Critical appraisal of intra-articular glucocorticoid injections for symptomatic osteoarthritis of the knee.

OBJECTIVE: Intra-articular (IA) injections of glucocorticoids (GCs) have been shown to decrease pain, increase mobility, and improve quality of life in patients with osteoarthritis (OA) of the knee. Concerns about cartilage loss with IA GCs have prompted reconsideration of their use in knee OA. This review has three objectives: 1) critically review the clinical, molecular, and structural effects of IA GCs in knee OA; 2) provide a design for a clinical trial aimed at improving our understanding of the long-term consequences of IA GCs; and 3) provide practical guidance on the use of IA GCs in patients with knee OA based on current information. DESIGN: A narrative review of current literature on the use of IA GCs for OA of the knee. RESULTS: Important questions remain to be fully answered with respect to IA GCs, including long-term effects on all aspects of the structural and molecular environment of the knee, and identification of factors that can reliably predict a positive or negative response to IA GCs. CONCLUSIONS: While awaiting results from an appropriately designed study, several provisional statements regarding IA GCs can be put forward: 1) IA GCs appear to be a relatively safe option that is effective in specific patients with symptomatic knee OA; 2) there is no definitive evidence that IA GCs accelerate joint deterioration to an important extent or hastens the requirement for knee replacement; and 3) there are few contraindications to IA GCs and injection-associated complications are rare when IA GCs are delivered with proper technique.

Potential diagnostic value of a type X collagen neo-epitope biomarker for knee osteoarthritis.

OBJECTIVE: Phenotypic changes of chondrocytes toward hypertrophy might be fundamental in the pathogenesis of osteoarthritis (OA), of which type X collagen (Col10) is a well-known marker. The purpose was to develop a specific immunoassay for blood quantification of a newly identified neo-epitope of type Col10 to assess its diagnostic value for radiographic knee OA. METHODS: A neo-epitope of Col10 was identified in urine samples from OA patients. A monoclonal antibody against the neo-epitope was produced in Balb/C mice. The enzyme responsible for the cleavage was identified. Immunohistochemical detection of this neo-epitope was performed on human OA cartilage. An immunoassay (Col10neo) was developed and quantified in two clinical studies: the C4Pain-003 and the NYU OA progression study. Receiver operating characteristic curve (ROC) curve analysis was carried out to evaluate the discriminative power of Col10neo between OA and rheumatoid arthritis (RA). RESULTS: A neo-epitope specific mAb was produced. The Cathepsin K-generated neo-epitope was localized to the pericellular matrix of chondrocytes, while its presence was extended and more prominent in superficial fibrillation in the cartilage with advanced degradation. In the C4Pain study, a higher level of Col10neo was seen in subjects with greater KL grade. The group of the highest tertile of Col10neo included more subjects with KL3-4. In the NYU study, Col10neo was statistically higher in OA than control or RA. ROC curve analysis revealed area under the curve was 0.88 (95% CI 0.81-0.94). CONCLUSION: Our findings indicate that Col10neo linked to hypertrophic chondrocytes could be used as a diagnostic biochemical marker for knee OA.

Clinimetrics of ultrasound pathologies in osteoarthritis: systematic literature review and meta-analysis.

OBJECTIVE: The aims of this study were to systematically review clinimetrics of commonly assessed ultrasound pathologies in knee, hip and hand osteoarthritis (OA), and to conduct a meta-analysis for each clinimetric. METHODS: Medline, Embase, and Cochrane Library databases were searched from their inceptions to September 2016. According to the Outcome Measures in Rheumatology (OMERACT) Instrument Selection Algorithm, data extraction focused on ultrasound technical features and performance metrics. Methodological quality was assessed with modified 19-item Downs and Black score and 11-item Quality Appraisal of Diagnostic Reliability (QAREL) score. Separate meta-analyses were performed for clinimetrics: (1) inter-rater/intra-rater reliability; (2) construct validity; (3) criteria validity; and (4) internal/external responsiveness. Statistical Package for the Social Sciences (SPSS), Excel and Comprehensive Meta-analysis were used. RESULT: Our search identified 1126 records; of these, 100 were eligible, including a total of 8542 patients and 32,373 joints. The average Downs and Black score was 13.01, and average QAREL was 5.93. The stratified meta-analysis was performed only for knee OA, which demonstrated moderate to substantial reliability [minimum kappa > 0.44(0.15,0.74), minimum intraclass correlation coefficient (ICC) > 0.82(0.73-0.89)], weak construct validity against pain (r = 0.12 to 0.27), function (r = 0.15 to 0.23), and blood biomarkers (r = 0.01 to 0.21), but weak to strong correlation with plain radiography (r = 0.13 to 0.60), strong association with Magnetic Resonance Imaging (MRI) [minimum r = 0.60(0.52,0.67)] and strong discrimination against symptomatic patients (OR = 3.08 to 7.46). There was strong criterion validity against cartilage histology [r = 0.66(-0.05,0.93)], and small to moderate internal [standardized mean difference(SMD) = 0.20 to 0.58] and external (r = 0.35 to 0.43) responsiveness to interventions. CONCLUSION: Ultrasound demonstrated strong criterion validity with cartilage histology, poor to strong correlation with patient findings and MRI, moderate reliability, and low responsiveness to interventions. PROSPERO REGISTRATION NO: CRD42016039954.

Whole-genome association analysis of treatment response in obsessive-compulsive disorder.

Up to 30% of patients with obsessive-compulsive disorder (OCD) exhibit an inadequate response to serotonin reuptake inhibitors (SRIs). To date, genetic predictors of OCD treatment response have not been systematically investigated using genome-wide association study (GWAS). To identify specific genetic variations potentially influencing SRI response, we conducted a GWAS study in 804 OCD patients with information on SRI response. SRI response was classified as 'response' (n=514) or 'non-response' (n=290), based on self-report. We used the more powerful Quasi-Likelihood Score Test (the MQLS test) to conduct a genome-wide association test correcting for relatedness, and then used an adjusted logistic model to evaluate the effect size of the variants in probands. The top single-nucleotide polymorphism (SNP) was rs17162912 (P=1.76 × 10(-8)), which is near the DISP1 gene on 1q41-q42, a microdeletion region implicated in neurological development. The other six SNPs showing suggestive evidence of association (P<10(-5)) were rs9303380, rs12437601, rs16988159, rs7676822, rs1911877 and rs723815. Among them, two SNPs in strong linkage disequilibrium, rs7676822 and rs1911877, located near the PCDH10 gene, gave P-values of 2.86 × 10(-6) and 8.41 × 10(-6), respectively. The other 35 variations with signals of potential significance (P<10(-4)) involve multiple genes expressed in the brain, including GRIN2B, PCDH10 and GPC6. Our enrichment analysis indicated suggestive roles of genes in the glutamatergic neurotransmission system (false discovery rate (FDR)=0.0097) and the serotonergic system (FDR=0.0213). Although the results presented may provide new insights into genetic mechanisms underlying treatment response in OCD, studies with larger sample sizes and detailed information on drug dosage and treatment duration are needed.

Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS.

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by intrusive thoughts and urges and repetitive, intentional behaviors that cause significant distress and impair functioning. The OCD Collaborative Genetics Association Study (OCGAS) is comprised of comprehensively assessed OCD patients with an early age of OCD onset. After application of a stringent quality control protocol, a total of 1065 families (containing 1406 patients with OCD), combined with population-based samples (resulting in a total sample of 5061 individuals), were studied. An integrative analyses pipeline was utilized, involving association testing at single-nucleotide polymorphism (SNP) and gene levels (via a hybrid approach that allowed for combined analyses of the family- and population-based data). The smallest P-value was observed for a marker on chromosome 9 (near PTPRD, P=4.13 × 10(-)(7)). Pre-synaptic PTPRD promotes the differentiation of glutamatergic synapses and interacts with SLITRK3. Together, both proteins selectively regulate the development of inhibitory GABAergic synapses. Although no SNPs were identified as associated with OCD at genome-wide significance level, follow-up analyses of genome-wide association study (GWAS) signals from a previously published OCD study identified significant enrichment (P=0.0176). Secondary analyses of high-confidence interaction partners of DLGAP1 and GRIK2 (both showing evidence for association in our follow-up and the original GWAS study) revealed a trend of association (P=0.075) for a set of genes such as NEUROD6, SV2A, GRIA4, SLC1A2 and PTPRD. Analyses at the gene level revealed association of IQCK and C16orf88 (both P<1 × 10(-)(6), experiment-wide significant), as well as OFCC1 (P=6.29 × 10(-)(5)). The suggestive findings in this study await replication in larger samples.

Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis.

OBJECTIVE: Pro- and anti-inflammatory mediators, such as IL-1ß and IL1Ra, are produced by joint tissues in osteoarthritis (OA), where they may contribute to pathogenesis. We examined whether inflammatory events occurring within joints are reflected in plasma of patients with symptomatic knee osteoarthritis (SKOA). DESIGN: 111 SKOA subjects with medial disease completed a 24-month prospective study of clinical and radiographic progression, with clinical assessment and specimen collection at 6-month intervals. The plasma biochemical marker IL1Ra was assessed at baseline and 18 months; other plasma biochemical markers were assessed only at 18 months, including IL-1ß, TNFα, VEGF, IL-6, IL-6Rα, IL-17A, IL-17A/F, IL-17F, CRP, sTNF-RII, and MMP-2. RESULTS: In cross-sectional studies, WOMAC (total, pain, function) and plasma IL1Ra were modestly associated with radiographic severity after adjustment for age, gender and body mass index (BMI). In addition, elevation of plasma IL1Ra predicted joint space narrowing (JSN) at 24 months. BMI did associate with progression in some but not all analyses. Causal graph analysis indicated a positive association of IL1Ra with JSN; an interaction between IL1Ra and BMI suggested either that BMI influences IL1Ra or that a hidden confounder influences both BMI and IL1Ra. Other protein biomarkers examined in this study did not associate with radiographic progression or severity. CONCLUSIONS: Plasma levels of IL1Ra were modestly associated with the severity and progression of SKOA in a causal fashion, independent of other risk factors. The findings may be useful in the search for prognostic biomarkers and development of disease-modifying OA drugs.

Meta-analysis of association between obsessive-compulsive disorder and the 3' region of neuronal glutamate transporter gene SLC1A1.

The neuronal glutamate transporter gene SLC1A1 is a candidate gene for obsessive-compulsive disorder (OCD) based on linkage studies and convergent evidence implicating glutamate in OCD etiology. The 3' end of SLC1A1 is the only genomic region with consistently demonstrated OCD association, especially when analyzing male-only probands. However, specific allele associations have not been consistently replicated, and recent OCD genome-wide association and meta-analysis studies have not incorporated all previously associated SLC1A1 SNPs. To clarify the nature of association between SLC1A1 and OCD, pooled analysis was performed on all available relevant raw study data, comprising a final sample of 815 trios, 306 cases and 634 controls. This revealed weak association between OCD and one of nine tested SLC1A1 polymorphisms (rs301443; uncorrected P = 0.046; non-significant corrected P). Secondary analyses of male-affecteds only (N = 358 trios and 133 cases) demonstrated modest association between OCD and a different SNP (rs12682807; uncorrected P = 0.012; non-significant corrected P). Findings of this meta-analysis are consistent with the trend of previous candidate gene studies in psychiatry and do not clarify the putative role of SLC1A1 in OCD pathophysiology. Nonetheless, it may be important to further examine the potential associations demonstrated in this amalgamated sample, especially since the SNPs with modest associations were not included in the more highly powered recent GWAS or in a past meta-analysis including five SLC1A1 polymorphisms. This study underscores the need for much larger sample sizes in future genetic association studies and suggests that next-generation sequencing may be beneficial in examining the potential role of rare variants in OCD.

Accelerating HIV epidemic control in Benue state, Nigeria, 2019-2021: the APIN program experience.

Introduction: As at 2019, Nigeria was ranked the fourth highest HIV burden in the world. There is varied geographical HIV prevalence in Nigeria. The progress made is inequitable across geographical locations and sub-populations (18). Benue state has the second highest HIV prevalence in Nigeria. In 2018, about 35,623 people living with HIV (PLHIV) were yet to commence antiretroviral treatment (ART) in the state, accounting for an estimated ART coverage gap of 11% out of the combined gap of 320,921 in the country. To close this gap, the Benue ART surge (BAS) was implemented. The aim of this study was to describe the BAS strategic approaches and demonstrate progress in expanding ART access for PLHIV in Benue State, Nigeria. Methods: BAS was implemented in 252 health facilities from May 2019 to September 2021. Data were collected and reported using an Excel-based dashboard and electronic medical records. The trend of HIV case identification, ART initiation, viral load suppression rate, and rate of interruption in treatment during the BAS period was then described and analyzed. Results: Out of 893,462 clients reached, 6.7% (n = 60,297) were diagnosed with HIV and 99.8% (n = 60,236) were initiated on ART. HIV case identification per month increased by 467% from 650 at baseline to a peak of 3685 in August 2020, and then declined by 35% to 2380 in September 2021. All new HIV-infected patients (100%) were linked to ART. Viral load testing coverage and viral load suppression rate increased from 30% (43,185/126,004) and 84% (n = 36,165/43,185) at baseline to 95% (n = 193,890/204,095) and 96% (185,785/193,890), respectively. Conclusion: Implementation of the BAS improved access to comprehensive HIV services in Benue State. The increase in HIV case identification and ART initiation significantly reduced the HIV treatment gap in the state. To fast track the attainment of UNAIDS 95-95-95 goals, lessons learnt from the BAS should be adapted and scaled up in the national HIV program in Nigeria.

Enhanced COMP catabolism detected in serum of patients with arthritis and animal disease models through a novel capture ELISA.

OBJECTIVE: The study aimed determining whether assessment of cartilage oligomeric matrix protein (COMP) degradation products could serve as a serological disease course and therapeutic response predictor in arthritis. METHODS: We generated a panel of monoclonal antibodies against COMP fragments and developed a novel capture enzyme-linked immunosorbent assay (ELISA) for detecting COMP fragments in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). This test was also used to monitor COMP fragments in surgically-induced OA, collagen-induced arthritis (CIA), and tumor necrosis factor (TNF) transgenic animal models. RESULTS: Compared with a commercial COMP ELISA kit that detected no significant difference in COMP levels between OA and control groups, a significant increase of the COMP fragments were noted in the serum of OA patients assayed by this newly established ELISA. In addition, serum COMP fragment levels were well correlated with severity in OA patients and the progression of surgically-induced OA in murine models. Furthermore, the serum levels of COMP fragments in RA patients, mice with CIA, and TNF transgenic mice were significantly higher when compared with their controls. Interestingly, treatment with TNFα inhibitors and methotrexate led to a significant decrease of serum COMP fragments in RA patients. Additionally, administration of Atsttrin [Tang, et al., Science 2011;332(6028):478] also resulted in a significant reduction in COMP fragments in arthritis mice models. CONCLUSION: A novel sandwich ELISA is capable of reproducibly measuring serum COMP fragments in both arthritic patients and rodent arthritis models. This test also provides a valuable means to utilize serum COMP fragments for monitoring the effects of interventions in arthritis.

Concordance between personality disorder assessment methods.

BACKGROUND: Studies have criticized the low level of agreement between the various methods of personality disorder (PD) assessment. This is an important issue for research and clinical purposes. METHOD: Seven hundred and forty-two participants in the Hopkins Epidemiology of Personality Disorders Study (HEPS) were assessed on two occasions using the Personality Disorder Schedule (PDS) and the International Personality Disorder Examination (IPDE). The concordance between the two diagnostic methods for all DSM-IV PDs was assessed using standard methods and also two item response analytic approaches designed to take account of measurement error: a latent trait-based approach and a generalized estimating equations (GEE)-based approach, with post-hoc adjustment. RESULTS: Raw criteria counts, using the intraclass correlation coefficient (ICC), κ and odds ratio (OR), showed poor concordance. The more refined statistical methods showed a moderate to moderately high level of concordance between the methods for most PDs studied. Overall, the PDS produced lower prevalences of traits but higher precision of measurement than the IPDE. Specific criteria within each PD showed varying endorsement thresholds and precision for ascertaining the disorder. CONCLUSIONS: Concordance in the raw measurement of the individual PD criteria between the two clinical methods is lacking. However, based on two statistical methods that adjust for differential endorsement thresholds and measurement error in the assessments, we deduce that the PD constructs themselves can be measured with a moderate degree of confidence regardless of the clinical approach used. This may suggest that the individual criteria for each PD are, in and of themselves, less specific for diagnosis, but as a group the criteria for each PD usefully identify specific PD constructs.

Is obsessive-compulsive disorder an anxiety disorder, and what, if any, are spectrum conditions? A family study perspective.

BACKGROUND: Experts have proposed removing obsessive-compulsive disorder (OCD) from the anxiety disorders section and grouping it with putatively related conditions in DSM-5. The current study uses co-morbidity and familiality data to inform these issues. METHOD: Case family data from the OCD Collaborative Genetics Study (382 OCD-affected probands and 974 of their first-degree relatives) were compared with control family data from the Johns Hopkins OCD Family Study (73 non-OCD-affected probands and 233 of their first-degree relatives). RESULTS: Anxiety disorders (especially agoraphobia and generalized anxiety disorder), cluster C personality disorders (especially obsessive-compulsive and avoidant), tic disorders, somatoform disorders (hypochondriasis and body dysmorphic disorder), grooming disorders (especially trichotillomania and pathological skin picking) and mood disorders (especially unipolar depressive disorders) were more common in case than control probands; however, the prevalences of eating disorders (anorexia and bulimia nervosa), other impulse-control disorders (pathological gambling, pyromania, kleptomania) and substance dependence (alcohol or drug) did not differ between the groups. The same general pattern was evident in relatives of case versus control probands. Results in relatives did not differ markedly when adjusted for demographic variables and proband diagnosis of the same disorder, though the strength of associations was lower when adjusted for OCD in relatives. Nevertheless, several anxiety, depressive and putative OCD-related conditions remained significantly more common in case than control relatives when adjusting for all of these variables simultaneously. CONCLUSIONS: On the basis of co-morbidity and familiality, OCD appears related both to anxiety disorders and to some conditions currently classified in other sections of DSM-IV.

Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study.

Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect.

Homeobox genes in obsessive-compulsive disorder.

BACKGROUND: Despite evidence that obsessive-compulsive disorder (OCD) is a familial neuropsychiatric condition, progress aimed at identifying genetic determinants of the disorder has been slow. The OCD Collaborative Genetics Study (OCGS) has identified several OCD susceptibility loci through linkage analysis. METHODS: In this study we investigate two regions on chromosomes 15q and 1q by first refining the linkage region using additional short tandem repeat polymorphic (STRP) markers. We then performed association analysis on single nucleotide polymorphisms (SNP) genotyped (markers placed every 2-4 kb) in the linkage regions in the OCGS sample of 376 rigorously phenotyped affected families. RESULTS: Three SNPs are most strongly associated with OCD: rs11854486 (P = 0.00005 [0.046 after adjustment for multiple tests]; genetic relative risk (GRR) = 11.1 homozygous and 1.6 heterozygous) and rs4625687 [P = 0.00007 (after adjustment = 0.06); GRR = 2.4] on 15q; and rs4387163 (P = 0.0002 (after adjustment = 0.08); GRR = 1.97) on 1q. The first SNP is adjacent to NANOGP8, the second SNP is in MEIS2, and the third is 150 kb between PBX1 and LMX1A. CONCLUSIONS: All the genes implicated by association signals are homeobox genes and are intimately involved in neurodevelopment. PBX1 and MEIS2 exert their effects by the formation of a heterodimeric complex, which is involved in development of the striatum, a brain region involved in the pathophysiology of OCD. NANOGP8 is a retrogene of NANOG, a homeobox transcription factor known to be involved in regulation of neuronal development. These findings need replication; but support the hypothesis that genes involved in striatal development are implicated in the pathogenesis of OCD.

Large-scale meta-analysis of interleukin-1 beta and interleukin-1 receptor antagonist polymorphisms on risk of radiographic hip and knee osteoarthritis and severity of knee osteoarthritis.

OBJECTIVE: To clarify the role of common genetic variation in the Interleukin-1ß (IL1B) and Interleukin-1R antagonist (IL1RN) genes on risk of knee and hip osteoarthritis (OA) and severity of knee OA by means of large-scale meta-analyses. METHODS: We searched PubMed for articles assessing the role of IL1B and IL1RN polymorphisms/haplotypes on the risk of hip and/or knee OA. Novel data were included from eight unpublished studies. Meta-analyses were performed using fixed- and random-effects models with a total of 3595 hip OA and 5013 knee OA cases, and 6559 and 9132 controls respectively. The role of ILRN haplotypes on radiographic severity of knee OA was tested in 1918 cases with Kellgren-Lawrence (K/L) 1 or 2 compared to 199 cases with K/L 3 or 4. RESULTS: The meta-analysis of six published studies retrieved from the literature search and eight unpublished studies showed no evidence of association between common genetic variation in the IL1B or IL1RN genes and risk of hip OA or knee OA (P>0.05 for rs16944, rs1143634, rs419598 and haplotype C-G-C (rs1143634, rs16944 and rs419598) previously implicated in risk of hip OA). The C-T-A haplotype formed by rs419598, rs315952 and rs9005, previously implicated in radiographic severity of knee OA, was associated with reduced severity of knee OA (odds ratio (OR)=0.71 95%CI 0.56-0.91; P=0.006, I(2)=74%), and achieved borderline statistical significance in a random-effects model (OR=0.61 95%CI 0.35-1.06 P=0.08). CONCLUSION: Common genetic variation in the Interleukin-1 region is not associated with prevalence of hip or knee OA but our data suggest that IL1RN might have a role in severity of knee OA.

Pandemic and bills: The impact of COVID-19 on energy usage of schools in South Africa.

The COVID-19 pandemic continues to wreak havoc on global operations and economies. Inadvertently, lock-downs and working from home have reduced the daily carbon footprints of inter alia transport and office buildings. A beneficial consequence of carbon footprint reductions is the ability to measure the differential demand of occupants, to benchmark the base load of buildings, and identify opportunities for efficiency improvements. In this paper we evaluate the change in energy demand in five public schools in South Africa with changes in occupancy due to the COVID-19-imposed lockdowns. We make recommendations to carry these savings into the everyday operation of the schools, and estimate the savings for forthcoming closures.

Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3-6 months' observation using advanced image analysis of 3T MRI?

PURPOSE: Prior investigations of magnetic resonance imaging (MRI) biomarkers of cartilage loss in knee osteoarthritis (OA) suggest that trials of interventions which affect this biomarker with adequate statistical power would require large clinical studies of 1-2 years duration. We hypothesized that smaller, shorter duration, "Proof of Concept" (PoC) studies might be achievable by: (1) selecting a population at high risk of rapid medial tibio-femoral (TF) progression, in conjunction with; (2) high-field MRI (3T), and; (3) using advanced image analysis. The primary outcome was the cartilage thickness in the central medial femur. METHODS: Multi-centre, non-randomized, observational cohort study at four sites in the US. Eligible participants were females with knee pain, a body mass index (BMI)> or =25 kg/m(2), symptomatic radiographic evidence of medial TF OA, and varus mal-alignment. The 29 participants had a mean age of 62 years, mean BMI of 36 kg/m(2), with eight index knees graded as Kellgren-Lawrence (K&L)=2 and 21 as K&L=3. Eligible participants had four MRI scans of one knee: two MRIs (1 week apart) were acquired as a baseline with follow-up MRI at 3 and 6 months. A trained operator, blind to time-point but not subject, manually segmented the cartilage from the Dual Echo Steady State water excitation MR images. Anatomically corresponding regions of interest were identified on each image by using a three-dimensional statistical shape model of the endosteal bone surface, and the cartilage thickness (with areas denuded of cartilage included as having zero thickness - ThCtAB) within each region was calculated. The percentage change from baseline at 3 and 6 months was assessed using a log-scale analysis of variance (ANOVA) model including baseline as a covariate. The primary outcome was the change in cartilage thickness within the aspect of central medial femoral condyle exposed within the meniscal window (w) during articulation, neglecting cartilage edges [nuclear (n)] (nwcMF x ThCtAB), with changes in other regions considered as secondary endpoints. RESULTS: Anatomical mal-alignment ranged from -1.9 degrees to 6.3 degrees , with mean 0.9 degrees . With one exception, no changes in ThCtAB were detected at the 5% level for any of the regions of interest on the TF joint at 3 or 6 months of follow-up. The change in the primary variable (nwcMF x ThCtAB) from (mean) baseline at 3 months from the log-scale ANOVA model was -2.1% [95% confidence interval (CI) (-4.4%, +0.2%)]. The change over 6 months was 0.0% [95% CI (-2.7%, +2.8%)]. The 95% CI for the change from baseline did not include zero for the cartilage thickness within the meniscal window of the lateral tibia (wLT x ThCtAB) at 6 month follow-up (-1.5%, 95% CI [-2.9, -0.2]), but was not significant at the 5% level after correction for multiple comparisons. CONCLUSIONS: The small inconsistent compartment changes, and the relatively high variabilities in cartilage thickness changes seen over time in this study, provide no additional confidence for a 3- or 6-month PoC study using a patient population selected on the basis of risk for rapid progression with the MRI acquisition and analyses employed.

A screen of SLC1A1 for OCD-related alleles.

SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and approximately 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one nonsynonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G > C, A27A; c.414A > G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases.

Obsessive-compulsive disorder: subclassification based on co-morbidity.

BACKGROUND: Obsessive-compulsive disorder (OCD) is probably an etiologically heterogeneous condition. Many patients manifest other psychiatric syndromes. This study investigated the relationship between OCD and co-morbid conditions to identify subtypes. METHOD: Seven hundred and six individuals with OCD were assessed in the OCD Collaborative Genetics Study (OCGS). Multi-level latent class analysis was conducted based on the presence of eight co-morbid psychiatric conditions [generalized anxiety disorder (GAD), major depression, panic disorder (PD), separation anxiety disorder (SAD), tics, mania, somatization disorders (Som) and grooming disorders (GrD)]. The relationship of the derived classes to specific clinical characteristics was investigated. RESULTS: Two and three classes of OCD syndromes emerge from the analyses. The two-class solution describes lesser and greater co-morbidity classes and the more descriptive three-class solution is characterized by: (1) an OCD simplex class, in which major depressive disorder (MDD) is the most frequent additional disorder; (2) an OCD co-morbid tic-related class, in which tics are prominent and affective syndromes are considerably rarer; and (3) an OCD co-morbid affective-related class in which PD and affective syndromes are highly represented. The OCD co-morbid tic-related class is predominantly male and characterized by high conscientiousness. The OCD co-morbid affective-related class is predominantly female, has a young age at onset, obsessive-compulsive personality disorder (OCPD) features, high scores on the 'taboo' factor of OCD symptoms, and low conscientiousness. CONCLUSIONS: OCD can be classified into three classes based on co-morbidity. Membership within a class is differentially associated with other clinical characteristics. These classes, if replicated, should have important implications for research and clinical endeavors.