A bis-quinoline ruthenium(II) arene complex with submicromolar cytotoxicity in castration-resistant prostate cancer cells.

A new Ru(II) arene chlorido organometallic complex [(η6-p-cymene)(L)RuCl]PF6 (named as pCYRuL) using 2-bis(quinolin-2-ylmethylene) hydrazine (L) was developed that exhibits potent anticancer activity against castration-resistant prostate cancer (CRPC) (IC50 = 0.71 µM), and it is 45 times more effective than the standard drug cisplatin (IC50 = 31.3 µM) in a castration-resistant human prostatic adenocarcinoma cell line (PC-3) but non-toxic in normal human kidney cells (HK2) as well as normal breast cells (MCF10A) and found that pCYRuL exerted anticancer activity via apoptosis induction and cell cycle arrest in the G2/M phase of PC-3 cells.

Design and Syntheses of Ruthenium ENE (E = S, Se) Pincer Complexes: A Versatile System for Catalytic and Biological Applications.

This report describes the synthesis of two ruthenium(II) ENE pincer complexes (E = S, C1 and E = Se, C2) by the reaction of bis(2-(phenylchalcogenyl)ethyl)amine (L1, L2) with RuCl2 (PPh3 )3 . The complexes were characterized with the help of 1 H and 13 C{1 H} NMR, FTIR, HRMS, cyclic voltammetry and elemental analysis techniques. The structure and bonding mode of ligand with ruthenium in C2 was established with the help of single crystal X-ray diffraction. The complex showed distorted octahedral geometry with two chlorine atoms trans to each other. The Ru-Se bond distances (Å) are 2.4564(3)-2.4630(3), Ru-N distance is 2.181(2), Ru-P distance is 2.2999(6), and Ru-Cl distances are 2.4078(6)-2.4314(6). The complexes showed good to excellent catalytic activity for the N-alkylation of o-phenylenediamine with benzyl alcohol derivatives to synthesize 1,2-disubstituted benzimidazole derivatives. The complexes were also found to be efficient for aerobic oxidation of benzyl alcohols to corresponding aldehydes which are precursors to the bisimines generated in situ during the synthesis of 1,2-disubstituted benzimidazole derivatives. Complex C2 where selenium is coordinated with ruthenium was found to be more efficient as compared to sulfur coordinated ruthenium complex C1. Since ruthenium complexes are getting increasing attention for developing new anticancer agents, the preliminary studies like binding behavior of both the complexes towards CT-DNA were studied by competitive binding with ethidium bromide (EthBr) using emission spectroscopy. In addition, the interactions of C1-C2 were also studied with bovine serum albumin (BSA) using steady state fluorescence quenching and synchronous fluorescence studies. A good stability of Ru(II) state was observed by cyclic voltammetric studies of C1-C2. Overall these molecules are good examples of bio-organometallic systems for catalytic and biological applications.

Azo-Stilbene and Pyridine-Amine Hybrid Multifunctional Molecules to Target Metal-Mediated Neurotoxicity and Amyloid-ß Aggregation in Alzheimer's Disease.

Neurodegenerative diseases such as Alzheimer's disease (AD) are associated with progressive neuronal cell death, and they are commonly correlated with aberrant protein misfolding and aggregation of Aß peptides. Transition metal ions (Cu, Fe, and Zn) have been shown to promote aggregation and oxidative stress through formation of Aß-metal complexes. In this context, integrating molecular scaffolds rationally is used here to generate multifunctional molecules as modulators for metal-induced abnormalities. This work encompasses two azo-stilbene (AS)-derived compounds (AS-HL1 and AS-HL2), the rationale behind the design, their synthesis, characterization, and metal chelation ability [Cu(II) and Zn(II)]. The molecular frameworks of the designed compounds consist of stilbene as an Aß-interacting moiety, whereas N,N,O and N,N,N,O donor atoms are linked to generate the metal chelation moiety. Furthermore, we went on exploring their multifunctionality with respect to (w.r.t.) (i) their metal chelating capacities and (ii) their utility to modulate the aggregation pathways of both metal-free and metal-bound amyloid-ß, (iii) scavenge free radicals, and (iv) inhibit the activity of acetylcholinesterase and (v) cytotoxicity. Moreover, the compounds were able to sequester Cu2+ from the Aß-Cu complex as studied by the UV-visible spectroscopic assay. Molecular docking studies were also performed with Aß and acetylcholinesterase enzyme. Overall, the studies presented here qualify these molecules as promising candidates for further investigation in the quest for finding a treatment for Alzheimer's disease.

High temperature spin crossover behaviour of mononuclear bis-(thiocyanato)iron(II) complexes with judiciously designed bidentate N-donor Schiff bases with varying substituents.

We present herein a family of molecular cis-[FeII(X-PPMA)2(NCS)2]·H2O [4-X-N-(phenyl(pyridin-2-yl)methylene)aniline; X-PPMA; X = -Cl (1), -Br (2), and -CH3 (3)] complexes that exhibit spin crossover behaviour above room temperature. Judiciously designed bidentate N-donor Schiff bases of 2-benzoylpyridine and para-substituted anilines in combination with Fe(NCS)2 were used for the synthesis of complexes 1-3. The relatively strong ligand field of the Schiff bases stabilises the low spin state of iron(II) up to 300 K which is evident from magnetic measurements, room temperature Mössbauer spectra and crystallographic bond/angle distortion parameters. Interestingly, complexes 1-3 crystallize in a tetragonal system with either a P43212 or P41212 chiral space group from achiral building units due to the supramolecular helical arrangements of molecules through intermolecular (pyridine)C-H⋯C(NCS) interactions in the crystalline state. Complexes 1 and 2 exhibit complete, gradual and slightly irreversible spin crossover behaviour in the temperature range of 300-500 K with equilibrium temperatures (T1/2) 375 K (1) and 380 K (2). The spin state evolution of iron(II) in complexes 1 and 2 is monitored between 150 K and 450 K through variable temperature crystallographic studies in the warming mode. The structural data are in good agreement with the 94% (1) and 87% (2) high spin conversion of iron(II) at 450 K. At a high temperature (450 K), some minor irreversible ligand motion is noticed in complexes 1 and 2, in addition to a complete solvent loss that may induce the slight irreversibility of the spin crossover. On the other hand, complex 3 shows a complete and gradual spin crossover in the temperature range of 10-475 K with strong irreversible features. The equilibrium temperatures obtained upon first warming (T1/2↑) and second cooling (T1/2↓) are 375 K and 200 K, respectively. In complex 3, the loss of a water molecule triggers strong deviations in the spin crossover behaviour. Moreover, dehydrated complex 3 exhibits photoswitching LIESST effect with a relaxation temperature T(LIESST) = 60 K.

Integration of Patient-reported Outcomes in a Total Joint Arthroplasty Program at a High-volume Academic Medical Center.

INTRODUCTION: Despite widely appreciated barriers to successful clinical implementation, the literature regarding how to operationalize electronic health record-integrated patient-reported outcomes (PROs) remains sparse. We offer a detailed summary of the implementation of PROs into the standard of care at a major tertiary academic medical center. METHODS: Collection of four Patient-Reported Outcomes Measurement Information System computer adaptive tests was piloted in a large academic orthopaedic surgery ambulatory clinic starting in October 2016. The Patient-Reported Outcomes Measurement Information System computer adaptive tests (Physical Function, Pain Intensity, Pain Interference, and Ability to Return to Social Roles and Activities) were initially implemented as manual order sets to be administered before surgery through 2 years after surgery. Completion rate over time, mean time to completion for all PRO domains, and the overall distribution of symptom severity were used to evaluate the success of the pilot. A subsequent optimization and redesign of the pilot was conducted using tablets, automation of questionnaire deployment, and improved results review to address obstacles encountered during the pilot phase. RESULTS: Two thousand nine distinct joint arthroplasty patients (mean age = 65) completed at least one set of PRO assessments, with overall completion rates reaching 68% and mean completion time of 3 minutes. Focal points during the implementation process included engagement and training of staff, selection of an appropriate patient population and outcome measures, and user friendly data displays for patients and providers. CONCLUSION: Our pilot program successfully demonstrated that PROs can be administered, scored, and made immediately available within the electronic health record to patients and their providers with minimal disruption of clinical workflows. Although considerable operational and technological challenges remain, we found that the implementation of PROs in clinical care within an ambulatory practice at an academic medical center can be achieved through a constellation of several key factors.

The Effect of Implant Design on Sagittal Plane Stability: A Randomized Trial of Medial- versus Posterior-Stabilized Total Knee Arthroplasty.

Up to 20% of total knee arthroplasty (TKA) patients report dissatisfaction with their outcome, especially with weight-bearing in flexion (WBiF) activities. Sagittal plane instability may contribute to dissatisfaction following TKA. We assessed the impact of implant design on TKA sagittal plane stability and clinical satisfaction. We randomized patients to receive one of two TKA implant designs: medial-stabilized (MS) or posterior-stabilized (PS). Sagittal stability was assessed using a KT-1000 arthrometer. Patient-reported outcome measures, including a custom bank of questions targeting patient satisfaction (0-100%) with WBiF activities, were administered to patients 2 years following surgery. The final analysis included 50 patients (25 MS, 25 PS). The MS group had greater sagittal plane stability than the PS group at 30-degree flexion (5.6 ± 1.9 vs. 10.2 ± 2.7 mm; p < 0.0001) but not at 90-degree flexion (4.1 ± 2 vs. 5.3 ± 3 mm; p = 0.14). Range of motion was not different (111.3 ± 10.4 vs. 114.7 ± 10.7 degrees; p = 0.31). There were no differences in the PROMIS (Patient-Reported Outcomes Measurement Information System) score, Oxford Knee Score, Knee Society Score, Forgotten Joint Score, or Veterans Rand. The MS group had no difference in satisfaction for WBiF activities versus non-WBiF activities (80.5 ± 18 vs. 88.3% ± 16.4%; p = 0.13), whereas the PS group had significantly worse satisfaction for WBiF versus non-WBiF activities (71.6 ± 24.6 vs. 87.8% ± 16.6%; p = 0.019). An MS prosthetic design was more stable in the sagittal plane in midflexion compared with a PS design. There was no difference in patient-reported outcomes, although custom survey data suggest improved satisfaction with MS design during WBiF activities.

Anterior versus posterior approach total hip arthroplasty: patient-reported and functional outcomes in the early postoperative period.

PURPOSE: Direct anterior approach total hip arthroplasty (DA THA) has been reported to improve early outcomes compared to posterior approach THA up to 6 weeks postoperatively. Limited weekly outcomes data are available prior to 6 weeks. We evaluate outcomes including when patients first drive a car, leave home, and discontinue their assist device. METHODS: Patients undergoing THA for primary osteoarthritis were prospectively enrolled. Outcomes data were collected preoperatively and postoperatively at weekly intervals for 6 weeks. RESULTS: 111 patients (55 DA and 56 posterior approach) were enrolled. There was no significant difference (p > 0.05) in pre-surgical Patient-Reported Outcomes Measurement Information System (PROMIS) scores or modified Harris Hip Score (mHHS).Postoperatively, the DA THA group had decreased length of stay (p = 0.0002) and increased distance walked on postoperative day 1 and 2 (p = 0.011, p = 0.0004). The DA group had lower pain scores (p < 0.05) and required less day 1 and total narcotics (p = 0.029, p = 0.01). The DA cohort had improved PROMIS Physical Function scores and mHHS up to 5 weeks postoperatively. DA patients discontinued their assistive device 8 days earlier (p = 0.01), left home 3 days earlier (p = 0.001), and drove a car 5 days earlier (p = 0.01). CONCLUSIONS: Patients undergoing DA THA discontinued their assistive device, left their home, and drove a car sooner than posterior approach patients. We found improvement in physical function with DA, and it persisted up to 5 weeks postoperatively. Furthermore, DA patients had significantly shorter length of stay, improved mobilisation, decreased narcotic requirements and improved inpatient pain scores compared to posterior approach THA. Future randomised controlled study should be performed to minimise the biases inherent in this study methodology and confirm the results.

Provider perspectives on the integration of patient-reported outcomes in an electronic health record.

OBJECTIVE: Integrating patient-reported outcomes (PROs) into electronic health records (EHRs) can improve patient-provider communication and delivery of care. However, new system implementation in health-care institutions is often accompanied by a change in clinical workflow and organizational culture. This study examines how well an EHR-integrated PRO system fits clinical workflows and individual needs of different provider groups within 2 clinics. MATERIALS AND METHODS: Northwestern Medicine developed and implemented an EHR-integrated PRO system within the orthopedics and oncology departments. We conducted interviews with 11 providers who had interacted with the system. Through thematic analysis, we synthesized themes regarding provider perspectives on clinical workflow, individual needs, and system features. RESULTS: Our findings show that EHR-integrated PROs facilitate targeted conversation with patients and automated triage for psychosocial care. However, physicians, psychosocial providers, and medical assistants faced different challenges in their use of the PRO system. Barriers mainly stemmed from a lack of actionable data, workflow disruption, technical issues, and a lack of incentives. DISCUSSION: This study sheds light on the ecosystem around EHR-integrated PRO systems (such as user needs and organizational factors). We present recommendations to address challenges facing PRO implementation, such as optimizing data collection and auto-referral processes, improving data visualizations, designing effective educational materials, and prioritizing the primary user group. CONCLUSION: PRO integration into routine care can be beneficial but also require effective technology design and workflow configuration to reach full potential use. This study provides insights into how patient-generated health data can be better integrated into clinical practice and care delivery processes.

A Comparison of Patient-Centered Outcome Measures to Evaluate Dysphagia and Dysphonia After Anterior Cervical Discectomy and Fusion.

OF BACKGROUND DATA: Dysphagia and dysphonia are the most common complications after anterior cervical diskectomy and fusion (ACDF). No consensus system exists currently in the spine literature for the classification of these conditions postoperatively. OBJECTIVE: The purpose of this analysis was to evaluate the validity and reliability of the Eating Assessment Tool (EAT-10) in the assessment of dysphagia when compared with the Bazaz score. A secondary goal was to assess the Voice Handicap Index (VHI-10) scores among patients following ACDF. METHODS: Patients treated with ACDF (one, two, or three level) for cervical radiculopathy and/or cervical myelopathy at two tertiary hospitals were administered patient-reported outcome metrics preoperatively as well as at multiple time points postoperatively. The metrics administered included the EAT-10, VHI-10, Bazaz, Neck Disbability Index, and EuroQol Five Dimensions questionnaire (EQ-5D)/visual analog scale. RESULTS: One hundred patients were included in this study. Eighty-nine percentage had a 1-year follow-up, and 100% had a 12-week follow-up. Mean Neck Disbability Index, EQ-5D, and EQ-visual analog scale scores all improved from baseline at both 6 months and 1 year postoperatively. Both the EAT-10 and VHI-10 demonstrated excellent internal reliability (α = 0.95 and α = 0.90, respectively). Analysis of variance of EAT-10 and VHI-10 scores by time point demonstrated a statistically significant relationship (P < 0.0001). The EAT-10 and VHI-10 scores were statistically greater on postoperative day 1 than at all other times (Tukey posthoc, P < 0.0001 and P < 0.004, respectively). Across all time points, 176 instances of clinically significant dysphagia (EAT-10 ≥ 3) were noted, 57 (32%) of which were classified as "None" on the Bazaz classification. CONCLUSIONS: The EAT-10 score is an accurate measure for mild to severe dysphagia and better captured significant dysphagia that would have otherwise been missed when the Bazaz score is used. EAT-10 and VHI-10 are better measures of postoperative dysphagia and dysphonia than the current metrics used in spine surgery. STUDY DESIGN: This was a prospective cohort study of consecutive patients.

The use of a novel tablet application to quantify dysfunction in cervical spondylotic myelopathy patients.

BACKGROUND CONTEXT: Despite the prevalence and importance of myelopathy, there is a paucity of objective and quantitative clinical measures. The most commonly used diagnostic tools available are nonquantitative physical exam findings (eg, pathologic reflexes, and gait disturbance) and subjective scoring systems (eg, modified Japanese Orthopaedic Association [mJOA]). A decline in fine motor coordination is a hallmark of early myelopathy, which may be useful for quantitative testing. PURPOSE: To identify if a novel tablet application could provide a quantitative measure of upper extremity dysfunction in cervical spondylotic myelopathy. STUDY DESIGN/SETTING: Prospective cohort study Patient Sample: Adult patients with a diagnosis of cervical spondylotic myelopathy from a board-certified, spine surgeon were compared with age-matched, healthy, and adult control patients. OUTCOME MEASURES: Self-reported function was assessed via the mJOA. Upper extremity function was measured via the fine motor skills (FiMS) tablet test. METHODS: Subjects and controls prospectively completed the mJOA paper survey and the FiMS tablet testing, which consisted of four challenges. RESULTS: After age-matching, 65 controls and 28 myelopathic patients were available for comparison. The mean mJOA was 13.5 ± 2.9 in the myelopathic cohort and 17.3 ± 1.1 in the control cohort (p < .0001). The average scores for challenges 1-4 in control patients were 24.4, 16.3, 3.2, and 6.6, respectively, whereas the average scores for the myelopathic patients were 16.6, 10.5, 1.4, and 1.8, respectively (p values for all four challenges <.001). Based upon the 15 control subjects who repeated FiMS testing four sequential times, intrarater reliability was excellent, yielding an interclass correlation coefficient of 0.88 CONCLUSIONS: The FiMS tablet application produced significantly lower scores in a myelopathic cohort when compared with an age-matched control cohort. This is true for all four challenges in the FiMS tablet application. The test can be completed in 1.5 minutes, producing a reliable, quantitative measure of cervical myelopathy upper extremity function. In summary, the FiMS tablet application is a novel, easily administered, objectively quantifiable test for analyzing cervical spondylotic myelopathy.

Validation of Patient-reported Outcomes Measurement Information System Computer Adaptive Tests in Lumbar Disk Herniation Surgery.

INTRODUCTION: Inadequate validation, floor/ceiling effects, and time constraints limit utilization of standardized patient-reported outcome measures. We aimed to validate Patient-reported Outcomes Measurement Information System (PROMIS) computer adaptive tests (CATs) for patients treated surgically for a lumbar disk herniation. METHODS: PROMIS, CATs, Oswestry Disability Index, and Short Form-12 measures were administered to 78 patients treated with lumbar microdiskectomy for symptomatic disk herniation with radiculopathy. RESULTS: PROMIS CATs demonstrated convergent validity with legacy measures; PROMIS scores were moderately to highly correlated with the Oswestry Disability Index and Short Form-12 physical component scores (r = 0.41 and 0.78, respectively). PROMIS CATs demonstrated similar responsiveness to change compared with legacy measures. On average, the PROMIS CATs were completed in 2.3 minutes compared with 5.7 minutes for legacy measures. DISCUSSION: The PROMIS CATs demonstrate convergent and known groups' validity and are comparable in responsiveness to legacy measures. These results suggest similar utility and improved efficiency of PROMIS CATs compared with legacy measures. LEVELS OF EVIDENCE: Level II.

The Effect of Local Versus Intravenous Corticosteroids on the Likelihood of Dysphagia and Dysphonia Following Anterior Cervical Discectomy and Fusion: A Single-Blinded, Prospective, Randomized Controlled Trial.

BACKGROUND: Dysphagia and dysphonia are the most common postoperative complications following anterior cervical discectomy and fusion (ACDF). Although most postoperative dysphagia is mild and transient, severe dysphagia can have profound effects on overall patient health and on surgical outcomes. The purpose of this study was to compare the efficacy of local to intravenous (IV) steroid administration during ACDF on postoperative dysphagia and dysphonia. METHODS: This was a single-blinded, prospective, randomized clinical trial. Seventy-five patients undergoing ACDF with cervical plating were randomized into 3 groups: control (no steroid), IV steroid (10 mg of IV dexamethasone at the time of closure), or local steroid (40 mg of local triamcinolone). Patient-reported outcome measures (PROMs) were collected for dysphagia, dysphonia, and neck pain postoperatively for 1 year. RESULTS: Patient demographics were similar. Postoperative day 1 PROMs showed significantly lower scores for dysphonia (p = 0.015) and neck pain (p = 0.034) in the local steroid group. At 2 weeks postoperatively, the local steroid cohort showed significantly decreased prevalence of severe dysphagia (Eating Assessment Tool-10 [EAT-10], severe dysphagia, p = 0.027) compared with the control and IV steroid groups. Both steroid groups had significantly less severe dysphagia when compared with the control group at the 6-week and 3-month time points. At 1 year postoperatively, both steroid groups had significantly reduced dysphagia rates (p = 0.014) compared with the control group. CONCLUSIONS: Both local and IV steroid administration after cervical plating in ACDF yielded better PROMs for dysphagia compared with a control group. This finding is particularly evident in the reduced number of patients who reported severe dysphagia symptoms following ACDF with local steroid application within the first 2 postoperative weeks. Future studies should attempt to stratify dysphagia severity when reporting outcomes related to anterior cervical spine surgery. LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

High-resolution magnetization transfer MRI in patients with cervical spondylotic myelopathy.

Magnetization transfer (MT) contrast has been established as a marker of myelin integrity, and cervical spondylotic myelopathy is known to cause demyelination. Ten patients with clinical and magnetic resonance imaging (MRI) manifestations of cervical spondylotic myelopathy (CSM) were compared to the MRIs of seven historic healthy controls, using the magnetization transfer ratio (MTR) and Nurick scores as the primary metrics. Transverse slices through the intervertebral discs of the cervical spine were acquired using a gradient echo sequence (MEDIC) with and without an MT saturation pulse on a 3 Tesla Siemens Prisma scanner (TR = 300 ms, TEeff = 17 ms, flip angle = 30°, in-plane resolution = 0.47 × 0.47 mm2). The CSM patients tended to have a lower mean MTR (30.4 ±â€¯6.5) than the controls (34.8 ±â€¯3.8), but the difference was not significant (independent samples t-test, p = 0.110, Cohen's d = 0.80). The mean MTR across all intervertebral disc levels was not significantly correlated to the Nurick score (Spearman's ρ = -0.489, p = 0.151). The intervertebral level with the lowest MTR in each cohort was not significantly different between groups (equal variances not assumed, t = 1.965, dof = 14.8, p = 0.068, Cohen's d = 0.88), but the CSM patients tended to have a lower MTR. The mean MTR at this level was negatively correlated to the Nurick score among CSM patients (Spearman's ρ = -0.725, p = 0.018). CSM patients tended to have decreased MTR indicating myelin degradation compared to our healthy subjects, and MTR was negatively correlated with the severity of CSM.

Validation of Patient Reported Outcomes Measurement Information System (PROMIS) Computer Adaptive Tests (CATs) in the Surgical Treatment of Lumbar Spinal Stenosis.

STUDY DESIGN: Prospective, cohort study. OBJECTIVE: Demonstrate validity of Patient reported outcomes measurement information system (PROMIS) physical function, pain interference, and pain behavior computer adaptive tests (CATs) in surgically treated lumbar stenosis patients. SUMMARY OF BACKGROUND DATA: There has been increasing attention given to patient reported outcomes associated with spinal interventions. Historical patient outcome measures have inadequate validation, demonstrate floor/ceiling effects, and infrequently used due to time constraints. PROMIS is an adaptive, responsive National Institutes of Health (NIH) assessment tool that measures patient-reported health status. METHODS: Ninety-eight consecutive patients were surgically treated for lumbar spinal stenosis and were assessed using PROMIS CATs, Oswestry disability index (ODI), Zurich Claudication Questionnaire (ZCQ), and Short-Form 12 (SF-12). Prior lumbar surgery, history of scoliosis, cancer, trauma, or infection were excluded. Completion time, preoperative assessment, 6 weeks and 3 months postoperative scores were collected. RESULTS: At baseline, 49%, 79%, and 81% of patients had PROMIS pain behavior (PB), pain interference (PI), and physical function (PF) scores greater than 1 standard deviation (SD) worse than the general population. 50.6% were categorized as severely disabled, crippled, or bed bound by ODI. PROMIS CATs demonstrated convergent validity through moderate to high correlations with legacy measures (r = 0.35-0.73). PROMIS CATs demonstrated known groups validity when stratified by ODI levels of disability. ODI improvements of at least 10 points on average had changes in PROMIS scores in the expected direction (PI = -12.98, PB = -9.74, PF = 7.53). PROMIS CATs demonstrated comparable responsiveness to change when evaluated against legacy measures. PROMIS PB and PI decreased 6.66 and 9.62 and PROMIS PF increased 6.8 points between baseline and 3-months post-op (P < 0.001). Completion time for the PROMIS CATs (2.6 min) compares favorably to ODI, ZCQ, and SF-12 scores (3.1, 3.6, and 3.0 min). CONCLUSION: PROMIS CATs demonstrate convergent validity, known groups validity, and responsiveness for surgically treated patients with lumbar stenosis to detect change over time and are more efficient than legacy instruments. LEVEL OF EVIDENCE: 2.

Validation of Patient-Reported Outcomes Measurement Information System (PROMIS) computerized adaptive tests in cervical spine surgery.

OBJECTIVE The Patient-Reported Outcomes Measurement Information System (PROMIS), which is funded by the National Institutes of Health, is a set of adaptive, responsive assessment tools that measures patient-reported health status. PROMIS measures have not been validated for surgical patients with cervical spine disorders. The objective of this project is to evaluate the validity (e.g., convergent validity, known-groups validity, responsiveness to change) of PROMIS computer adaptive tests (CATs) for pain behavior, pain interference, and physical function in patients undergoing cervical spine surgery. METHODS The legacy outcome measures Neck Disability Index (NDI) and SF-12 were used as comparisons with PROMIS measures. PROMIS CATs, NDI-10, and SF-12 measures were administered prospectively to 59 consecutive tertiary hospital patients who were treated surgically for degenerative cervical spine disorders. A subscore of NDI-5 was calculated from NDI-10 by eliminating the lifting, headaches, pain intensity, reading, and driving sections and multiplying the final score by 4. Assessments were administered preoperatively (baseline) and postoperatively at 6 weeks and 3 months. Patients presenting for revision surgery, tumor, infection, or trauma were excluded. Participants completed the measures in Assessment Center, an online data collection tool accessed by using a secure login and password on a tablet computer. Subgroup analysis was also performed based on a primary diagnosis of either cervical radiculopathy or cervical myelopathy. RESULTS Convergent validity for PROMIS CATs was supported with multiple statistically significant correlations with the existing legacy measures, NDI and SF-12, at baseline. Furthermore, PROMIS CATs demonstrated known-group validity and identified clinically significant improvements in all measures after surgical intervention. In the cervical radiculopathy and myelopathic cohorts, the PROMIS measures demonstrated similar responsiveness to the SF-12 and NDI scores in the patients who self-identified as having postoperative clinical improvement. PROMIS CATs required a mean total of 3.2 minutes for PROMIS pain behavior (mean ± SD 0.9 ± 0.5 minutes), pain interference (1.2 ± 1.9 minutes), and physical function (1.1 ± 1.4 minutes) and compared favorably with 3.4 minutes for NDI and 4.1 minutes for SF-12. CONCLUSIONS This study verifies that PROMIS CATs demonstrate convergent and known-groups validity and comparable responsiveness to change as existing legacy measures. The PROMIS measures required less time for completion than legacy measures. The validity and efficiency of the PROMIS measures in surgical patients with cervical spine disorders suggest an improvement over legacy measures and an opportunity for incorporation into clinical practice.

The inflammatory gene pathway is not a major contributor to polycystic ovary snydrome.

CONTEXT: Although inflammation is clearly associated with obesity, diabetes, and insulin resistance, the role of chronic inflammation in the etiology of polycystic ovary syndrome (PCOS) is unclear. OBJECTIVE: To determine whether chronic inflammation plays a causal role in the etiology of PCOS, we tested for an association between PCOS and genetic markers mapping to 80 members of the inflammatory pathway. DESIGN: This was a case-control association study. SETTING: The setting was an academic medical center. PATIENTS OR PARTICIPANTS: A total of 905 index case patients with PCOS and 955 control women (108 intensively phenotyped subjects with normal androgen levels and regular menses and 847 minimally phenotyped subjects with regular menses and no history of PCOS). INTERVENTIONS: Subjects were genotyped at single nucleotide polymorphisms mapping to 80 inflammatory genes. Logistic regression was used to test for an association between 822 single nucleotide polymorphisms and PCOS after adjustment for population stratification, body mass index, and/or age. In the index patients, we also tested for association with 11 quantitative traits (body mass index and testosterone, fasting insulin, fasting glucose, 2-hour postchallenge glucose, LH, FSH, total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride levels). MAIN OUTCOME MEASURES: The evidence for an association with PCOS and with 11 quantitative traits was investigated. RESULTS: Nominally significant evidence for an association was observed with MAP3K7, IKBKG, TNFRS11A, AKT2, IL6R, and IRF1, but no results remained statistically significant after adjustment for multiple testing. CONCLUSIONS: Genetic variation in the inflammatory pathway is not a major contributor to the etiology of PCOS or related quantitative traits in women with PCOS.

Accumulation of cadmium in insulin-producing ß cells.

Evidence suggests that chronic low level cadmium exposure impairs the function of insulin-producing ß cells and may be associated with type-2 diabetes mellitus. Herein, we describe the cadmium content in primary human islets and define the uptake kinetics and effects of environmentally relevant cadmium concentrations in cultured ß cells. The average cadmium content in islets from 10 non-diabetic human subjects was 29 ± 7 nmol/g protein (range 7 to 72 nmol/g protein). Exposure of the ß-cell line MIN6 to CdCl 2 concentrations between 0.1 and 1.0 µmol/L resulted in a dose- and time-dependent uptake of cadmium over 72 h. This uptake resulted in an induction of metallthionein expression, likely enhancing cellular cadmium accumulation. Furthermore, cadmium accumulation resulted in an inhibition of glucose stimulated insulin secretion in MIN6 cells and primary mouse islets. Our results indicate that this impairment in ß-cell function is not due to an increase in cell death or due to an increase in oxidative stress. We conclude that mouse ß cells accumulate cadmium in a dose- and time-dependent manner over a prolonged time course at environmentally relevant concentrations. This uptake leads to a functional impairment of ß-cell function without significant alterations in cell viability, expression of genes important for ß-cell function or increase in oxidative stress.

Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents ß cell failure in rodent models of type 2 diabetes.

The failure of pancreatic ß cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from ß cell failure. We previously found that the hormone 17ß-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against ß cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERß in a rat ß cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα-/-) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα-/- mice were predisposed to islet lipid accumulation and ß cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited ß cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent ß cell failure in T2D.