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Background Lower low-density lipoprotein cholesterol (LDL-C) is significantly associated with improved prognosis in patients with coronary artery disease (CAD). However, LDL-C reduction does not decrease all-cause mortality among CAD patients when renal function impairs. The association between low baseline LDL-C (< 1.8 mmol/L) and mortality is unknown among patients with CAD and advanced kidney disease (AKD). The current study aimed to evaluate prognostic value of low baseline LDL-C level for all-cause death in these patients. Methods In this observational study, 803 CAD patients complicated with AKD (eGFR < 30 mL/min/1.73 m 2 ) were enrolled between January 2008 to December 2018. Patients were divided into two groups (LDL-C < 1.8 mmol/L, n  = 138; LDL-C ≥ 1.8 mmol/L, n  = 665). We used Kaplan-Meier methods and Cox regression analyses to assess the association between baseline low LDL-C levels and long-term all-cause mortality. Results Among 803 participants (mean age 67.4 years; 68.5% male), there were 315 incidents of all-cause death during a median follow-up of 2.7 years. Kaplan–Meier analysis showed that low LDL-C levels were associated with worse prognosis. After adjusting for full 24 confounders (e.g., age, diabetes, heart failure, and dialysis, etc.), multivariate Cox regression analysis revealed that lower LDL-C level (< 1.8 mmol/L) was significantly associated with higher risk of all-cause death (adjusted HR, 1.38; 95% CI, 1.01–1.89). Conclusions Our data demonstrated that among patients with CAD and AKD, a lower baseline LDL-C level (< 1.8 mmol/L) did not present a higher survival rate but was related to a worse prognosis, suggesting a cautiousness of too low LDL-C levels among patients with CAD and AKD.

BackgroundLiver disease progression after Hepatitis C Virus (HCV) eradication following direct-acting antiviral (DAA) treatment in the real-life setting according to Human Immunodeficiency Virus (HIV) coinfection was evaluated.MethodsPatients consecutively enrolled in PITER between April 2014 and June 2019 and with at least 12-weeks follow-up following treatment were analysed. Cox regression analysis were used to evaluate HIV coinfection and factors independently associated with liver disease outcomes following viral eradication in DAA treated patients with pre-treatment liver cirrhosis.Results93 HIV/HCV coinfected and 1109 HCV monoinfected patients were evaluated during a median follow-up of 26.7 (range 6–44.6) and 24.6 (range 6.8–47.3) months, respectively. No difference in the cumulative HCC incidence and hepatic decompensation was observed between coinfected and monoinfected patients. Age (Hazard Ratio [HR] = 1.08; 95% CI 1.04–1.13), male sex (HR = 2.76; 95% CI 1.28–5.96), lower albumin levels (HR = 3.94; 95% CI 1.81–8.58), genotype 3 (HR = 5.05; 95% CI 1.75–14.57) and serum anti-HBc positivity (HR = 1.99, 95% CI 1.01–3.95) were independently associated with HCC incidence. Older age (HR = 1.03; 95% CI 1.00–1.07), male sex (HR = 2.13; 95% CI 1.06–4.26) and lower albumin levels (HR = 3.75; 95% CI 1.89–7.46) were independently associated with the appearance of a decompensating event after viral eradication.ConclusionDifferent demographic, clinical and genotype distribution between HIV coinfected vs those monoinfected, was observed in a representative cohort of HCV infected patients in Italy. Once liver cirrhosis is established the disease progression is decreased, but still persists regardless of viral eradication in both coinfected and monoinfected patients. In patients with cirrhosis, HIV coinfection was not associated with a higher probability of liver complications, after viral eradication.

Background The advanced disease management (ADM) package, which aims to reduce morbidity and mortality in people with Advanced HIV disease (AHD, WHO stage III/IV and/or CD4 count < 200 cells/mm 3 or age < 5 years), is not fully implemented in India. We assessed the feasibility of implementing the full WHO ADM package as part of routine HIV care under the programmatic setting in antiretroviral therapy centers of Mumbai. Methods We implemented the ADM package (screening, treatment, and prophylaxis for major opportunistic infections, rapid ART initiation, and ART adherence support) in 17 ART centers from October 2020 to December 2021. Treatment naïve and experienced persons with AHD, including children, were enrolled. We assessed the feasibility through coverage of ADM package components and reported the proportion of rapid ART initiation (≤ 7 days), cotrimoxazole prophylaxis, TB preventive treatment (TPT) for those eligible [(excluded active TB disease ( n  = 280) and those completed TPT prior to enrolment ( n  = 1,186)], TB-LAM screening (excluded current TB disease), and cryptococcal antigen (CrAg) assay (excluded children < 10 years of age). We used a point of care test for TB (LAM) and cryptococcus (CrAg) screening. We followed the prospective cohort for one year (through 31 July 2022) to document outcomes for survival and lost to follow- up (LTFU). Results We identified 4,334 PLHIV with AHD and provided the full ADM package to 64% (2,779/4,334); 297 did not receive ADM (146 died, 151 LTFU), and 1,258 received routine standard of care (587 had TB, 366 were at decentralized sites, and 305 LAM/CrAg kits were not available) with existing ART center staff. Nearly 78% (385/494) of treatment naïve were rapidly initiated on ART. Nearly 82% (1,129/1,383) and 99% (2,751/2,779) received TPT and cotrimoxazole prophylaxis, respectively. Of the eligible, 99% (2,508/2,524) and 98% (2,715/2,758) were screened for TB and cryptococcal infection, respectively. At the end of 12 months, 88% (2,458/2,779) were alive, 8% (210/2,779) died, and 4% (111/2,779) were LTFU. Mean survival time was significantly ( p  < 0.001) higher among treatment experienced people; 11.6 months (95% CI: 11.5,11.7) compared to treatment naïve people 10.8 months (95% CI: 10.5,11.0). Conclusion With careful anticipatory planning, stakeholder engagement, and training, implementing the full ADM package is feasible in a routine program setting with existing human resources. Additional intensive case management may be necessary for the reduction of mortality among treatment naïve PLHIV.

Background There are currently no standard diagnostic criteria for characterizing advanced Parkinson’s disease (APD) in clinical practice, a critical component in determining ongoing clinical care and therapeutic strategies, including transitioning to device-aided treatment. The goal of this analysis was to determine the proportion of APD vs. non-advanced PD (non-APD) patients attending specialist PD clinics and to demonstrate the clinical burden of APD. Methods OBSERVE-PD, a cross-sectional, international, observational study, was conducted with 2615 PD patients at 128 movement disorder centers in 18 countries. Motor and non-motor symptoms, activities of daily living, and quality-of-life end points were assessed. The correlation between physician’s global assessment of advanced PD and the advanced PD criteria from a consensus of an international group of experts (Delphi criteria for APD) were evaluated. Results According to physician’s judgment, 51% of patients were considered to have APD. There was a moderate correlation between physician’s judgment and Delphi criteria for APD (K = 0.430; 95% CI 0.406–0.473). Activities of daily living, motor symptom severity, dyskinesia duration/disability, “Off” time duration, non-motor symptoms, and quality-of-life scores were worse among APD vs. non-APD patients ( p  < 0.0001 for all). APD patients (assessed by physicians) had higher disease burden by motor and non-motor symptoms compared with non-APD patients and a negative impact on activities of daily living and quality of life. Conclusions These findings aid in identifying standard APD classification parameters for use in practicing physicians. Improvements in identification of APD patients may be particularly relevant for optimizing treatment strategies including transitioning to device-aided treatment.

Advanced stage of Parkinson’s disease (APD) diagnosis is challenging for general neurologists. The 5–2–1 Criteria and the Cuestionario De Enfermedad de Parkinson Avanzada (CDEPA) have been validated for screening for APD. This article reports the period-prevalence of APD defined by a movement disorder expert, the 5–2–1 Criteria, and CDEPA and to improve the screening performance of the 5–2–1 Criteria A cross-sectional retrospective study at the Parkinson’s disease (PD) clinic of a tertiary hospital in Bangkok, Thailand amongst all PD patients aged ≥ 18 years was performed from January 2016 to January 2020. We compared the characteristics of APD and non-APD patients. We externally validated the 5–2–1 Criteria and CDEPA. We explored improving the 5–2–1 Criteria. Of 480 PD patients with complete data, the period-prevalence of APD by the movement disorder expert, the 5–2–1 Criteria and CDEPA were 37.1 %, 48.5 %, and 27.5 %, respectively. Adding requiring help with an activity of daily living and freezing of gait to the original 5–2–1 Criteria enhanced the sensitivity from 86.5 % (95 %CI 80.6, 91.2) to 94.9 % (95 %CI 90.6, 97.7) and negative predictive value (NPV) from 90.3 % (95 %CI 85.9, 93.7) to 96 % (95 %CI 92.6, 98.2). However, the CDEPA had a sensitivity of 62.9 % (95 %CI 55.4, 70) and NPV of 81.0 (95 %CI 76.5, 85). The 5–2–1 Criteria had a good screening tool performance for general neurologists to refer APD patients for optimal treatments. The modified 5–2–1 Criteria had better performance than the original one. External validation is needed. •Prevalence of advanced Parkinson’s disease is 37.1 % in Thai single tertiary center.•5–2–1 criteria is highly accurate screening tool for advanced Parkinson’s disease.•Modified 5–2–1 criteria has better screening performance than original criteria.

Parkinson's disease (PD) is the second most common progressive neurodegenerative disease. In the advanced stages, the continuous delivery of levodopa (LD) as levodopa-carbidopa intestinal gel (LCIG) has demonstrated significant improvement of motor and nonmotor complications and improvement of the patients' quality of life (QoL). Despite the growing global experience with this treatment, anumber of unsolved practical issues remain, and currently, the data on the reasons that can lead to the discontinuation of LCIG are scarce. In the present study, we aimed to analyze the causes that led to the discontinuation of LCIG therapy. In this retrospective study, after 10 years of experience with LCIG as a therapeutic option in advanced PD, we analyzed the data of all dropout cases among the 204 patients that initiated LCIG therapy in two Romanian centers. Of the 204 patients enrolled, 43 patients dropped out. Disease duration until LCIG infusion was significantly longer (11.67±4.98 vs 9.44±3.44) and the overall clinical picture more sever (both regarding motor symptoms and cognitive decline) in dropout patients (compared to patients who continued treatment). The dropout patients also presented significant differences regarding the incidence of polyneuropathy (32.5% vs 11.18%). The main cause of discontinuation was death. The causes of discontinuation from LCIG therapy in Romanian patients are similar to those from other centers; however, the rate of dropouts is somewhat lower. The clinician's experience in selecting and treating the patients in advanced stages of PD can increase therapeutic adherence. Also, the presence of a well-trained caregiver along with the availability of a proper aftercare system is mandatory for maintaining the long-term benefits of the therapy and the overall best outcome possible. Targeted prospective studies are needed to confirm whether a more severe stage of the disease and cognitive impairment at the time of initiation, respectively, the association of polyneuropathy can be considered as predictive factors for dropout.

Motor complications related to the chronic administration of levodopa and failure to prevent the neurodegenerative disease process counterbalance the pivotal discovery of levodopa as the cornerstone of PD treatment. Excellent motor control is offered early during the course of treatment, but this diminishes as pathological changes in the striatum lead to synaptic dopamine levels becoming completely dependent on exogenous dopamine. This non-physiologic stimulation of dopamine receptors eventually manifests as OFF episodes. As no disease modifying therapy exists for PD that can disrupt these pathological changes, most research and treatment focuses on optimization of dopaminergic stimulation of striatal receptors so that they mimic tonic, physiologic stimulation as closely as possible. Strategies focusing on these challenges have included non-pharmacologic approaches, optimizing levodopa pharmacokinetics, using adjunctive treatments including those with non-dopaminergic mechanisms, and implementing rescue therapies. Device aided therapies, including surgery, are also available. In this review, we will focus on effective management of motor symptoms related to OFF periods, including emerging strategies. Unmet clinical needs will be discussed, including non-motor symptoms, targeted molecular therapies and disease modifying therapy.

There is insufficient data in the literature regarding the real-life, daily clinical practice evaluation of patients with advanced Parkinson's disease (APD). We are not sure what is the upper limit of dopaminergic medication, especially the levodopa (LD) dosage, and how it is influenced by access and suitability to the various add-on and device-aided therapies (DAT). This retrospective study explored the profile of APD patients that were considered and systematically evaluated regarding the suitability for DAT. We analyzed the data from 311 consecutive patients with APD hospitalized between 2011 and 2017 that 1) described at least 2 hrs/day off periods divided into at least two instances/day (except early morning akinesia), 2) were in stage 3 or above on the Hoehn and Yahr scale, 3) were with or without dyskinesia, and 4) received at least four levodopa doses/day combined with adjuvant therapy. Of the 311 patients enrolled initially, 286 patients showed up for the second visit, of which in 125 cases we assessed that DAT would be necessary. Finally, 107 patients were tested in our clinic to confirm the efficacy of LCIG. Patients selected for DAT had significantly longer off periods, more frequent dyskinesia, early morning akinesia, and freezing despite having significantly higher LD doses than those with an improved conservative therapy. Patients with APD can have a variety of symptoms, and because symptoms and therapeutical efficacy can be manifested in many different combinations, it is not possible to decide using a single, rigid set of criteria which APD patient is eligible for DAT. Nevertheless, treating physicians should refer APD patients to a specialized movement disorder center when patients with an average daily dose of LD of at least 750-1000 mg and maximal complementary therapies present daily motor complications that significantly reduce the quality of life.

•15 years after start, the STN-DBS system was still active in 8/9 survivors.•The STN-DBS system was eventually inactivated in 4/23 patients operated 1993–2001.•Axial motor and non-motor functions deteriorated severely over time, despite STN-DBS.•After 37 years with PD and 15 with STN-DBS, one patient could still live at home. Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for motor fluctuations in Parkinson's disease (PD), but does not halt disease progression. The long-term deterioration of key functions such as cognition, speech, ability to swallow, gait, urinary bladder control, orientation and reality perception is decisive for patients’ independency in daily life. In this paper we investigated patients with advanced PD operated at our center with STN-DBS for at least 15 years ago, in respect to key clinical milestones reflecting their overall function in daily living. Retrospective analysis of clinical data concerning key clinical milestones including death in PD-patients, 15 years or more after they underwent STN-DBS surgery. All PD-patients implanted with STN-DBS at Sahlgrenska Hospital before January 1, 2001, were regularly assessed until death, drop-out, or January 11, 2016. Sixteen men and seven women with a median (range) disease duration of 18 (10–28) years were operated with STN-DBS. The median (range) follow-up time post-surgery was 12 (2–18) years and 692 person-years of disease duration were observed. In January 2016, nine PD-patients (39%) were still alive (eight with active STN-DBS). Initially, motor symptoms improved in all patients. Sustained benefit (implying active stimulation at the last follow up) was maintained in 19 of them (83%) but STN-DBS was inactivated in four (17%) due to inefficacy. Over time, all patients deteriorated slowly, and a majority developed severe non-motor and axial symptoms such as dementia, inability to talk, swallow and walk, urinary incontinence, psychosis, and need for nursing home care. At the last follow up, 16/23 (70%) patients were treated with antidepressants. A majority of PD-patients experience sustained motor benefit with continuous STN-DBS. However, over time, non-motor and axial symptoms slowly and severely restrict PD-patients’ function in their daily living.

Background Breathlessness is the most common and intrusive symptom of advanced non-malignant respiratory and cardiac conditions. The Breathlessness Intervention Service (BIS) is a multi-disciplinary complex intervention, theoretically underpinned by a palliative care approach, utilising evidence-based non-pharmacological and pharmacological interventions to support patients with advanced disease in managing their breathlessness. Having published the effectiveness and cost effectiveness of BIS for patients with advanced cancer and their carers, we sought to establish its effectiveness, and cost effectiveness, in advanced non-malignant conditions. Methods This was a single-centre Phase III fast-track single-blind mixed method RCT of BIS versus standard care for breathless patients with non-malignant conditions and their carers. Randomisation was to one of two groups (randomly permuted blocks). Eighty-seven patients referred to BIS were randomised (intervention arm n = 44; control arm n = 43 received BIS after four-week wait); 79 (91 %) completed to key outcome measurement. The primary outcome measure was 0–10 numeric rating scale for patient distress due to breathlessness at four weeks. Secondary outcome measures were Chronic Respiratory Questionnaire, Hospital Anxiety and Depression Scale, Client Service Receipt Inventory, EQ-5D and topic-guided interviews. Results Qualitative analyses showed the positive impact of BIS on patients with non-malignant conditions and their carers; quantitative analyses showed a non-significant greater reduction in the primary outcome (‘distress due to breathlessness’), when compared to standard care, of –0.24 (95 % CI: –1.30, 0.82). BIS resulted in extra mean costs of £799, reducing to £100 when outliers were excluded; neither difference was statistically significant. The quantitative findings contrasted with those previously reported for patients with cancer and their carers, which showed BIS to be both clinically and cost effective. For patients with non-malignant conditions there was a notable trend of improvement over both trial arms to the key measurement point; participants may have experienced a therapeutic effect from the research interviews, diluting the intervention’s impact. Conclusions BIS had a statistically non-significant effect for patients with non-malignant conditions, and slightly increased service costs, but had a qualitatively positive impact consistent with findings for advanced cancer. Trials of palliative care interventions should consider multiple, mixed method, primary outcomes and ensure that protocols limit potential contaminating therapeutic effects in study designs. Trial registration Current Controlled Trials ISRCTN04119516 (December 2008); ClinicalTrials.gov NCT00678405 (May 2008)