol/L [3.1 mg/dl], respectively, p<0.001 for all). In the subgroup analysis according to different types of LLT we observed a significantly higher mean reduction of LDL-C by statin combined with ezetimibe treatment, followed by PCSK9 inhibitors, statins in monotherapy, and monotherapy with ezetimibe (-2.48 [-95.9 mg/dl], -2.16 [-83.5 mg/dl], -2.03 [-78.5 mg/dl], and -1.50 mmol/L [-58 mg/dl], respectively, test for overall effect: p<0.001). The pooled LDL-C was reduced by 33.44% (-2.14 mmol/L [-82.8 mg/dl], p<0.001) and failed to reach the goal treatment (<3.5 mmol/L) by 12.6% (95%CI, 12.4 – 12.9%). 38.7% of children achieved the LDL-C goal, 23.9% fell short by up to 10%, 10.7% experienced moderate failure (were over the LDL-C target between >10-20%), and 26.7% failed by more than 20% to reach the LDL-C target. When comparing different regions, only Sweden and Greece achieved the LDL-C goal <3.5 mmol/L in the follow-up, followed by the Netherlands, Norway, Poland, USA, UK, France, Spain, Belgium, and Austria (with the following additional required LDL-C reduction to be on the goal: 2.2%, 3.4%, 3.5%, 8.9%, 10.2%, 11.2%, 11.2%, 15%, 19.4%, respectively). For other investigated countries over 20% mean LDL-C reduction was required. All parameters related to endocrine function and demographic indices were unaffected by LLT therapy (p>0.05). The adverse events were not reported significantly higher when compared to the control and the prevalence of therapy discontinuation was only 0.8%. Conclusions Despite the efficacy of LLT in children with HeFH and the low occurrence of discontinuation-related adverse events, achieving LDL-C treatment goals was relatively rare, with large differences between the investigated countries. These results underscore the importance of considering early combination therapy of statins and ezetimibe, and PCSK9 inhibitors (if available) to attain LDL-C goals effectively.Lipoproteins reduction with LLT.Goal achievement and therapy safety.

The meaning of organizational culture and structure for interprofessional collaboration

Abstract In Germany, early neurological rehabilitation (ENR) acts as a link between acute inpatient care and rehabilitation, aiming to restore patients’ ability to rehabilitate amid their complex clinical conditions. Interprofessional cooperation (IPC) is crucial for harmonized treatment due to patients’ vulnerability. An interprofessional team comprising medical, nursing, and various therapy professionals is essential for this purpose. To explore the meaning of organizational culture and structure to IPC, 15 group discussions in 5 clinics were conducted with n = 76 participants. 1. Weekly team meetings are used to coordinate treatment goals and outcomes, but their implementation varies from clinic to clinic. Two types of meetings were identified: those that focus primarily on billing compliance and others that address patients’ long-term perspectives. However, both require additional social service involvement and are not sufficient to adequately address daily tasks, requiring additional IPC coordination. Some clinics have therefore introduced daily meetings to improve the coordination of IPC tasks. 2. Therapy planning and therapist assignment shape IPC and task fulfillment. Three therapy planning methods were observed: centralized, block-based, and flexible, each with different therapist allocation strategies. Centralized planning with flexible allocation leads to appointment pressure and interprofessional communication challenges. Block therapy reduces therapist turnover and promotes better interprofessional coordination in patient care. Flexible therapy planning is conducted through daily interprofessional meetings with shared task allocation and planning leads to a shared understanding. Initial analysis underscores the meaning of organizational structure on interprofessional task fulfillment in ENR, emphasizing the importance of enhancing different cooperation formats which can balance stability and flexibility and integrate social services effectively in patientcare. Key messages • Morning interprofessional meetings on the ward facilitate flexible responses to daily changes in patients’ health conditions and promote interprofessional collaboration. • The consideration of occupational group-specific processes in ward organization is a necessary structural prerequisite for successful interprofessional collaboration.

Micropulse Laser versus Eplerenone for Chronic Central Serous Chorioretinopathy: A 12-Month Comparison.

To compare the long-term efficacy of navigated subthreshold micropulse laser (NSML) and continuous oral eplerenone (EPL) in chronic central serous chorioretinopathy (cCSC). This retrospective observational study included 44 eyes with cCSC (EPL: n = 26; NSML: n = 18). Best-corrected visual acuity (BCVA), central macular thickness (CMT), subretinal fluid (SRF) height, and subfoveal choroidal thickness (SFCT) were evaluated over 12months. Both groups showed significant improvements in BCVA and CMT (p < 0.05). Complete SRF resolution was achieved in both groups by 12months, with NSML showing faster resolution (2.77 ± 1.43 vs. 6.34 ± 2.17months, p < 0.001). The EPL group demonstrated significant SFCT reduction at 6 and 12months (p = 0.001), while the NSML group showed no significant SFCT changes (p > 0.05). Both NSML and EPL improved retinal morphology and visual function in patients with cCSC. NSML achieved faster SRF resolution, while EPL resulted in more significant choroidal thickness reduction. These findings suggest distinct mechanisms of action: NSML primarily affects the retinal pigment epithelium, while EPL modulates choroidal vasculature. Treatment choice may depend on individual patient characteristics and treatment goals.

DETECTING CHANGES IN COMFORT, PAIN, AND MOBILITY OVER CLINICAL MILESTONES FOR INDIVIDUALS WITH LOWER LIMB LOSS

BACKGROUND: Functional mobility, comfort and the absence of pain are key goals of prosthetic treatment. Outcome measures (OMs) evaluate the impact of treatment and normative and minimal detectable change (MDC) values are key to interpreting these scores and measuring treatment outcomes. OBJECTIVES: This study seeks to 1) present practice-based normative values of four commonly used OMs at four prosthetic milestones and 2) explore the MDC of the measures over the treatment period. METHODOLOGY: A chart review was conducted of OMs collected with individuals with lower limb loss between January 1, 2015, and December 31, 2023. This included data for individuals with unilateral transtibial (TT), transfemoral (TF) and rotationplasty (RP) amputations and bilateral transtibial amputation (BTT). OMs included the Socket Comfort Score (SCS), Pain Scale (PS), 2 Minute Walk Test (2MWT), and Prosthetic Limb Users Survey of Mobility (PLUS-M). Data were collected at four milestone time points: (1) Baseline and (2) Discharge from Rehabilitation for those in initial prosthetic rehabilitation, and (3) Initial Evaluation and (4) Definitive Delivery for those receiving a replacement socket. Normative values and MDC values were calculated. FINDINGS: Data from 30 individuals undergoing in-patient rehabilitation and 74 individuals receiving a replacement socket were included. Practice-based normative data were different for each level of amputation and milestone and had the following ranges: SCS: 5.7 – 9.1, PS: 0.8 – 3.7, 2MWT: 68.4 – 146.3 m and PLUS-M: 38.9 – 57.3. MDC values also varied based on time in treatment (Rehabilitation: SCS = 2.5, PS = 1.6, 2MWT = 32.6, PLUS-M = 8.8; Replacement Socket: SCS = 3.1, PS = 2.6, 2MWT = 38.9, PLUS-M = 4.0). All measures had a statistically significant change over the intervention, however, no average scores changed by greater than the MDC. CONCLUSIONS: The normative data and MDC scores demonstrate the PS &amp; PLUS-M are useful measures of pain and mobility at all points within treatment. The 2MWT is indicated for individuals in rehabilitation, while the SCS is indicated for those receiving a replacement socket, as both effectively measure treatment goals that are particularly important for each phase of rehabilitation. This provides clinicians with practice-based evidence that enables them to interpret OM scores, a critical part of the decision-making process along the treatment journey. Layman's Abstract When someone receives a prosthesis, the key goals are to promote mobility and comfort and to reduce pain. Outcome measures are questionnaires or performance-based tests that measure the impact of prosthetic treatment. The scores are interpreted by comparing them to normal values and assessing changes over time against a predetermined threshold for what constitutes a significant amount of change. This study analyzed outcome measure scores collected in clinical practice over a 9-year period, from 2015 - 2023. We included individuals with lower limb loss and presented normal values along with threshold change values taken from a clinical setting for four commonly used measures that assess comfort, pain, and mobility. The data included 30 individuals currently attending initial rehabilitation and 74 individuals who had prior experience using a prosthesis. All the normal values were different for each level of amputation and each milestone within rehabilitation. Suggestions are provided regarding which outcome measures are most useful for assessing changes at different points in time. By providing clinicians with evidence based on clinical practice, we can help them use outcome measures to inform decision-making throughout the rehabilitation journey. Article PDF Link: https://jps.library.utoronto.ca/index.php/cpoj/article/view/43890/33243 How To Cite: Pousett B.M, Harasym C.C, Rapaport M.S, Richardson T, Spellen J, Moe D.W, et al. Detecting changes in comfort, pain, and mobility over clinical milestones for individuals with lower limb loss. Canadian Prosthetics &amp; Orthotics Journal. 2024; Volume 7, Issue 1, No.7. https://doi.org/10.33137/cpoj.v7i1.43890 Corresponding Author: Brittany Mae Pousett, CP(C), MSc.540 SE Marine Dr, Vancouver, BC, Canada, V5X 2T4Tel: 604.321.1115E-Mail: brittany@pousett.caORCID ID: https://orcid.org/0000-0002-2272-7847

The essence of contextual therapy, its place in the field of family therapy, and its role in the future.

This article aims to present the basic tenets of contextual therapy and its treatment goals, methodology, and theory of change. It provides an orientation for readers who are new to the approach and should serve as an updated frame of reference for readers already familiar with it. An important contribution of this article is that it clarifies the place of contextual therapy in the vast field of family therapy and dispels some common misunderstandings about the path of its founder, Ivan Boszormenyi-Nagy (1920-2007). Additionally, it demonstrates why contextual therapy should be counted among the postmodern, collaborative approaches to family therapy, which contradicts the usual view that it belongs to the earlier modern models of family therapy. Furthermore, it shows that contextual therapy is well-equipped to incorporate the current and future contributions of human sciences and offers unique therapeutic resources to address the individual and relational consequences of injustices that should remain relevant for the foreseeable future.

Toward Process-Oriented, Dimensional Approaches for Diagnosis and Treatment of Speech Sound Disorders in Children: Position Statement and Future Perspectives.

Children with speech sound disorders (SSD) form a heterogeneous group, with respect to severity, etiology, proximal causes, speech error characteristics, and response to treatment. Infants develop speech and language in interaction with neurological maturation and general perceptual, motoric, and cognitive skills in a social-emotional context. After a brief introduction into psycholinguistic models of speech production and levels of causation, in this review article, we present an in-depth overview of mechanisms and processes, and the dynamics thereof, which are crucial in typical speech development. These basic mechanisms and processes are: (a) neurophysiological motor refinement, that is, the maturational articulatory mechanisms that drive babbling and the more differentiated production of larger speech patterns; (b) sensorimotor integration, which forms the steering function from phonetics to phonology; and (c) motor hierarchy and articulatory phonology describing the gestural organization of syllables, which underlie fluent speech production. These dynamics have consequences for the diagnosis and further analysis of SSD in children. We argue that current diagnostic classification systems do not do justice to the multilevel, multifactorial, and interactive character of the underlying mechanisms and processes. This is illustrated by a recent Dutch study yielding distinct performance profiles among children with SSD, which allows for a dimensional interpretation of underlying processing deficits. Analyses of mainstream treatments with respect to the treatment goals and the speech mechanisms addressed show that treatment programs are quite transparent in their aims and approach and how they contribute to remediating specific deficits or mechanisms. Recent studies into clinical reasoning reveal that the clinical challenge for speech-language pathologists is how to select the most appropriate treatment at the most appropriate time for each individual child with SSD. We argue that a process-oriented approach has merits as compared to categorical diagnostics as a toolbox to aid in the interpretation of the speech profile in terms of underlying deficits and to connect these to a specific intervention approach and treatment target.

Therapy with transitions from one bone-forming agent to another: a retrospective cohort study on Teriparatide and Romosozumab

Abstract This study aimed to evaluate the effectiveness of sequential therapy with a bone formation-promoting agent (either teriparatide or romosozumab) for osteoporosis treatment following prior treatment with the other bone-forming agent (teriparatide or romosozumab). This is a multicenter retrospective cohort study observing two groups for comparison: one with 69 patients transitioning from teriparatide to romosozumab (the T2R group) and the other with 25 patients transitioning from romosozumab to teriparatide (the R2T group), monitored for 12 months on the second drug. Key outcomes included changes in bone mineral density (BMD), bone turnover marker changes, and adverse events. The mean ages of each group were 72.3 years in the T2R group and 67.6 years in the R2T group, with the proportions of women being 91.3% and 80.0% respectively. The percent changes of BMD in the lumbar spine after 12 months of sequential therapy were + 10.78% in the T2Rgroup (P&amp;lt;.001 versus baseline) and − 0.02% in the R2T group (P=.875). The percent changes in BMD in the total hip and femoral neck were + 4.41% and + 4.41% in the T2R group, and -1.33% and -0.83% in the R2T group, respectively. When comparing the two groups, BMD changes at all sites in the T2R group were significantly higher than those in the R2T group (P&amp;lt;.001). Furthermore, when examining the changes in the proportion of patients who achieved the osteoporosis treatment goal of a T-score exceeding -2.5, no significant increase was observed in the R2T group, whereas a significant increase was observed in the lumbar spine in the T2R group. Regarding therapy switching between bone-forming agents, this study suggests that transitioning from teriparatide to romosozumab increases BMD more effectively than transitioning in the opposite sequence.

Investigating the impact of tocilizumab on serum cytokines concentrations in Japanese FMF patients: a sub-analysis of the NUH01FMF study

Familial Mediterranean Fever (FMF) is the most common hereditary autoinflammatory disease, characterized by recurrent fever, arthritis, rash, and serositis, and is caused by mutations in the MEFV gene coding for the pyrin protein. The primary treatment goal is to prevent acute attacks and minimize subclinical inflammation to avoid secondary amyloidosis with colchicine as the first-line treatment. However, 10-20% of patients are colchicine-resistant or intolerant. While the therapeutic potential of IL-6 inhibitors such as tocilizumab (TCZ) has been suggested, the detailed serum cytokine profiles after TCZ treatment in patients with FMF remain largely unexplored. This study focused on a sub-analysis of a clinical trial evaluating TCZ in patients with colchicine-resistant FMF (crFMF). We analyzed the serum cytokine profiles at 0, 2, 4, 8, 12, 16, 20, and 24 weeks in the TCZ and placebo groups. Our findings revealed a decrease in serum C-X-C motif chemokine ligand 1 and vascular endothelial growth factor levels in the TCZ group at week 4 compared to baseline, which persisted until week 24, indicating the potential of TCZ to manage crFMF by modulating specific inflammatory cytokines. Further research is required to confirm these findings and optimize the treatment strategies for FMF.

International Society for Diseases of the Esophagus consensus on management of the failed fundoplication.

Fundoplication is a durable, effective, and well-accepted treatment for gastroesophageal reflux disease. Nonetheless, troublesome postoperative symptoms do occasionally occur with management varying widely among centers. In an attempt to standardize definition and management of postfundoplication symptoms, a panel of international experts convened by the Guidelines Committee of the International Society for Diseases of the Esophagus devised a list of 33 statements across 5 domains through a Delphi approach, with at least 80% agreement to establish consensus. Eight statements were endorsed for the domain of Definitions, four for the domain of Investigations, nine for Dysphagia, nine for Heartburn, and four for Revisional surgery. This consensus defined as the treatment goal of fundoplication the resolution of symptoms rather than normalization of physiology or anatomy. Required investigations of all symptomatic postfundoplication patients were outlined. Further management was standardized by patients' symptomatology. The appropriateness of revisional fundoplication and the techniques thereof were described and the role of revisional surgery for therapies other than fundoplication were assessed. Fundoplication remains a frequently-performed operation, and this is the first international consensus on the management of various postfundoplication problems.

Metformin Exhibits Anti-Inflammatory Effects by Regulating microRNA-451/CXCL16 and B Cell Leukemia/Lymphoma 2 in Patients With Osteoarthritis.

Osteoarthritis (OA) is the most common cause of chronic disability in joints among older individuals. The primary goal of OA treatment is pain relief to improve the quality of life. Inflammation and aging are involved in the pathogenesis of pain in OA. In this study, we evaluated the ability of metformin to regulate microRNAs, such as miR-451 and miR-15b, and their target proteins, CXCL16 and B cell leukemia/lymphoma 2 (BCL-2), involved in inflammation and apoptosis. In this double-blind placebo-controlled clinical trial, patients were randomly divided into two groups: one receiving metformin and the other receiving a placebo for four months (starting at 0.5 g/day for the first week, increasing to 1 g/day for the second week, and increasing to 1.5 g/day for the remaining period). In addition to evaluating the clinical response using the Knee Injury and Osteoarthritis Outcome Score questionnaire, miR-451 and miR-15b expression levels were detected using real-time polymerase chain reaction. The serum levels of CXCL16 and BCL-2 were evaluated using enzyme-linked immunosorbent assay kits before (time zero) and after treatment (month four). Metformin increased miR-451 expression levels simultaneously with pain reduction, whereas miR-15b expression did not change significantly after four months of treatment. Also, metformin decreased the serum levels of BCL-2 and CXCL16 in patients with OA. The effects of metformin in reducing pain can be attributed to many factors, including its anti-inflammatory and antiaging effects. Our findings suggest that metformin may reduce pain and inflammation in patients with OA through the regulation of miR-451/CXCL16 and BCL-2.

Sociodemographic inequalities in the uptake of prenatal HIV testing in Ethiopia: Systematic review and meta-analysis.

In order to attain the ambitious 95-95-95 UNAIDS goals, HIV testing serves as the pivotal starting point and plays a crucial role in preventing, treating, and managing HIV. Equal access to HIV testing is crucial to stop the spread of the virus. Measuring healthcare disparities is vital for promoting fairness in health services and achieving global goals for HIV prevention and treatment. Ethiopia is actively engaged in efforts to achieve these goals and is dedicated to combating HIV/AIDS. To the best of our knowledge, no previous systematic review or meta-analysis has been conducted on sociodemographic inequalities in prenatal HIV testing in Ethiopia. Hence, this study aims to assess sociodemographic inequalities in prenatal HIV testing in Ethiopia. We conducted an extensive search across various databases, such as PubMed, Scopus, Google Scholar, and Embase, to collect articles and reports. The data we gathered was then exported to R software for further analysis. Our analysis involved performing a meta-analysis of proportions using a random effect model. To assess the variability among the included studies, we used statistical measures such as I2 statistics and the Cochran's Q test. The results of the pooled prenatal HIV testing, along with its corresponding 95% confidence interval, were presented using a forest plot. A comprehensive analysis of 20 research papers on prenatal HIV testing in Ethiopia revealed that the overall pooled prevalence of testing was 69% (95% CI [60.0-80.0]). Factors such as higher education, urban residence, income, a positive attitude towards testing, marriage, and discussions about testing during antenatal care (ANC) were found to positively influence testing rates. The prevalence of prenatal HIV testing among antenatal care attendees in Ethiopia falls short of the UNAIDS target. In order to enhance the testing rates, it is advised to implement targeted initiatives within Ethiopia's public health programs. To ensure effectiveness, these initiatives should adopt a sustainable and customized approach that takes into account the specific needs and circumstances of women, particularly those who are economically disadvantaged. Ethiopia can make significant strides in enhancing the prenatal HIV testing landscape by effectively implementing policies and programs that prioritize the welfare of the less privileged. As limitation this systematic review did not include longitudinal and qualitative studies that might have provided different results. Trial registration in PROSPERO with ID: CRD42024550564.

Comparative Analysis of Inflammatory Bowel Disease Management: Hospital-based Versus Community-based Care.

Inflammatory bowel disease (IBD) encompasses chronic gastrointestinal disorders characterized by recurrent inflammation. Achieving mucosal healing and preventing disease progression are primary treatment goals. This study aimed to compare disease characteristics, medication utilization, procedures performed, and hospitalizations between IBD patients treated in hospital and community settings using the Leumit Health Service database. A retrospective cohort study was conducted using data from the Leumit Health Service, comprising 3020 patients diagnosed with IBD from January 2010 to December 2019. Patients were divided based on primary care setting: hospital-based or community-based. Data included demographic characteristics, disease type, medication usage, procedures, and outcomes. Statistical analyses assessed differences between groups. Hospital-treated patients were significantly younger (49.4±18.4 vs. 40.4±18.7, P<0.001 ), had higher rates of Crohn's disease (45.9% vs. 71.4%, P<0.001), exhibited higher inflammatory markers (calprotectin 768±2182 vs. 1305±2526, P<0.001), lower albumin (4.23±0.27 vs. 4.12±0.32, P<0.001), hemoglobin levels (13.4±1.6 vs. 12.9±1.6, P<0.001), and lower BMI (26.2±5.3 vs. 24.6±5.6, P<0.001) compared with community-treated patients. Hospital-treated patients had more endoscopic procedures, higher medication utilization rates, shorter treatment durations, and increased hospitalization occurrence (12.1% vs. 23.6%, P<0.001), length (0.67±3.34 vs. 1.45±5.88, P<0.001), and colectomies (4.73% vs. 15.8%, P<0.001). Disparities exist in IBD management between hospital and community settings, influenced by disease severity and treatment approaches. Hospital-based care is associated with more aggressive disease and intensive interventions, while community-based care may reflect milder disease and conservative management. Integrating specialized care models and personalized approaches across settings can optimize patient outcomes and health care delivery for IBD management. Further research is needed to understand these disparities' underlying mechanisms and develop comprehensive care strategies.

Clinical reality and challenges with familial hypercholesterolemia patients' management. 2024 results from the Regional Center for Rare Diseases (RCRD) Registry in Poland

BackgroundDespite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients. MethodsThe registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5). ResultsWe studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27–57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8–13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107–184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32–86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5–145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors. ConclusionsIn Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets – even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101.