Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: Results from the Ontario Neurodegenerative Disease Research Initiative.

INTRODUCTION: We investigated whether novel plasma biomarkers are associated with cognition, cognitive decline, and functional independence in activities of daily living across and within neurodegenerative diseases. METHODS: Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), phosphorylated tau (p-tau)181 and amyloid beta (Aß)42/40 were measured using ultra-sensitive Simoa immunoassays in 44 healthy controls and 480 participants diagnosed with Alzheimer's disease/mild cognitive impairment (AD/MCI), Parkinson's disease (PD), frontotemporal dementia (FTD) spectrum disorders, or cerebrovascular disease (CVD). RESULTS: GFAP, NfL, and/or p-tau181 were elevated among all diseases compared to controls, and were broadly associated with worse baseline cognitive performance, greater cognitive decline, and/or lower functional independence. While GFAP, NfL, and p-tau181 were highly predictive across diseases, p-tau181 was more specific to the AD/MCI cohort. Sparse associations were found in the FTD and CVD cohorts and for Aß42/40 . DISCUSSION: GFAP, NfL, and p-tau181 are valuable predictors of cognition and function across common neurodegenerative diseases, and may be useful in specialized clinics and clinical trials.

Characteristics of the Ontario Neurodegenerative Disease Research Initiative cohort.

INTRODUCTION: Understanding synergies between neurodegenerative and cerebrovascular pathologies that modify dementia presentation represents an important knowledge gap. METHODS: This multi-site, longitudinal, observational cohort study recruited participants across prevalent neurodegenerative diseases and cerebrovascular disease and assessed participants comprehensively across modalities. We describe univariate and multivariate baseline features of the cohort and summarize recruitment, data collection, and curation processes. RESULTS: We enrolled 520 participants across five neurodegenerative and cerebrovascular diseases. Median age was 69 years, median Montreal Cognitive Assessment score was 25, median independence in activities of daily living was 100% for basic and 93% for instrumental activities. Spousal study partners predominated; participants were often male, White, and more educated. Milder disease stages predominated, yet cohorts reflect clinical presentation. DISCUSSION: Data will be shared with the global scientific community. Within-disease and disease-agnostic approaches are expected to identify markers of severity, progression, and therapy targets. Sampling characteristics also provide guidance for future study design.

Integrated Care in Parkinson's Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Quality of life in Parkinson's disease (PD) is affected by motor and nonmotor symptoms, necessitating an integrated care approach. Existing care models vary considerably in numerous domains. The objectives of this study were to perform a systematic review and meta-analysis of PD integrated care models and develop recommendations for a representative model. METHODS: We conducted a systematic review of published integrated care models and a meta-analysis of randomized, controlled trials examining integrated care versus standard care. The primary outcome was health-related quality of life using a validated PD scale. We evaluated levels of care integration using the Rainbow Model of Integrated Care. RESULTS: Forty-eight publications were identified, including 8 randomized, controlled trials with health-related quality of life data (n = 1,149 total PD patients). Qualitative evaluation of individual care model integration guided by the Rainbow Model of Integrated Care revealed frequent clinical and professional integration, but infrequent organizational and population-based integration elements. Meta-analysis of randomized, controlled trials revealed significant heterogeneity (I2 = 90%, P < 0.0001). Subgroup analysis including only outpatient care models (n = 5) indicated homogeneity of effects (I2 = 0%, P = 0.52) and improved health-related quality of life favoring integrated care, with a small effect size (standardized mean difference [SMD], -0.17; 95% CI, -0.31 to -0.03; P = 0.02). CONCLUSIONS: Outpatient integrated PD care models may improve patient-reported health-related quality of life compared with standard care; however, because of variable methodological approaches and a high risk of bias related to inherent difficulties in study design (eg, blinding of participants and interventionists), generalizability of these results are difficult to establish. The Rainbow Model of Integrated Care is a promising method of evaluating elements and levels of integration from individual patient care to population health in a PD context. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC. on behalf of International Parkinson and Movement Disorder Society.

Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus.

BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In April 2014, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. The initial search also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. No new trials were eligible in 2014. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome. Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta-analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36). Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38). Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73). Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17ß-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI -0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods. We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal).

The Ontario Neurodegenerative Disease Research Initiative (ONDRI).

Because individuals develop dementia as a manifestation of neurodegenerative or neurovascular disorder, there is a need to develop reliable approaches to their identification. We are undertaking an observational study (Ontario Neurodegenerative Disease Research Initiative [ONDRI]) that includes genomics, neuroimaging, and assessments of cognition as well as language, speech, gait, retinal imaging, and eye tracking. Disorders studied include Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson's disease, and vascular cognitive impairment. Data from ONDRI will be collected into the Brain-CODE database to facilitate correlative analysis. ONDRI will provide a repertoire of endophenotyped individuals that will be a unique, publicly available resource.

Mutations in the glucocerebrosidase gene are common in patients with Parkinson's disease from Eastern Canada.

BACKGROUND: Mutations in the ß-glucocerebrosidase gene (GBA) have been implicated as a risk factor for Parkinson's disease (PD). However, GBA mutations in PD patients of different ethnic origins were reported to be inconsistent. METHODS: We sequenced all exons of the GBA gene in 225 PD patients and 110 control individuals from Eastern Canada. RESULT: Two novel GBA variants of c.-119 A/G and S(-35)N, five known GBA mutations of R120W, N370S, L444P, RecNciI and RecTL mutation (del55/D409H/RecNciI) as well as two non-pathological variants of E326K and T369M were identified from PD patients while only one mutation of S13L and two non-pathological variants of E326K and T369M were found in the control individuals. The frequency of GBA mutations within PD patients (4.4%) is 4.8 times higher than the 0.91% observed in control individuals (X(2) = 2.91, p = 0.088; odds ratio = 4.835; 95% confidence interval = 2.524-9.123). The most common mutations of N370S and L444P accounted for 36.0% (9/25) of all the GBA mutations in this Eastern Canadian PD cohort. The frequency (6.67%) of E326K and T369M in PD patients is comparable to 7.27% in control individuals (X(2) = 0.042, p = 0.8376), further supporting that these two variants have no pathological effects on PD. Phenotype analysis showed that no significant difference in family history, age at onset and cognitive impairment was identified between the GBA mutation carriers and non-GBA mutation carriers. CONCLUSION: GBA mutations were found to be a common genetic risk factor for PD in Eastern Canadian patients.

VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families.

Our group previously described and mapped to chromosomal region 12p13 a form of dominantly inherited hereditary spastic ataxia (HSA) in three large Newfoundland (Canada) families. This report identifies vesicle-associated membrane protein 1 (VAMP1), which encodes a critical protein for synaptic exocytosis, as the responsible gene. In total, 50 affected individuals from these families and three independent probands from Ontario (Canada) share the disease phenotype together with a disruptive VAMP1 mutation that affects a critical donor site for the splicing of VAMP1 isoforms. This mutation leads to the loss of the only VAMP1 isoform (VAMP1A) expressed in the nervous system, thus highlighting an association between the well-studied VAMP1 and a neurological disorder. Given the variable phenotype seen in the affected individuals examined here, we believe that VAMP1 should be tested for mutations in patients with either ataxia or spastic paraplegia.

Steroidal contraceptives: effect on carbohydrate metabolism in women without diabetes mellitus.

BACKGROUND: Many hormonal contraceptives have been associated with changes in carbohydrate metabolism. Alterations may include decreased glucose tolerance and increased insulin resistance, which are risk factors for Type 2 diabetes mellitus and cardiovascular disease. These issues have been raised primarily with contraceptives containing estrogen. OBJECTIVES: To evaluate the effect of hormonal contraceptives on carbohydrate metabolism in healthy women and those at risk for diabetes due to overweight. SEARCH METHODS: In April 2014, we searched the computerized databases MEDLINE, POPLINE, CENTRAL, and LILACS for studies of hormonal contraceptives and carbohydrate metabolism. We also searched for clinical trials in ClinicalTrials.gov and ICTRP. The initial search also included EMBASE. SELECTION CRITERIA: All randomized controlled trials were considered if they examined carbohydrate metabolism in women without diabetes who used hormonal contraceptives for contraception. Comparisons could be a placebo, a non-hormonal contraceptive, or another hormonal contraceptive that differed in drug, dosage, or regimen. Interventions included at least three cycles. Outcomes included glucose and insulin measures. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified during the literature searches. The data were extracted and entered into RevMan. We wrote to researchers for missing data. For continuous variables, the mean difference (MD) was computed with 95% confidence interval (CI) using a fixed-effect model. For dichotomous outcomes, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 31 trials that met the inclusion criteria. No new trials were eligible in 2014. Twenty-one trials compared combined oral contraceptives (COCs); others examined different COC regimens, progestin-only pills, injectables, a vaginal ring, and implants. None included a placebo. Of 34 comparisons, eight had any notable difference between the study groups in an outcome.Twelve trials studied desogestrel-containing COCs, and the few differences from levonorgestrel COCs were inconsistent. A meta-analysis of two studies showed the desogestrel group had a higher mean fasting glucose (MD 0.20; 95% CI 0.00 to 0.41). Where data could not be combined, single studies showed lower mean fasting glucose (MD -0.40; 95% CI -0.72 to -0.08) and higher means for two-hour glucose response (MD 1.08; 95% CI 0.45 to 1.71) and insulin area under the curve (AUC) (MD 20.30; 95% CI 4.24 to 36.36).Three trials examined the etonogestrel vaginal ring and one examined an etonogestrel implant. One trial showed the ring group had lower mean AUC insulin than the levonorgestrel-COC group (MD -204.51; 95% CI -389.64 to -19.38).Of eight trials of norethisterone preparations, five compared COCs and three compared injectables. In a COC trial, a norethisterone group had smaller mean change in glucose two-hour response than a levonorgestrel-COC group (MD -0.30; 95% CI -0.54 to -0.06). In an injectable study, a group using depot medroxyprogesterone acetate had higher means than the group using norethisterone enanthate for fasting glucose (MD 10.05; 95% CI 3.16 to 16.94), glucose two-hour response (MD 17.00; 95% CI 5.67 to 28.33), and fasting insulin (MD 3.40; 95% CI 2.07 to 4.73).Among five recent trials, two examined newer COCs with different estrogen types. One showed the group with nomegestrel acetate plus 17ß-estradiol had lower means than the levonorgestrel group for incremental AUC glucose (MD -1.43; 95% CI -2.55 to -0.31) and glycosylated hemoglobin (HbA1c) (MD -0.10; 95% CI -0.18 to -0.02). Two trials compared extended versus conventional (cyclic) regimens. With a dienogest COC, an extended-use group had greater mean change in AUC glucose (MD 82.00; 95% CI 10.72 to 153.28). In a small trial using two levonorgestrel COCs, the lower-dose group showed smaller mean change in fasting glucose (MD -3.00; 95% CI -5.89 to -0.11), but the obese and normal weight women did not differ significantly. AUTHORS' CONCLUSIONS: Current evidence suggests no major differences in carbohydrate metabolism between different hormonal contraceptives in women without diabetes. We cannot make strong statements due to having few studies that compared the same types of contraceptives. Many trials had small numbers of participants and some had large losses. Many of the earlier studies had limited reporting of methods.We still know very little about women at risk for metabolic problems due to being overweight. More than half of the trials had weight restrictions as inclusion criteria. Only one small trial stratified the groups by body mass index (obese versus normal).

Oral contraceptives for functional ovarian cysts.

BACKGROUND: Functional ovarian cysts are a common gynecological problem among women of reproductive age worldwide. When large, persistent, or painful, these cysts may require operations, sometimes resulting in removal of the ovary. Since early oral contraceptives were associated with a reduced incidence of functional ovarian cysts, many clinicians inferred that birth control pills could be used to treat cysts as well. This became a common clinical practice in the early 1970s. OBJECTIVES: This review examined all randomized controlled trials that studied oral contraceptives as therapy for functional ovarian cysts. SEARCH METHODS: In March 2014, we searched the databases of CENTRAL, PubMed, EMBASE, and POPLINE, as well as clinical trials databases (ClinicalTrials.gov and ICTRP). We also examined the reference lists of articles. For the initial review, we wrote to authors of identified trials to seek articles we had missed. SELECTION CRITERIA: We included randomized controlled trials in any language that included oral contraceptives used for treatment and not prevention of functional ovarian cysts. Criteria for diagnosis of cysts were those used by authors of trials. DATA COLLECTION AND ANALYSIS: Two authors independently abstracted data from the articles. One entered the data into RevMan and a second verified accuracy of data entry. For dichotomous outcomes, we computed the Mantel-Haenszel odds ratio with 95% confidence interval (CI). For continuous outcomes, we calculated the mean difference with 95% CI. MAIN RESULTS: We identified eight randomized controlled trials from four countries; the studies included a total of 686 women. Treatment with combined oral contraceptives did not hasten resolution of functional ovarian cysts in any trial. This held true for cysts that occurred spontaneously as well as those that developed after ovulation induction. Most cysts resolved without treatment within a few cycles; persistent cysts tended to be pathological (e.g., endometrioma or para-ovarian cyst) and not physiological. AUTHORS' CONCLUSIONS: Although widely used for treating functional ovarian cysts, combined oral contraceptives appear to be of no benefit. Watchful waiting for two or three cycles is appropriate. Should cysts persist, surgical management is often indicated.

Combination contraceptives: effects on weight.

BACKGROUND: Weight gain is often considered a side effect of combination hormonal contraceptives, and many women and clinicians believe that an association exists. Concern about weight gain can limit the use of this highly effective method of contraception by deterring the initiation of its use and causing early discontinuation among users. However, a causal relationship between combination contraceptives and weight gain has not been established. OBJECTIVES: The aim of the review was to evaluate the potential association between combination contraceptive use and changes in weight. SEARCH METHODS: In November 2013, we searched the computerized databases CENTRAL (The Cochrane Library), MEDLINE, POPLINE, EMBASE, and LILACS for studies of combination contraceptives, as well as ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP). For the initial review, we also wrote to known investigators and manufacturers to request information about other published or unpublished trials not discovered in our search. SELECTION CRITERIA: All English-language, randomized controlled trials were eligible if they had at least three treatment cycles and compared a combination contraceptive to a placebo or to a combination contraceptive that differed in drug, dosage, regimen, or study length. DATA COLLECTION AND ANALYSIS: All titles and abstracts located in the literature searches were assessed. Data were entered and analyzed with RevMan. A second author verified the data entered. For continuous data, we calculated the mean difference and 95% confidence interval (CI) for the mean change in weight between baseline and post-treatment measurements using a fixed-effect model. For categorical data, such as the proportion of women who gained or lost more than a specified amount of weight, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 49 trials that met our inclusion criteria. The trials included 85 weight change comparisons for 52 distinct contraceptive pairs (or placebos). The four trials with a placebo or no intervention group did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight change. Most comparisons of different combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight change did not differ between groups where this was studied. AUTHORS' CONCLUSIONS: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. Trials to evaluate the link between combination contraceptives and weight change require a placebo or non-hormonal group to control for other factors, including changes in weight over time.

Steroidal contraceptives: effect on bone fractures in women.

BACKGROUND: Steroidal contraceptive use has been associated with changes in bone mineral density in women. Whether such changes increase the risk of fractures later in life is not clear. Osteoporosis is a major public health concern. Age-related decline in bone mass increases the risk of fracture, especially of the spine, hip, and wrist. Concern about bone health influences the recommendation and use of these effective contraceptives globally. OBJECTIVES: Our aim was to evaluate the effect of using hormonal contraceptives before menopause on the risk of fracture in women. SEARCH METHODS: Through April 2014, we searched for studies of fracture or bone health and hormonal contraceptives in MEDLINE, POPLINE, CENTRAL, EMBASE, and LILACS, as well as ClinicalTrials.gov and ICTRP. We examined reference lists of relevant articles for other trials. For the initial review, we wrote to investigators to find additional trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) were considered if they examined fractures, bone mineral density (BMD), or bone turnover markers in women with hormonal contraceptive use prior to menopause. Eligible interventions included comparisons of a hormonal contraceptive with a placebo or with another hormonal contraceptive that differed in terms of drug, dosage, or regimen. They also included providing a supplement to one group. DATA COLLECTION AND ANALYSIS: We assessed all titles and abstracts identified through the literature searches. Mean differences were computed using the inverse variance approach. For dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) was calculated. Both included the 95% confidence interval (CI) and used a fixed-effect model. Due to differing interventions, no trials could be combined for meta-analysis. We applied principles from GRADE to assess the evidence quality and address confidence in the effect estimates. In addition, a sensitivity analysis included trials that provided sufficient data for this review and evidence of at least moderate quality. MAIN RESULTS: We found 19 RCTs that met our eligibility criteria. Eleven trials compared different combined oral contraceptives (COCs) or regimens of COCs; five examined an injectable versus another injectable, implant, or IUD; two studied implants, and one compared the transdermal patch versus the vaginal ring. No trial had fracture as an outcome. BMD was measured in 17 studies and 12 trials assessed biochemical markers of bone turnover. Depot medroxyprogesterone acetate (DMPA) was associated with decreased bone mineral density (BMD). The placebo-controlled trials showed BMD increases for DMPA plus estrogen supplement and decreases for DMPA plus placebo supplement. COCs did not appear to negatively affect BMD, and some formulations had more positive effects than others. However, no COC trial was placebo-controlled. Where studies showed differences between groups in bone turnover markers, the results were generally consistent with those for BMD. For implants, the single-rod etonogestrel group showed a greater BMD decrease versus the two-rod levonorgestrel group but results were not consistent across all implant comparisons.The sensitivity analysis included 11 trials providing evidence of moderate or high quality. Four trials involving DMPA showed some positive effects of an estrogen supplement on BMD, a negative effect of DMPA-subcutaneous on lumbar spine BMD, and a negative effect of DMPA on a bone formation marker. Of the three COC trials, one had a BMD decrease for the group with gestodene plus EE 15 µg. Another indicated less bone resorption in the group with gestodene plus EE 30 µg versus EE 20 µg. AUTHORS' CONCLUSIONS: Whether steroidal contraceptives influence fracture risk cannot be determined from existing information. The evidence quality was considered moderate overall, largely due to the trials of DMPA, implants, and the patch versus ring. The COC evidence varied in quality but was low overall. Many trials had small numbers of participants and some had large losses. Health care providers and women should consider the costs and benefits of these effective contraceptives. For example, injectable contraceptives and implants provide effective, long-term birth control yet do not involve a daily regimen. Progestin-only contraceptives are considered appropriate for women who should avoid estrogen due to medical conditions.

Continuous or extended cycle vs. cyclic use of combined hormonal contraceptives for contraception.

BACKGROUND: The avoidance of menstruation through continuous or extended (greater than 28 days) administration of combination hormonal contraceptives (CHCs) has gained legitimacy through its use in treating endometriosis, dysmenorrhea, and menstruation-associated symptoms. Avoidance of menstruation through extended or continuous use of CHCs for reasons of personal preference may have additional advantages to women, including improved compliance, greater satisfaction, fewer menstrual symptoms, and less menstruation-related absenteeism from work or school. OBJECTIVES: To determine the differences between continuous or extended-cycle CHCs (pills, patch, ring) in regimens of greater than 28 days of active hormone compared with traditional cyclic dosing (21 days of active hormone and 7 days of placebo, or 24 days of active hormones and 4 days of placebo). Our hypothesis was that continuous or extended-cycle CHCs have equivalent efficacy and safety but improved bleeding profiles, amenorrhea rates, adherence, continuation, participant satisfaction, and menstrual symptoms compared with standard cyclic CHCs. SEARCH METHODS: We searched computerized databases (Cochrane Central Register of Controlled Trials, PUBMED, EMBASE, POPLINE, LILACS) for trials using continuous or extended CHCs (oral contraceptives, contraceptive ring and patch) during the years 1966 to 2013. We also searched the references in review articles and publications identified for inclusion in the protocol. Investigators were contacted regarding additional references. SELECTION CRITERIA: All randomized controlled trials in any language comparing continuous or extended-cycle (greater than 28 days of active hormones) versus traditional cyclic administration (21 days of active hormones and 7 days of placebo, or 24 days of active hormones and 4 days of placebo) of CHCs for contraception. DATA COLLECTION AND ANALYSIS: Titles and abstracts identified from the literature searches were assessed for potential inclusion. Data were extracted onto data collection forms and then entered into RevMan 5. Peto odds ratios with 95% confidence intervals were calculated for all outcomes for dichotomous outcomes. Weighted mean difference was calculated for continuous outcomes. The trials were critically appraised by examining the following factors: study design, blinding, randomization method, group allocation concealment, exclusions after randomization, loss to follow-up, and early discontinuation. Because the included trials did not have a standard treatment (type of CHC formulation, route of delivery, or time length for continuous dosing), we could not aggregate data into meta-analysis. MAIN RESULTS: Twelve randomized controlled trials met our inclusion criteria. Study findings were similar between 28-day and extended or continuous regimens in regard to contraceptive efficacy (i.e., pregnancy rates) and safety profiles. When compliance was reported, no difference between 28-day and extended or continuous cycles was found. Participants reported high satisfaction with both dosing regimens, but this was not an outcome universally studied. Overall discontinuation and discontinuation for bleeding problems were not uniformly higher in either group. The studies that reported menstrual symptoms found that the extended or continuous group fared better in terms of headaches, genital irritation, tiredness, bloating, and menstrual pain. Eleven out of the twelve studies found that bleeding patterns were either equivalent between groups or improved with extended or continuous cycles over time. Endometrial lining assessments by ultrasound and/or endometrial biopsy were done in some participants and were all normal after cyclic or extended CHC use. AUTHORS' CONCLUSIONS: The 2014 update yielded four additional trials but unchanged conclusions. Evidence from existing randomized control trials comparing continuous or extended-cycle CHCs (greater than 28 days of active combined hormones) to traditional cyclic dosing (21 days of active hormone and 7 days of placebo, or 24 days of active hormone and 4 days of placebo) is of good quality. However, the variations in type of hormones and time length for extended-cycle dosing make a formal meta-analysis impossible. Future studies should choose a previously described type of CHC and dosing regimen. More attention needs to be directed towards participant satisfaction, continuation, and menstruation-associated symptoms.

Advancing Parkinson's Disease Research in Canada: The Canadian Open Parkinson Network (C-OPN) Cohort.

Background: Enhancing the interactions between study participants, clinicians, and investigators is imperative for advancing Parkinson's disease (PD) research. The Canadian Open Parkinson Network (C-OPN) stands as a nationwide endeavor, connecting the PD community with ten accredited universities and movement disorders research centers spanning, at the time of this analysis, British Columbia, Alberta, Ontario, and Quebec. Objective: Our aim is to showcase C-OPN as a paradigm for bolstering national collaboration to accelerate PD research and to provide an initial overview of already collected data sets. Methods: The C-OPN database comprises de-identified data concerning demographics, symptoms and signs, treatment approaches, and standardized assessments. Additionally, it collects venous blood-derived biomaterials, such as for analyses of DNA, peripheral blood mononuclear cells (PBMC), and serum. Accessible to researchers, C-OPN resources are available through web-based data management systems for multi-center studies, including REDCap. Results: As of November 2023, the C-OPN had enrolled 1,505 PD participants. The male-to-female ratio was 1.77:1, with 83% (n = 1098) residing in urban areas and 82% (n = 1084) having pursued post-secondary education. The average age at diagnosis was 60.2±10.3 years. Herein, our analysis of the C-OPN PD cohort encompasses environmental factors, motor and non-motor symptoms, disease management, and regional differences among provinces. As of April 2024, 32 research projects have utilized C-OPN resources. Conclusions: C-OPN represents a national platform promoting multidisciplinary and multisite research that focuses on PD to promote innovation, exploration of care models, and collaboration among Canadian scientists.

Teamwork and communication between people living with Parkinson's disease (PD), physicians, health professionals, and research scientists is important for improving the lives of those living with this condition. The Canadian Open Parkinson Network (C-OPN) is a Canada-wide initiative, connecting the PD community with ten accredited universities and movement disorders research centers located in ­ at the time of this analysis­British Columbia, Alberta, Ontario, and Quebec. The aim of this paper is to showcase C-OPN as a useful resource for physician and research scientists studying PD in Canada and around the world, and to provide snapshot of already collected data. The C-OPN database comprises de-identified (meaning removal of any identifying information, such as name or date of birth) data concerning lifestyle, disease symptoms, treatments, and results from standardized tests. It also collects blood samples for further analysis. As of November 2023, C-OPN had enrolled 1,505 PD participants across Canada. Most of the participants were male (64%), living in urban areas (83%), and completed post-secondary education (82%). The average age at diagnosis was 60.2±10.3 years. In this paper, we look at environmental factors, motor and non-motor symptoms, different disease management strategies, and regional differences between provinces. In conclusion, C-OPN represents a national platform that encourages multidisciplinary and multisite research focusing on PD to promote innovation and collaboration among Canadian scientists.

Functional alteration of PARL contributes to mitochondrial dysregulation in Parkinson's disease.

Molecular genetics has linked mitochondrial dysfunction to the pathogenesis of Parkinson's disease by the discovery of rare, inherited mutations in gene products that associate with the mitochondria. Mutations in PTEN-induced kinase-1 (PINK1), which encodes a mitochondrial kinase, and PARKIN, encoding an E3 ubiquitin ligase, are the most frequent causes of recessive Parkinson's disease. Recent functional studies have revealed that PINK1 recruits PARKIN to mitochondria to initiate mitophagy, an important autophagic quality control mechanism that rids the cell of damaged mitochondria. PINK1 is post-translationally processed into a cleaved form whose levels are tightly regulated, although the significance of this processing is unknown. Here we demonstrate that the mitochondrial protease presenilin-associated rhomboid-like (PARL) can affect the proteolytic processing of PINK1 and that normal PINK1 localization and stability requires PARL's catalytic activity. PARL deficiency impairs PARKIN recruitment to mitochondria, suggesting PINK1's processing and localization are important in determining its interaction with PARKIN. We sequenced the PARL gene in Parkinson's disease patients and discovered a novel missense mutation in a functional domain of PARL's N-terminus. This PARL mutant is not sufficient to rescue PARKIN recruitment, suggesting that impaired mitophagy may be an underlying mechanism of disease pathogenesis in patients with PARL mutations.

Theory-based interventions for contraception.

BACKGROUND: The explicit use of theory in research helps expand the knowledge base. Theories and models have been used extensively in HIV-prevention research and in interventions for preventing sexually transmitted infections (STIs). The health behavior field uses many theories or models of change. However, educational interventions addressing contraception often have no stated theoretical base. OBJECTIVES: Review randomized controlled trials (RCTs) that tested a theoretical approach to inform contraceptive choice; encourage contraceptive use; or promote adherence to, or continuation of, a contraceptive regimen. SEARCH METHODS: Through June 2013, we searched computerized databases for trials that tested a theory-based intervention for improving contraceptive use (MEDLINE, POPLINE, CENTRAL, PsycINFO, ClinicalTrials.gov, and ICTRP). Previous searches also included EMBASE. For the initial review, we wrote to investigators to find other trials. SELECTION CRITERIA: Trials tested a theory-based intervention for improving contraceptive use. We excluded trials focused on high-risk groups and preventing sexually transmitted infections or HIV. Interventions addressed the use of one or more contraceptive methods for contraception. The reports provided evidence that the intervention was based on a specific theory or model. The primary outcomes were pregnancy, contraceptive choice or use, and contraceptive adherence or continuation. DATA COLLECTION AND ANALYSIS: The primary author evaluated abstracts for eligibility. Two authors extracted data from included studies. For the dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated using a fixed-effect model. Cluster randomized trials used various methods of accounting for the clustering, such as multilevel modeling. Most reports did not provide information to calculate the effective sample size. Therefore, we presented the results as reported by the investigators. No meta-analysis was conducted due to differences in interventions and outcome measures. MAIN RESULTS: We included three new trials for a total of 17. Ten randomly assigned individuals and seven were cluster-randomized. Eight trials showed some intervention effect.Two of 12 trials with pregnancy or birth data showed some effect. A theory-based group was less likely than the comparison group to have a second birth (OR 0.41; 95% CI 0.17 to 1.00) or to report a pregnancy (OR 0.24 (95% CI 0.10 to 0.56); OR 0.27 (95% CI 0.11 to 0.66)). The theoretical bases were social cognitive theory (SCT) and another social cognition model.Of 12 trials with data on contraceptive use (non-condom), six showed some effect. A theory-based group was more likely to consistently use oral contraceptives (OR 1.41; 95% CI 1.06 to 1.87), hormonal contraceptives (reported relative risk (RR) 1.30; 95% CI 1.06 to 1.58) or dual methods (reported RR 1.36; 95% CI 1.01 to 1.85); to use an effective contraceptive method (reported effect size 1.76; OR 2.04 (95% CI 1.47 to 2.83)) or use more habitual contraception (reported P < 0.05); and were less likely to use ineffective contraception (OR 0.56; 95% CI 0.31 to 0.98). Theories and models included the Health Belief Model (HBM), SCT, SCT plus another theory, other social cognition, and motivational interviewing (MI).For condom use, a theory-based group had favorable results in 5 of 11 trials. The main differences were reporting more consistent condom use (reported RR 1.57; 95% CI 1.28 to 1.94) and more condom use during last sex (reported results: risk ratio 1.47 (95% CI 1.12 to 1.93); effect size 1.68; OR 2.12 (95% CI 1.24 to 3.56); OR 1.45 (95% CI 1.03 to 2.03)). The theories were SCT, SCT plus another theory, and HBM.Nearly all trials provided multiple sessions or contacts. SCT provided the basis for seven trials focused on adolescents, of which five reported some effectiveness. Two others based on other social cognition models had favorable results with adolescents. Of six trials including adult women, five provided individual sessions. Some effect was seen in two using MI and one using the HBM. Two based on the Transtheoretical Model did not show any effect. AUTHORS' CONCLUSIONS: Eight trials provided evidence of high or moderate quality. Family planning researchers and practitioners could adapt the effective interventions, although most provided group sessions for adolescents. Three were conducted outside the USA. Clinics and low-resource settings need high-quality evidence on changing behavior. Thorough use of single theories would help in identifying what works, as would better reporting on research design and intervention implementation.

20 µg versus >20 µg estrogen combined oral contraceptives for contraception.

BACKGROUND: Concern about estrogen-related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). However, reducing the amount of estrogen to improve safety could result in decreased contraceptive effectiveness and unacceptable changes in bleeding patterns. OBJECTIVES: To test the hypothesis that COCs containing ≤ 20 µg ethinyl estradiol (EE) perform similarly as those containing > 20 µg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects. SEARCH METHODS: In July 2013, we searched CENTRAL, MEDLINE, and POPLINE, and examined references of potentially eligible trials. We also searched for recent clinical trials using ClinicalTrials.gov and ICTRP. No new trials met the inclusion criteria. Previous searches included EMBASE. For the initial review, we wrote to oral contraceptive manufacturers to identify trials. SELECTION CRITERIA: English-language reports of randomized controlled trials were eligible that compare a COC containing ≤ 20 µg EE with a COC containing > 20 µg EE. We excluded studies where the interventions were designed to be administered for less than three consecutive cycles or to be used primarily as treatment for non-contraceptive conditions. Trials had to report on contraceptive effectiveness, bleeding patterns, trial discontinuation due to bleeding-related reasons or other side effects, or side effects to be included in the review. DATA COLLECTION AND ANALYSIS: One author evaluated all titles and abstracts from literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from studies identified for inclusion. We wrote to the researchers when additional information was needed. Data were entered and analyzed with RevMan. MAIN RESULTS: No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher-estrogen pills, several COCs containing 20 µg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). AUTHORS' CONCLUSIONS: While COCs containing 20 µg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low-dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow-up rates are essential for meaningful interpretation of results.

Progestin-only pills for contraception.

BACKGROUND: The introduction of a new progestin-only oral contraceptive in Europe has renewed interest in this class of oral contraceptives. Unlike the more widely used combined oral contraceptives containing an estrogen plus progestin, these pills contain only a progestin (progestogen) and are taken without interruption. How these pills compare to others in their class or to combined oral contraceptives is not clear. OBJECTIVES: This review examined randomized controlled trials of progestin-only pills for differences in efficacy, acceptability, and continuation rates. SEARCH METHODS: Through October 2013, we searched the computerized databases MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), POPLINE, and LILACS for studies of progestin-only pills. We also searched for current trials via ClinicalTrials.gov and ICTRP. Previous searches also included EMBASE. SELECTION CRITERIA: We included all randomized controlled trials in any language that included progestin-only pills for contraception.  We incorporated any comparison with a progestin-only pill; this could include different doses, other progestin-only pills, combined oral contraceptives, or other contraceptives. DATA COLLECTION AND ANALYSIS: The first author abstracted the data and entered the information into RevMan 5. Another author performed a second, independent data abstraction to verify the initial data entry.We attempted to extract life-table rates (actuarial or continuous) and used the rate difference as the effect measure. Where life-table rates were not published, we used the incidence rate ratio (ratio of Pearl rates). Where only the crude number of events was published, we calculated the Peto odds ratio with 95% confidence interval (CI) using a fixed-effect model. For continuous variables, the mean difference (MD) was computed with 95% CI. Because of disparate exposures, we were not able to combine studies in meta-analysis. MAIN RESULTS: Six trials met the inclusion criteria. We have not found any new studies since the initial review. In the trial comparing the desogestrel versus levonorgestrel progestin-only pill, desogestrel was not associated with a significantly lower risk of accidental pregnancy; the rate ratio was 0.27 (95% CI 0.06 to 1.19). However, the desogestrel progestin-only pill caused more bleeding problems, although this difference was not statistically significant. The trial comparing low-dose mifepristone versus a levonorgestrel progestin-only pill found similar pregnancy rates. In the trial comparing ethynodiol diacetate versus a combined oral contraceptive, irregular cycles occurred in all women assigned to the progestin-only pill (odds ratio 135.96; 95% CI 7.61 to 2421.02). In a trial comparing two progestin-only and two combined oral contraceptives, the progestin-only pill containing levonorgestrel 30 µg had higher efficacy than did the pill containing norethisterone 350 µg. An early trial found megestrol acetate inferior to other progestin-only pills in terms of efficacy. A study of the timing of pill initiation after birth found no important differences, but high losses to follow up undermined the trial. AUTHORS' CONCLUSIONS: Evidence is insufficient to compare progestin-only pills to each other or to combined oral contraceptives.

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Strategies to improve adherence and acceptability of hormonal methods of contraception.

BACKGROUND: Worldwide, hormonal contraceptives are among the most popular reversible contraceptives. Despite their high theoretical effectiveness, typical use results in much lower effectiveness. In large part, this disparity reflects difficulties in adherence to the contraceptive regimen and low rates for long-term continuation. OBJECTIVES: The intent was to determine the effectiveness of ancillary counseling techniques to improve adherence to, and continuation of, hormonal methods of contraception. SEARCH METHODS: Through August 2013, we searched computerized databases for randomized controlled trials (RCTs) comparing client-provider interventions with standard family planning counseling. Sources included CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov and ICTRP. Earlier searches also included LILACS, PsycINFO, Dissertation Abstracts, African Index Medicus, and IMEMR. SELECTION CRITERIA: We included RCTs of an intensive counseling technique or other client-provider intervention compared to routine family planning counseling. Interventions included group motivation; structured, peer, or multi-component counseling; and intensive reminders of appointments or next dosing. Outcome measures were discontinuation, reasons for discontinuation, number of missed pills or on-time injections, and pregnancy. DATA COLLECTION AND ANALYSIS: One author evaluated the titles and abstracts from the searches to determine eligibility. Two authors extracted data from the included studies. We calculated the Mantel-Haenszel odds ratio (OR) for dichotomous outcomes. For continuous variables, the mean difference (MD) was computed; RevMan uses the inverse variance approach. For all analyses, 95% confidence intervals (CI) were also computed. Since the studies identified differed in both interventions and outcome measures, we did not conduct a meta-analysis. MAIN RESULTS: Nine RCTs met our inclusion criteria. Five involved direct counseling; of those, two also provided multiple contacts by telephone. Four other trials provided intensive reminders, two of which also provided health education information. Three trials showed some benefit of the experimental intervention. In a counseling intervention, women who received repeated structured information about the injectable depot medroxyprogesterone acetate (DMPA) were less likely to discontinue the method by 12 months (OR 0.27; 95% CI 0.16 to 0.44) than women who had routine counseling. The intervention group was also less likely to discontinue due to menstrual disturbances (OR 0.20; 95% CI 0.11 to 0.37). Another trial showed a group with special counseling plus phone calls was more likely than the special-counseling group to report consistent use of oral contraceptives (OC) at 3 months (OR 1.41; 95% CI 1.06 to 1.87), though not at 12 months. The group with only special counseling did not differ significantly from those with standard care for any outcome. The third trial compared daily text-message reminders about OCs plus health information versus standard care. Women in the text-message group were more likely than the standard-care group to continue OC use by six months (OR 1.54; 95% CI 1.14 to 2.10). The text-message group was also more likely to avoid an interruption in OC use longer than seven days (OR 1.53; 95% CI 1.13 to 2.07). AUTHORS' CONCLUSIONS: Only three trials showed some benefit of strategies to improve adherence and continuation. However, several had small sample sizes and six had high losses to follow up. The overall quality of evidence was considered moderate. The intervention type and intensity varied greatly across the studies. A combination of intensive counseling and multiple contacts and reminders may be needed to improve adherence and acceptability of contraceptive use. High-quality RCTs with adequate power and well-designed interventions could help identify ways to improve adherence to, and continuation of, hormonal contraceptive methods.