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BackgroundUreteral obstruction after percutaneous nephrolithotomy (PCNL) may require prolonged drainage with a nephrostomy tube (NT) or ureteral stent, but it is not well understood how and why this occurs. The goal of this study was to identify risk factors associated with postoperative ureteral obstruction to help guide drainage tube selection.MethodsProspective data from adult patients enrolled in the Registry for Stones of the Kidney and Ureter (ReSKU) who underwent PCNL from 2016 to 2020 were used. Patients who had postoperative NTs with antegrade imaging-based flow assessment on postoperative day one (POD1) were included. Patients with transplanted kidneys or those without appropriate preoperative imaging were excluded. We assessed the association between patient demographics, stone characteristics, and intraoperative factors using POD1 antegrade flow, a proxy for ureteral patency, as the primary outcome. Stepwise selection was used to develop a multivariate logistic regression model controlling for BMI, stone location, stone burden, ipsilateral ureteroscopy (URS), access location, estimated blood loss, and operative time.ResultsWe analyzed 241 cases for this study; 204 (84.6%) had a visual clearance of stone. Antegrade flow on POD1 was absent in 76 cases (31.5%). A multivariate logistic regression model found that stones located anywhere other than in the renal pelvis (OR 2.63, 95% CI 1.29-5.53; p = 0.01), non-lower pole access (OR 2.81, 95% CI 1.42-5.74; p

AimsTreatment for urinary incontinence (UI) includes pelvic floor muscle training (PFMT). There is limited data appraising the characteristics of PFMT devices. We aimed to ascertain the primary use, strengths and weaknesses of PFMT devices available online, through evaluation of consumer reviews.MethodsWe performed an analysis of PFMT devices on Amazon.com. Four key device categories were recognized. Reviews from the five most frequently-reviewed products per category were analyzed (n = 20). W characterized device use, strengths and weaknesses using thematic analysis.ResultsWe evaluated 2574 PFMT device reviews including 1168 vibrating Kegel balls, 750 non-vibrating Kegel balls, 411 pelvic floor or thigh exercisers, and 245 electric probes. Non-vibrating Kegel balls were rated highest (4.6/5 stars), followed by vibrating Kegel balls, electric probes and pelvic floor or thigh exercisers (4.4/5, 4.1/5, and 3.8/5 stars, respectively). Most reviews were positive (77%) or negative (16%) with few neutral (7%). While all were marketed to treat UI, most reviews did not mention the intended use. Vibrating and non-vibrating Kegel balls and electric probes were most likely to be used for UI, and pelvic floor or thigh exercisers for toning. Some used non-vibrating and vibrating Kegel balls for sexual function. Electric probes were the most beneficial device for incontinence control (27%, 67/245). Twenty-five percent of all product reviews praised device ease of use and good quality or design. A minority of reviewers found products difficult to use, of poor quality or design and uncomfortable.ConclusionConsumers utilized online PFMT devices for multiple purposes, including UI, toning and sexual function. Reviewers generally praised PFMT products, particularly electric probes for UI.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.

AimsTreatment for urinary incontinence (UI) includes pelvic floor muscle training (PFMT). There is limited data appraising the characteristics of PFMT devices. We aimed to ascertain the primary use, strengths and weaknesses of PFMT devices available online, through evaluation of consumer reviews.MethodsWe performed an analysis of PFMT devices on Amazon.com. Four key device categories were recognized. Reviews from the five most frequently-reviewed products per category were analyzed (n = 20). W characterized device use, strengths and weaknesses using thematic analysis.ResultsWe evaluated 2574 PFMT device reviews including 1168 vibrating Kegel balls, 750 non-vibrating Kegel balls, 411 pelvic floor or thigh exercisers, and 245 electric probes. Non-vibrating Kegel balls were rated highest (4.6/5 stars), followed by vibrating Kegel balls, electric probes and pelvic floor or thigh exercisers (4.4/5, 4.1/5, and 3.8/5 stars, respectively). Most reviews were positive (77%) or negative (16%) with few neutral (7%). While all were marketed to treat UI, most reviews did not mention the intended use. Vibrating and non-vibrating Kegel balls and electric probes were most likely to be used for UI, and pelvic floor or thigh exercisers for toning. Some used non-vibrating and vibrating Kegel balls for sexual function. Electric probes were the most beneficial device for incontinence control (27%, 67/245). Twenty-five percent of all product reviews praised device ease of use and good quality or design. A minority of reviewers found products difficult to use, of poor quality or design and uncomfortable.ConclusionConsumers utilized online PFMT devices for multiple purposes, including UI, toning and sexual function. Reviewers generally praised PFMT products, particularly electric probes for UI.

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

ObjectiveTo augment the educational resources available to training programs and trainees in musculoskeletal (MSK) radiology by creating a comprehensive series of Web-based open-access core curriculum lectures.Materials and methodsSpeakers with recognized content and lecturing expertise in MSK radiology were invited to create digitally recorded lecture presentations across a series of 42 core curriculum topics in MSK imaging. Resultant presentation recordings, organized under curriculum subject headings, were archived as open-access video file recordings for online viewing on a dedicated Web page (http://radiologycorelectures.org/msk/). Information regarding the online core curriculum lecture series was distributed to members of the International Skeletal Society, Society of Skeletal Radiology, Society of Chairs of Academic Radiology Departments, and the Association of Program Directors in Radiology. Web page and online lecture utilization data were collected using Google Analytics (Alphabet, Mountain View, CA, USA).ResultsForty-two lectures, by 38 speakers, were recorded, edited and hosted online. Lectures spanned ACGME curriculum categories of musculoskeletal trauma, arthritis, metabolic diseases, marrow, infection, tumors, imaging of internal derangement of joints, congenital disorders, and orthopedic imaging. Online access to the core curriculum lectures was opened on March 4, 2018. As of January 20, 2019, the core curriculum lectures have had 77,573 page views from 34,977 sessions.ConclusionsTo date, the MSK core curriculum lecture series lectures have been widely accessed and viewed. It is envisioned that the initial success of the project will serve to promote ongoing content renewal and expansion to the lecture materials over time.

ObjectiveTo augment the educational resources available to training programs and trainees in musculoskeletal (MSK) radiology by creating a comprehensive series of Web-based open-access core curriculum lectures.Materials and methodsSpeakers with recognized content and lecturing expertise in MSK radiology were invited to create digitally recorded lecture presentations across a series of 42 core curriculum topics in MSK imaging. Resultant presentation recordings, organized under curriculum subject headings, were archived as open-access video file recordings for online viewing on a dedicated Web page (http://radiologycorelectures.org/msk/). Information regarding the online core curriculum lecture series was distributed to members of the International Skeletal Society, Society of Skeletal Radiology, Society of Chairs of Academic Radiology Departments, and the Association of Program Directors in Radiology. Web page and online lecture utilization data were collected using Google Analytics (Alphabet, Mountain View, CA, USA).ResultsForty-two lectures, by 38 speakers, were recorded, edited and hosted online. Lectures spanned ACGME curriculum categories of musculoskeletal trauma, arthritis, metabolic diseases, marrow, infection, tumors, imaging of internal derangement of joints, congenital disorders, and orthopedic imaging. Online access to the core curriculum lectures was opened on March 4, 2018. As of January 20, 2019, the core curriculum lectures have had 77,573 page views from 34,977 sessions.ConclusionsTo date, the MSK core curriculum lecture series lectures have been widely accessed and viewed. It is envisioned that the initial success of the project will serve to promote ongoing content renewal and expansion to the lecture materials over time.

BACKGROUND:Three motor phenotypes have been described in PD: postural instability and gait difficulty (PIGD) dominant, tremor-dominant (TD), and indeterminate (IND) subtype. These phenotypes have been associated with different cognitive trajectories, motor outcomes, and biomarkers profiles. However, whether motor subtype classifications change with treatment and disease progression is not well established. METHODS:To evaluate motor subtype ratio changes, we used the chi-square test for the off and on state motor subtypes for 115 PD participants in the BioFIND study and used repeated-measures analyses to evaluate longitudinal changes in 162 PD participants with five-year follow-up in the PPMI study. RESULTS:PIGD and TD subtypes in moderate to advanced PD participants change with dopaminergic agents. For those who shifted subtypes, improvement in tremor accounted for the transition of 15 (25.4%) TD participants, while the lack of tremor improvement along with minimal changes in PIGD score resulted in changes for eight (19.0%) PIGD individuals. Analyses of PPMI data revealed that all three subgroups had a significant decrease in subtype ratio with disease progression and a significant decline in subtype ratio occurred only in the TD subgroup with dopaminergic agents. The impact of dopaminergic medication effect on subtype shift for each visit was also more notable with disease advancement. CONCLUSIONS:Motor subtypes are not fixed but change with progression of the disease and with treatment. Improvement in tremor was the main contributor to motor phenotype transitions in the BioFIND cohort. A more stable classification system for subtypes based on underlying biological differences is desirable.

BackgroundProgressive supranuclear palsy (PSP) -Richardson's Syndrome and Corticobasal Syndrome (CBS) are the two classic clinical syndromes associated with underlying four repeat (4R) tau pathology. The PSP Rating Scale is a commonly used assessment in PSP clinical trials; there is an increasing interest in designing combined 4R tauopathy clinical trials involving both CBS and PSP.ObjectivesTo determine contributions of each domain of the PSP Rating Scale to overall severity and characterize the probable sequence of clinical progression of PSP as compared to CBS.MethodsMulticenter clinical trial and natural history study data were analyzed from 545 patients with PSP and 49 with CBS. Proportional odds models were applied to model normalized cross-sectional PSP Rating Scale, estimating the probability that a patient would experience impairment in each domain using the PSP Rating Scale total score as the index of overall disease severity.ResultsThe earliest symptom domain to demonstrate impairment in PSP patients was most likely to be Ocular Motor, followed jointly by Gait/Midline and Daily Activities, then Limb Motor and Mentation, and finally Bulbar. For CBS, Limb Motor manifested first and ocular showed less probability of impairment throughout the disease spectrum. An online tool to visualize predicted disease progression was developed to predict relative disability on each subscale per overall disease severity.ConclusionThe PSP Rating Scale captures disease severity in both PSP and CBS. Modelling how domains change in relation to one other at varying disease severities may facilitate detection of therapeutic effects in future clinical trials.

ObjectiveExamine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms.BackgroundCSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear.MethodsBioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined.ResultsCSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid1-42 was lower in PD versus controls (P

OBJECTIVE:Examine relationships among neurodegenerative biomarkers and PD motor and nonmotor symptoms. BACKGROUND:CSF alpha-synuclein is decreased in PD versus healthy controls, but whether plasma and saliva alpha-synuclein differentiate these groups is controversial. Correlations of alpha-synuclein among biofluids (CSF, plasma, saliva) or biomarkers (eg, beta-amyloid, tau [total, phosphorylated]) are not fully understood. The relationships of these biomarkers with PD clinical features remain unclear. METHODS:BioFIND, a cross-sectional, observational study, examines clinical and biomarker characteristics in moderate-advanced PD and matched healthy controls. We compared alpha-synuclein concentrations across diagnosis, biofluids, and CSF biomarkers. Correlations of CSF biomarkers and MDS-UPDRS, motor phenotype, MoCA, and rapid eye movement sleep behavior disorder questionnaire scores in PD were examined. RESULTS:CSF alpha-synuclein was lower in PD versus controls (P = .01), controlling for age, gender, and education. Plasma and saliva alpha-synuclein did not differ between PD and controls, and alpha-synuclein did not significantly correlate among biofluids. CSF beta-amyloid1-42 was lower in PD versus controls (P

ObjectiveTo determine the ability of CSF biomarkers to predict disease progression in progressive supranuclear palsy (PSP).MethodsWe compared the ability of baseline CSF β-amyloid1-42, tau, phosphorylated tau 181 (p-tau), and neurofilament light chain (NfL) concentrations, measured by INNO-BIA AlzBio3 or ELISA, to predict 52-week changes in clinical (PSP Rating Scale [PSPRS] and Schwab and England Activities of Daily Living [SEADL]), neuropsychological, and regional brain volumes on MRI using linear mixed effects models controlled for age, sex, and baseline disease severity, and Fisher F density curves to compare effect sizes in 50 patients with PSP. Similar analyses were done using plasma NfL measured by single molecule arrays in 141 patients.ResultsHigher CSF NfL concentration predicted more rapid decline (biomarker × time interaction) over 52 weeks in PSPRS (p = 0.004, false discovery rate-corrected) and SEADL (p = 0.008), whereas lower baseline CSF p-tau predicted faster decline on PSPRS (p = 0.004). Higher CSF tau concentrations predicted faster decline by SEADL (p = 0.004). The CSF NfL/p-tau ratio was superior for predicting change in PSPRS, compared to p-tau (p = 0.003) or NfL (p = 0.001) alone. Higher NfL concentrations in CSF or blood were associated with greater superior cerebellar peduncle atrophy (fixed effect, p ≤ 0.029 and 0.008, respectively).ConclusionsBoth CSF p-tau and NfL correlate with disease severity and rate of disease progression in PSP. The inverse correlation of p-tau with disease severity suggests a potentially different mechanism of tau pathology in PSP as compared to Alzheimer disease.

ObjectiveTo examine the utility and reliability of volumetric MRI in measuring disease progression in the 4 repeat tauopathies, progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), to support clinical development of new tau-directed therapeutic agents.MethodsSix- and 12-month changes in regional MRI volumes and PSP Rating Scale scores were examined in 55 patients with PSP and 33 patients with CBS (78% amyloid PET negative) compared to 30 normal controls from a multicenter natural history study. Longitudinal voxel-based morphometric analyses identified patterns of volume loss, and region-of-interest analyses examined rates of volume loss in brainstem (midbrain, pons, superior cerebellar peduncle), cortical, and subcortical regions based on previously validated atlases. Results were compared to those in a replication cohort of 226 patients with PSP with MRI data from the AL-108-231 clinical trial.ResultsPatients with CBS exhibited greater baseline atrophy and greater longitudinal atrophy rates in cortical and basal ganglia regions than patients with PSP; however, midbrain and pontine atrophy rates were similar. Voxel-wise analyses showed distinct patterns of regional longitudinal atrophy in each group as compared to normal controls. The midbrain/pons volumetric ratio differed between diagnoses but remained stable over time. In both patient groups, brainstem atrophy rates were correlated with disease progression measured using the PSP Rating Scale.ConclusionsVolume loss is quantifiable over a period of 6 months in CBS and PSP. Future clinical trials may be able to combine CBS and PSP to measure therapeutic effects.

BackgroundIdentifying PD-specific biomarkers in biofluids will greatly aid in diagnosis, monitoring progression, and therapeutic interventions. PD biomarkers have been limited by poor discriminatory power, partly driven by heterogeneity of the disease, variability of collection protocols, and focus on de novo, unmedicated patients. Thus, a platform for biomarker discovery and validation in well-characterized, clinically typical, moderate to advanced PD cohorts is critically needed.MethodsBioFIND (Fox Investigation for New Discovery of Biomarkers in Parkinson's Disease) is a cross-sectional, multicenter biomarker study that established a repository of clinical data, blood, DNA, RNA, CSF, saliva, and urine samples from 118 moderate to advanced PD and 88 healthy control subjects. Inclusion criteria were designed to maximize diagnostic specificity by selecting participants with clinically typical PD symptoms, and clinical data and biospecimen collection utilized standardized procedures to minimize variability across sites.ResultsWe present the study methodology and data on the cohort's clinical characteristics. Motor scores and biospecimen samples including plasma are available for practically defined off and on states and thus enable testing the effects of PD medications on biomarkers. Other biospecimens are available from off state PD assessments and from controls.ConclusionOur cohort provides a valuable resource for biomarker discovery and validation in PD. Clinical data and biospecimens, available through The Michael J. Fox Foundation for Parkinson's Research and the National Institute of Neurological Disorders and Stroke, can serve as a platform for discovering biomarkers in clinically typical PD and comparisons across PD's broad and heterogeneous spectrum. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Familial idiopathic basal ganglia calcification (IBGC) or Fahr's disease is a rare neurodegenerative disorder characterized by calcium deposits in the basal ganglia and other brain regions, which is associated with neuropsychiatric and motor symptoms. Familial IBGC is genetically heterogeneous and typically transmitted in an autosomal dominant fashion. We performed a mutational analysis of SLC20A2, the first gene found to cause IBGC, to assess its genetic contribution to familial IBGC. We recruited 218 subjects from 29 IBGC-affected families of varied ancestry and collected medical history, neurological exam, and head CT scans to characterize each patient's disease status. We screened our patient cohort for mutations in SLC20A2. Twelve novel (nonsense, deletions, missense, and splice site) potentially pathogenic variants, one synonymous variant, and one previously reported mutation were identified in 13 families. Variants predicted to be deleterious cosegregated with disease in five families. Three families showed nonsegregation with clinical disease of such variants, but retrospective review of clinical and neuroimaging data strongly suggested previous misclassification. Overall, mutations in SLC20A2 account for as many as 41% of our familial IBGC cases. Our screen in a large series expands the catalog of SLC20A2 mutations identified to date and demonstrates that mutations in SLC20A2 are a major cause of familial IBGC. Non-perfect segregation patterns of predicted deleterious variants highlight the challenges of phenotypic assessment in this condition with highly variable clinical presentation.