Associations of symptomatic knee OA with histopathologic features in subchondral bone

© 2019, American College of Rheumatology Objective: Subchondral bone and the osteochondral junction are thought to contribute to osteoarthritis (OA) knee pain. We undertook this study to identify osteochondral pathologies specifically associated with symptomatic human knee OA. Methods: Medial tibial plateau samples from 2 groups of subjects (n = 31 per group) were matched for macroscopic chondropathy scores. The symptomatic chondropathy group had undergone total knee replacement for OA knee pain, at which time specimens of the medial tibial plateau were obtained. The asymptomatic chondropathy group included subjects who died of unrelated illness (specimens were obtained at postmortem examination) and who had not previously sought help for knee pain. OA histopathology, immunoreactivity for nerve growth factor (NGF) and CD68 (macrophages), tartrate-resistant acid phosphatase–positive subchondral osteoclasts, and synovitis were compared between groups. Results: Mankin scores, subchondral bone density, and subchondral CD68-immunoreactive macrophage infiltration were similar between the 2 groups. NGF-like immunoreactivity was found in subchondral mononuclear cells and osteoclasts, as well as in chondrocytes. NGF in osteochondral channels and osteoclast densities in subchondral bone were higher in the symptomatic chondropathy group than in the asymptomatic chondropathy group (P < 0.01 and P = 0.02, respectively), as were synovitis scores (P < 0.01). Osteochondral pathology was not significantly associated with synovitis score. The differences in NGF expression and in osteoclast density remained significant after adjustment for age and synovitis score (P = 0.01 and P = 0.04, respectively). Osteochondral NGF and osteoclast densities, together with synovitis scores, explained ~28% of sample allocation to symptomatic or asymptomatic groups. Conclusion: Subchondral pathology was associated with symptomatic knee OA, independent of chondropathy and synovitis. Increased NGF expression in osteochondral channels and increased osteoclast density appear to be key features associated with bone pain in knee OA

Two-Dimensional Helioseismic Power, Phase, and Coherence Spectra of {\it Solar Dynamics Observatory} Photospheric and Chromospheric Observables

While the {\it Helioseismic and Magnetic Imager} (HMI) onboard the {\it Solar Dynamics Observatory} (SDO) provides Doppler velocity [$V$], continuum intensity [$I_C$], and line-depth [$Ld$] observations, each of which is sensitive to the five-minute acoustic spectrum, the {\it Atmospheric Imaging Array} (AIA) also observes at wavelengths -- specifically the 1600 and 1700 Angstrom bands -- that are partly formed in the upper photosphere and have good sensitivity to acoustic modes. In this article we consider the characteristics of the spatio--temporal Fourier spectra in AIA and HMI observables for a 15-degree region around NOAA Active Region 11072. We map the spatio--temporal-power distribution for the different observables and the HMI Line Core [$I_L$], or Continuum minus Line Depth, and the phase and coherence functions for selected observable pairs, as a function of position and frequency. Five-minute oscillation power in all observables is suppressed in the sunspot and also in plage areas. Above the acoustic cut-off frequency, the behaviour is more complicated: power in HMI $I_C$ is still suppressed in the presence of surface magnetic fields, while power in HMI $I_L$ and the AIA bands is suppressed in areas of surface field but enhanced in an extended area around the active region, and power in HMI $V$ is enhanced in a narrow zone around strong-field concentrations and suppressed in a wider surrounding area. The relative phase of the observables, and their cross-coherence functions, are also altered around the active region. These effects may help us to understand the interaction of waves and magnetic fields in the different layers of the photosphere, and will need to be taken into account in multi-wavelength local helioseismic analysis of active regions.Comment: 18 pages, 15 figures, to be published in Solar Physic

Surveillance for Waterborne-Disease Outbreaks Associated with Drinking Water--United States, 2001-2002

PROBLEM/CONDITION: Since 1971, CDC, the U.S. Environmental Protection Agency, and the Council of State and Territorial Epidemiologists have maintained a collaborative surveillance system for collecting and periodically reporting data related to occurrences and causes of waterborne-disease outbreaks (WBDOs). This surveillance system is the primary source of data concerning the scope and effects of waterborne disease outbreaks on persons in the United States. REPORTING PERIOD COVERED: This summary includes data on WBDOs associated with drinking water that occurred during January 2001-December 2002 and on three previously unreported outbreaks that occurred during 2000. DESCRIPTION OF SYSTEM: Public health departments in the states, territories, localities, and the Freely Associated States are primarily responsible for detecting and investigating WBDOs and voluntarily reporting them to CDC on a standard form. The surveillance system includes data for outbreaks associated with both drinking water and recreational water; only outbreaks associated with drinking water are reported in this summary. RESULTS: During 2001-2002, a total of 31 WBDOs associated with drinking water were reported by 19 states. These 31 outbreaks caused illness among an estimated 1,020 persons and were linked to seven deaths. The microbe or chemical that caused the outbreak was identified for 24 (77.4%) of the 31 outbreaks. Of the 24 identified outbreaks, 19 (79.2%) were associated with pathogens, and five (20.8%) were associated with acute chemical poisonings. Five outbreaks were caused by norovirus, five by parasites, and three by non-Legionella bacteria. All seven outbreaks involving acute gastrointestinal illness of unknown etiology were suspected of having an infectious cause. For the first time, this MMWR Surveillance Summary includes drinking water-associated outbreaks of Legionnaires disease (LD); six outbreaks of LD occurred during 2001-2002. Of the 25 non-Legionella associated outbreaks, 23 (92.0%) were reported in systems that used groundwater sources; nine (39.1%) of these 23 groundwater outbreaks were associated with private noncommunity wells that were not regulated by EPA. INTERPRETATION: The number of drinking water-associated outbreaks decreased from 39 during 1999-2000 to 31 during 2001-2002. Two (8.0%) outbreaks associated with surface water occurred during 2001-2002; neither was associated with consumption of untreated water. The number of outbreaks associated with groundwater sources decreased from 28 during 1999-2000 to 23 during 2001-2002; however, the proportion of such outbreaks increased from 73.7% to 92.0%. The number of outbreaks associated with untreated groundwater decreased from 17 (44.7%) during 1999-2000 to 10 (40.0%) during 2001-2002. Outbreaks associated with private, unregulated wells remained relatively stable, although more outbreaks involving private, treated wells were reported during 2001-2002. Because the only groundwater systems that are required to disinfect their water supplies are public systems under the influence of surface water, these findings support EPA\u27s development of a groundwater rule that specifies when corrective action (including disinfection) is required. PUBLIC HEALTH ACTION: CDC and EPA use surveillance data 1) to identify the types of water systems, their deficiencies, and the etiologic agents associated with outbreaks and 2) to evaluate the adequacy of technologies for providing safe drinking water. Surveillance data are used also to establish research priorities, which can lead to improved water-quality regulations. CDC and EPA recently completed epidemiologic studies that assess the level of waterborne illness attributable to municipal drinking water in nonoutbreak conditions. The decrease in outbreaks in surface water systems is attributable primarily to implementation of provisions of EPA rules enacted since the late 1980s. Rules under development by EPA are expected to protect the public further from microbial contaminants while addressing risk tradeoffs of disinfection byproducts in drinking water

Surveillance for Waterborne-Disease Outbreaks Associated With Recreational Water--United States, 2001-2002

PROBLEM/CONDITION: Since 1971, CDC, the U.S. Environmental Protection Agency, and the Council of State and Territorial Epidemiologists have maintained a collaborative surveillance system for collecting and periodically reporting data related to occurrences and causes of waterborne-disease outbreaks (WBDOs) related to drinking water; tabulation of recreational water-associated outbreaks was added to the surveillance system in 1978. This surveillance system is the primary source of data concerning the scope and effects of waterborne disease outbreaks on persons in the United States. REPORTING PERIOD COVERED: This summary includes data on WBDOs associated with recreational water that occurred during January 2001-December 2002 and on a previously unreported outbreak that occurred during 1998. DESCRIPTION OF SYSTEM: Public health departments in the states, territories, localities, and the Freely Associated States are primarily responsible for detecting and investigating WBDOs and voluntarily reporting them to CDC on a standard form. The surveillance system includes data for outbreaks associated with both drinking water and recreational water; only outbreaks associated with recreational water are reported in this summary. RESULTS: During 2001-2002, a total of 65 WBDOs associated with recreational water were reported by 23 states. These 65 outbreaks caused illness among an estimated 2,536 persons; 61 persons were hospitalized, eight of whom died. This is the largest number of recreational water-associated outbreaks to occur since reporting began in 1978; the number of recreational water-associated outbreaks has increased significantly during this period (p INTERPRETATION: The 30 outbreaks involving gastroenteritis comprised the largest proportion of recreational water-associated outbreaks during this reporting period. These outbreaks were associated most frequently with Cryptosporidium (50.0%) in treated water venues and with toxigenic Escherichia coli (25.0%) and norovirus (25.0%) in freshwater venues. The increase in the number of outbreaks since 1993 could reflect improved surveillance and reporting at the local and state level, a true increase in the number of WBDOs, or a combination of these factors. PUBLIC HEALTH ACTION: CDC uses surveillance data to identify the etiologic agents, types of aquatics venues, water-treatment systems, and deficiencies associated with outbreaks and to evaluate the adequacy of efforts (e.g., regulations and public awareness activities) for providing safe recreational water. Surveillance data are also used to establish public health prevention priorities, which might lead to improved water-quality regulations at the local, state, and federal levels

Molecular correlates of vaccine-induced protection against typhoid fever

BACKGROUNDTyphoid fever is caused by the Gram-negative bacterium Salmonella enterica serovar Typhi and poses a substantial public health burden worldwide. Vaccines have been developed based on the surface Vi-capsular polysaccharide of S. Typhi; these include a plain-polysaccharide-based vaccine, ViPS, and a glycoconjugate vaccine, ViTT. To understand immune responses to these vaccines and their vaccine-induced immunological protection, molecular signatures were analyzed using bioinformatic approaches.METHODSBulk RNA-Seq data were generated from blood samples obtained from adult human volunteers enrolled in a vaccine trial, who were then challenged with S. Typhi in a controlled human infection model (CHIM). These data were used to conduct differential gene expression analyses, gene set and modular analyses, B cell repertoire analyses, and time-course analyses at various post-vaccination and post-challenge time points between participants receiving ViTT, ViPS, or a control meningococcal vaccine.RESULTSTranscriptomic responses revealed strong differential molecular signatures between the 2 typhoid vaccines, mostly driven by the upregulation in humoral immune signatures, including selective usage of immunoglobulin heavy chain variable region (IGHV) genes and more polarized clonal expansions. We describe several molecular correlates of protection against S. Typhi infection, including clusters of B cell receptor (BCR) clonotypes associated with protection, with known binders of Vi-polysaccharide among these.CONCLUSIONThe study reports a series of contemporary analyses that reveal the transcriptomic signatures after vaccination and infectious challenge, while identifying molecular correlates of protection that may inform future vaccine design and assessment.TRIAL REGISTRATIONClinicalTrials.gov NCT02324751

The Tides They Are A-Changin': A Comprehensive Review of Past and Future Nonastronomical Changes in Tides, Their Driving Mechanisms, and Future Implications:A comprehensive review of past and future non‐astronomical changes in tides, their driving mechanisms and future implications

Scientists and engineers have observed for some time that tidal amplitudes at many locations are shifting considerably due to non-astronomical factors. Here we review comprehensively these important changes in tidal properties, many of which remain poorly understood. Over long geological time-scales, tectonic processes drive variations in basin size, depth, and shape, and hence the resonant properties of ocean basins. On shorter geological time-scales, changes in oceanic tidal properties are dominated by variations in water depth. A growing number of studies have identified widespread, sometimes regionally-coherent, positive and negative trends in tidal constituents and levels during the 19th, 20th and early 21st centuries. Determining the causes is challenging because a tide measured at a coastal gauge integrates the effects of local, regional, and oceanic changes. Here, we highlight six main factors that can cause changes in measured tidal statistics on local scales, and a further eight possible regional/global driving mechanisms. Since only a few studies have combined observations and models, or modelled at a temporal/spatial resolution capable of resolving both ultra-local and large-scale global changes, the individual contributions from local and regional mechanisms remain uncertain. Nonetheless, modelling studies project that sea-level rise and climate change will continue to alter tides over the next several centuries, with regionally coherent modes of change caused by alterations to coastal morphology and ice sheet extent. Hence, a better understanding of the causes and consequences of tidal variations is needed to help assess the implications for coastal defense, risk assessment, and ecological change

Assessing dysphagia via telerehabilitation: patient perceptions and satisfaction

To gain insight into factors which may infl uence future acceptance of dysphagia management via telerehabilitation, patients’ perceptions were examined before and after a telerehabilitation assessment session. Forty adult patients with dysphagia(M = 66 years, SD = 16.25) completed pre- and post-session questionnaires which consisted of 14 matched questions worded to suit pre- and post-conditions. Questions explored comfort with the use of telerehabilitation, satisfaction with audio and video quality, benefi ts of telerehabilitation assessments and patients’ preferred assessment modality. Questions were rated on a 5-point scale (1 = strongly disagree, 3 = unsure, 5 = strongly agree). Patients’ comfort with assessment via telerehabilitation was high in over 80% of the group both pre- and post-assessment. Pre-assessment, patients were unsure what to expect with the auditory and visual aspects of the videoconference, however there were signifi cant positive changes reported post-experience. In relation to perceived benefits of telerehabilitation services in general, most patients believed in the value of telerehabilitation and post-assessment this increased to 90 – 100% agreement. Although 92% felt they would be comfortable receiving services via telerehabilitation, 45% of patients indicated ultimate preference for a traditional faceto-face assessment. The data highlight that patients are interested in and willing to receive services via telerehabilitation; however, any concerns should be addressed pre-assessment

New research directions on disparities in obesity and type 2 diabetes

Obesity and type 2 diabetes disproportionately impact U.S. racial and ethnic minority communities and lowâ income populations. Improvements in implementing efficacious interventions to reduce the incidence of type 2 diabetes are underway (i.e., the National Diabetes Prevention Program), but challenges in effectively scalingâ up successful interventions and reaching atâ risk populations remain. In October 2017, the National Institutes of Health convened a workshop to understand how to (1) address socioeconomic and other environmental conditions that perpetuate disparities in the burden of obesity and type 2 diabetes; (2) design effective prevention and treatment strategies that are accessible, feasible, culturally relevant, and acceptable to diverse population groups; and (3) achieve sustainable health improvement approaches in communities with the greatest burden of these diseases. Common features of guiding frameworks to understand and address disparities and promote health equity were described. Promising research directions were identified in numerous areas, including study design, methodology, and core metrics; program implementation and scalability; the integration of medical care and social services; strategies to enhance patient empowerment; and understanding and addressing the impact of psychosocial stress on disease onset and progression in addition to factors that support resiliency and health.This report discusses a workshop convened by the National Institutes of Health to understand how to (1) address socioeconomic and other environmental conditions that perpetuate disparities in the burden of obesity and type 2 diabetes; (2) design effective prevention and treatment strategies that are accessible, feasible, culturally relevant, and acceptable to diverse population groups; and (3) achieve sustainable health improvement approaches in communities with the greatest burden of these diseases.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154507/1/nyas14270_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154507/2/nyas14270.pd

SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial

Background Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer, Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. Methods The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1–5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. Discussion SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC