Design of the elusive proteinaceous oxygen donor copper site suggests a promising future for copper for MRI contrast agents.

We report the preparation and spectroscopic characterization of a highly elusive copper site bound exclusively to oxygen donor atoms within a protein scaffold. Despite copper generally being considered unsuitable for use in MRI contrast agents, which in the clinic are largely Gd(III) based, the designed copper coiled coil displays relaxivity values equal to, or superior than, those of the Gd(III) analog at clinical field strengths. The creation of this new-to-biology proteinaceous CuOx-binding site demonstrates the power of the de novo peptide design approach to access chemistry for abiological applications, such as for the development of MRI contrast agents.

Modelling Heterogeneous Anomalous Dynamics of Radiation-Induced Double-Strand Breaks in DNA during Non-Homologous End-Joining Pathway.

The process of end-joining during nonhomologous repair of DNA double-strand breaks (DSBs) after radiation damage is considered. Experimental evidence has revealed that the dynamics of DSB ends exhibit subdiffusive motion rather than simple diffusion with rare directional movement. Traditional models often overlook the rare long-range directed motion. To address this limitation, we present a heterogeneous anomalous diffusion model consisting of subdiffusive fractional Brownian motion interchanged with short periods of long-range movement. Our model sheds light on the underlying mechanisms of heterogeneous diffusion in DSB repair and could be used to quantify the DSB dynamics on a time scale inaccessible to single particle tracking analysis. The model predicts that the long-range movement of DSB ends is responsible for the misrepair of DSBs in the form of dicentric chromosome lesions.

Medical morbidity and risk of general hospital admission associated with concurrent anorexia nervosa and COVID-19: An observational study.

OBJECTIVE: Investigate medical morbidity and risk of general hospital admission for patients with concurrent coronavirus disease 2019 (COVID-19) and anorexia nervosa (AN) who have not received severe acute respiratory syndrome coronavirus 2 vaccination. METHODS: United Kingdom eating disorders clinicians contributed to a database of patients with an eating disorder and COVID-19. We used this to investigate demography, symptoms, hospitalization, treatment, and outcomes for those with AN. RESULTS: We describe data for 49 patients (median age 21.5 years [interquartile range 17.0-33.5], 46 female) including 36 adults and 13 under-18-year-olds. Three (6.1% [95% confidence interval 1.3%-17.9]) were admitted to a general hospital. For this sample, the expected age-standardized hospital admission rate per COVID-19 case (based on the general population of England) was 2.6% and therefore not significantly different to the hospitalization rate we observed. Three (including two of those admitted to hospital) contracted pneumonia. One had severe pneumonia and was admitted to an intensive care unit. No deaths or use of mechanical ventilation were recorded. DISCUSSION: To our knowledge, this represents the first study investigating medical morbidity or frequency of hospitalization for patients with COVID-19 and AN. We did not find evidence that patients with AN are at increased risk of severe COVID-19. PUBLIC SIGNIFICANCE: Medical morbidity and risk of hospitalization associated with concurrent COVID-19 and anorexia nervosa (AN) had not, to our knowledge, been studied before. We used a database of patients with eating disorders and COVID-19 (to which United Kingdom clinicians had contributed) to investigate presentation, treatment, outcomes, and COVID-19 severity for those with AN and COVID-19. We did not find evidence that patients with AN are at increased risk of severe COVID-19.

Survey of the publics' preferences for communication of medical radiation risk.

To comply with the Ionising Radiations (Medical Exposures) Regulations 2017, patients need to be adequately informed of medical radiation risks prior to exposure. This study used a survey developed in partnership with patients and members of the public to explore patient preferences for radiation risk communication. It was distributed through social media between 28/4/2020 and 18/7/2020. All respondents (N= 376) wanted to be informed about radiation risk, though the threshold at which they wished to be informed varied. The current practice of displaying posters in waiting areas does not meet the expressed preference of the patients if used in isolation. Only 6% of respondents were satisfied with the commonly used statement that the 'risk is low' if used in isolation. The majority of respondents (73%) said they would not be concerned about an increase in the risk of cancer of less than 1 in 10 000. The level of risk at which patients express a concern and the methodology for risk communication has been evaluated and based on these findings, and pre-existing literature, a graded approach to radiation risk communication based on modality is proposed. Patients must be involved throughout the evolution of this practice.

Collybistin SH3-protein isoforms are expressed in the rat brain promoting gephyrin and GABA-A receptor clustering at GABAergic synapses.

Collybistin (CB) is a guanine nucleotide exchange factor (GEF) selectively localized at GABAergic and glycinergic postsynapses. Analysis of mRNA shows that several isoforms of collybistin are expressed in the brain. Some of the isoforms have a SH3 domain (CBSH3+) and some have no SH3 domain (CBSH3-). The CBSH3+ mRNAs are predominantly expressed over CBSH3-. However, in an immunoblot study of mouse brain homogenates, only CBSH3+ protein isoforms were detected, proposing that CBSH3- protein might not be expressed in the brain. The expression or lack of expression of CBSH3- protein is an important issue because CBSH3- has a strong effect in promoting the postsynaptic clustering of gephyrin and GABA-A receptors (GABAA Rs). Moreover CBSH3- is constitutively active; therefore lower expression of CBSH3- protein might play a relatively stronger functional role than the more abundant but self-inhibited CBSH3+ isoforms, which need to be activated. We are now showing that: (a) CBSH3- protein is expressed in the brain; (b) parvalbumin positive (PV+) interneurons show higher expression of CBSH3- protein than other neurons; (c) CBSH3- is associated with GABAergic synapses in various regions of the brain and (d) knocking down CBSH3- in hippocampal neurons decreases the synaptic clustering of gephyrin and GABAA Rs. The results show that CBSH3- protein is expressed in the brain and that it plays a significant role in the size regulation of the GABAergic postsynapse.

Versatile Para-Substituted Pyridine Lanthanide Coordination Complexes Allow Late Stage Tailoring of Complex Function.

A series of cationic and neutral p-Br and p-NO2 pyridine substituted Eu(III) and Gd(III) coordination complexes serve as versatile synthetic intermediates. Nucleophilic aromatic substitution occurs readily at the para position under mild conditions, allowing C-N and C-C bond forming reactions to take place, permitting the introduction of azide, amino and alkynyl substituents. For Eu(III) complexes, this approach allows late stage tuning of absorption and emission spectral properties, exemplified by the lowering of the energy of an LMCT transition accompanied by a reduction in the Eu-Npy bond length. Additionally, these complexes provide direct access to the corresponding Eu(II) analogues. With the Gd(III) series, the nature of the p-substituent does not significantly change the EPR properties (linewidth, relaxation times), as required for their development as EPR spin probes that can be readily conjugated to biomolecules under mild conditions.

Testing a multicomponent lifestyle intervention for combatting childhood obesity.

BACKGROUND: Childhood obesity is a major global health concern. Weight-management camps involving delivery of a program of physical activity, health education, and healthy eating are an effective treatment, although post-intervention weight-management is less well understood. Our objective was to assess the effectiveness of a weight-management camp followed by a community intervention in supporting weight-management for overweight children and children with obesity. METHODS: Participants were overweight Qatari schoolchildren or schoolchildren with obesity, ages 8-14 years, (n = 300) recruited over a three-year period across 14 randomly selected schools in the Doha area. They attended a two-week weight management camp, then a 10-week program of weekly lifestyle education and physical activity sessions, which also included behavior change techniques. The programme was cognitive behavioural therapy (CBT)-focused with a strong element of behavioural economics blended in. RESULTS: Participants saw a significant BMI SDS reduction as a result of the entire intervention (camp + education and activity sessions) both at the individual (p < 0.0001) and cluster/school (p = 0.0002) levels, and weight loss occurred during each intervention stage separately for the camp (p < 0.0001 for both the individual and cluster/school levels) and the lifestyle education and activity phase (p < 0.0001 and p = 0.0220 at the individual and cluster/school levels, respectively). CONCLUSIONS: Weekly lifestyle education and activity sessions which include behavior change techniques may be useful in promoting continued weight management in the period following intensive, immersive childhood obesity interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT02972164 , November 23, 2016.

Using virtual worlds as a platform for collaborative meetings in healthcare: a feasibility study.

BACKGROUND: Healthcare teams often consist of geographically dispersed members. Virtual worlds can support immersive, high-quality, multimedia interaction between remote individuals; this study investigated use of virtual worlds to support remote healthcare quality improvement team meetings. METHODS: Twenty individuals (12 female, aged 25-67 [M = 42.3, SD = 11.8]) from 6 healthcare quality improvement teams conducted collaborative tasks in virtual world or face-to-face settings. Quality of collaborative task performances were measured and questionnaires and interviews were used to record participants' experiences of conducting the tasks and using the virtual world software. RESULTS: Quality of collaborative task outcomes was high in both face-to-face and virtual world settings. Participant interviews elicited advantages for using virtual worlds in healthcare settings, including the ability of the virtual environment to support tools that cannot be represented in equivalent face-to-face meetings, and the potential for virtual world settings to cause improvements in group-dynamics. Reported disadvantages for future virtual world use in healthcare included the difficulty that people with weaker computer skills may experience with using the software. Participants tended to feel absorbed in the collaborative task they conducted within the virtual world, but did not experience the virtual environment as being 'real'. CONCLUSIONS: Virtual worlds can provide an effective platform for collaborative meetings in healthcare quality improvement, but provision of support to those with weaker computer skills should be ensured, as should the technical reliability of the virtual world being used. Future research could investigate use of virtual worlds in other healthcare settings.

Full 3D position reconstruction of a radioactive source based on a novel hyperbolic geometrical algorithm.

A new method to locate, with millimetre uncertainty, in 3D, a γ -ray source emitting multiple γ -rays in a cascade, employing conventional LaBr3(Ce) scintillation detectors, has been developed. Using 16 detectors in a symmetrical configuration the detector energy and time signals, resulting from the γ -ray interactions, are fed into a new source position reconstruction algorithm. The Monte-Carlo based Geant4 framework has been used to simulate the detector array and a 60Co source located at two positions within the spectrometer central volume. For a source located at (0,0,0) the algorithm reports X, Y, Z values of -0.3 ± 2.5, -0.4 ± 2.4, and -0.6 ± 2.5 mm, respectively. For a source located at (20,20,20) mm, with respect to the array centre, the algorithm reports X, Y, Z values of 20.2 ± 1.0, 20.2 ± 0.9, and 20.1 ± 1.2 mm. The resulting precision of the reconstruction means that this technique could find application in a number of areas including nuclear medicine, national security, radioactive waste assay and proton beam therapy.

Age-related variation in the oral microbiome of urban Cooper's hawks (Accipiter cooperii).

BACKGROUND: Bird species worldwide are affected by trichomoniasis caused by the protist Trichomonas gallinae. In avivorous raptors such as Cooper's hawks (Accipiter cooperii), nestlings are more susceptible than fledglings and adults. Previous research suggested a link between oral pH and susceptibility: the oral pH of fledgling and adult hawks is more than seven times more acidic than that of nestlings. We speculated that this age-specific difference in pH would correspond to age-specific differences in the oral microbiota of Cooper's hawks. We examined the oral microbiomes of 31 healthy, wild Cooper's hawks in Tucson, Arizona (USA). Individuals represented three age classes (nestlings, fledglings, and adults). We designed our study with multiple controls, replicated sampling, mock communities, and stringent quality-controls to address challenges that can limit the inferential quality of microbiome data sets. RESULTS: Richness of bacterial communities in oral cavities of Cooper's hawks differed as a function of age but not as a function of sex, sampling date, or sampling location. Bacterial communities in oral cavities of nestlings differed from those of fledglings and adults, whereas communities in fledglings and adults did not differ from each other. Communities were similar in males and females and did not differ over the sampling season. Prevalence of acid-producing bacteria in fledgling and adults vs. nestlings is consistent with previous reports of age-specific variation in oral pH, but further research is needed to establish a causal link to pH levels or susceptibility to disease. Analyses of mock communities demonstrated high repeatability and showed that operon number and read abundance were highly correlated. CONCLUSIONS: The oral microbiota of wild Cooper's hawks differs between nestlings and older birds. Variation in the oral microbiome is consistent with differences in oral pH between nestlings and older individuals. Overall our study provides a first perspective on bacterial communities associated with oral cavities of a wild raptor.

Progressive brain atrophy in chronically infected and treated HIV+ individuals.

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

New Approaches to Cryopreservation of Cells, Tissues, and Organs.

In this concept article, we outline a variety of new approaches that have been conceived to address some of the remaining challenges for developing improved methods of biopreservation. This recognizes a true renaissance and variety of complimentary, high-potential approaches leveraging inspiration by nature, nanotechnology, the thermodynamics of pressure, and several other key fields. Development of an organ and tissue supply chain that can meet the healthcare demands of the 21st century means overcoming twin challenges of (1) having enough of these lifesaving resources and (2) having the means to store and transport them for a variety of applications. Each has distinct but overlapping logistical limitations affecting transplantation, regenerative medicine, and drug discovery, with challenges shared among major areas of biomedicine including tissue engineering, trauma care, transfusion medicine, and biomedical research. There are several approaches to biopreservation, the optimum choice of which is dictated by the nature and complexity of the tissue and the required length of storage. Short-term hypothermic storage at temperatures a few degrees above the freezing point has provided the basis for nearly all methods of preserving tissues and solid organs that, to date, have proved refractory to cryopreservation techniques successfully developed for single-cell systems. In essence, these short-term techniques have been based on designing solutions for cellular protection against the effects of warm and cold ischemia and basically rely upon the protective effects of reduced temperatures brought about by Arrhenius kinetics of chemical reactions. However, further optimization of such preservation strategies is now seen to be restricted. Long-term preservation calls for much lower temperatures and requires the tissue to withstand the rigors of heat and mass transfer during protocols designed to optimize cooling and warming in the presence of cryoprotective agents. It is now accepted that with current methods of cryopreservation, uncontrolled ice formation in structured tissues and organs at subzero temperatures is the single most critical factor that severely restricts the extent to which tissues can survive procedures involving freezing and thawing. In recent years, this major problem has been effectively circumvented in some tissues by using ice-free cryopreservation techniques based upon vitrification. Nevertheless, despite these promising advances there remain several recognized hurdles to be overcome before deep-subzero cryopreservation, either by classic freezing and thawing or by vitrification, can provide the much-needed means for biobanking complex tissues and organs for extended periods of weeks, months, or even years. In many cases, the approaches outlined here, including new underexplored paradigms of high-subzero preservation, are novel and inspired by mechanisms of freeze tolerance, or freeze avoidance, in nature. Others apply new bioengineering techniques such as nanotechnology, isochoric pressure preservation, and non-Newtonian fluids to circumvent currently intractable problems in cryopreservation.

Case study on the effect continuous CO2 enrichment, via biogas scrubbing, has on biomass production and wastewater treatment in a high rate algal pond.

Microalgae grown in high rate algal ponds (HRAP) treating wastewater are considered a promising feed for biofuel production. Biomass productivity is often considered to be limited by carbon availability, with the addition of CO2 being the proposed solution. Biogas from anaerobic wastewater treatment potentially provides a cheap, co-located CO2 source. Two identical 223 m2 HRAPs were constructed at Melbourne Water's Western Treatment Plant, where biogas from an anaerobic lagoon is used to generate electricity. One HRAP was fed secondary treated wastewater that had been enriched with CO2 recovered from the biogas using industry standard biogas scrubbers, the Enriched HRAP, while the other HRAP was fed the same wastewater expect it had by passed the biogas scrubbers, the Control HRAP. The biomass production and wastewater treatment performance of the two HRAPs was compared over 12 months. The inlet to the Enriched HRAP had significantly higher free CO2 and inorganic carbon, 175.00 ±â€¯49.30 mg L-1 and 110.00 ±â€¯10.2 mg L-1, than the inlet to the Control HRAP, 9.30 ±â€¯7.08 mg L-1 and 89.62 ±â€¯5.12 mg L-1. There were no significant differences in biomass production between the HRAPs as measured by dry matter, particulate organic carbon or nitrogen. Chlorophyll a was statistically higher in the Enriched HRAP, however, this measurement is potentially unreliable. Regarding wastewater treatment, only total nitrogen and ammonium removal differed significantly between the HRAPs, with the Control HRAP, 59.13 ±â€¯21.13% and 76.46 ±â€¯32.33%, slightly outperforming the Enriched HRAP, 53.52 ±â€¯17.41% and 68.76 ±â€¯31.17%. Overall, neither biomass production nor wastewater treatment was meaningfully improved by CO2 enrichment, however, wastewater treatment was still effective in both HRAPs.

Rates of Neuropsychological Dysfunction in Fibromyalgia and Rheumatoid Arthritis: An Automated Clinical Rating Approach.

BACKGROUND/OBJECTIVE: Fibromyalgia (FM) is a chronic pain syndrome of unknown etiology that can include subjective cognitive symptoms and variable evidence of cognitive dysfunction. Rates of occurrence and severity of cognitive impairment remain unclear. Additionally, comparison of this group with other pain conditions has been limited. The current cross-sectional study sought to identify rates of clinically significant cognitive impairment in FM and rheumatoid arthritis (RA) using an automated clinical rating approach. METHODS: A total of 61 females (32 with FM, 29 with RA) completed a comprehensive neuropsychological (NP) battery and an assessment of personality and psychological distress. All study measures were completed in one visit and all participants were recruited over the span of 3 years. Demographically corrected NP scores were used to compare participants with normative expectations and a summary score was calculated to compare groups on NP impairment. RESULTS: Compared to normative expectations using a 1 standard deviation cutoff, moderately increased rates of cognitive deficits were observed in both groups (FM = 23.3%, RA = 34.5%), with most test scores in affected individuals falling in the mild to moderate ranges of impairment. Compared to RA, FM participants endorsed higher and significant levels of psychological symptoms overall. These were not associated with cognitive performance in either patient group. CONCLUSIONS: Increased rates of cognitive dysfunction as well as psychological distress exist in both FM and RA compared to a normative sample. However, psychological distress was unrelated to cognition in both groups. These findings have implications regarding the clinical presentation of individuals with FM and RA.

Vitrification tendency and stability of DP6-based vitrification solutions for complex tissue cryopreservation.

Vitrification tendency and stability of the amorphous state were analyzed by means of differential scanning calorimetry (DSC) for the vitrification solution DP6, with and without additional solutes to enhance ice suppression. This study is a part of an ongoing research effort to characterize the thermophysical and mechanical properties of DP6 and its derivatives, and their qualities as cryoprotective solutions. DP6 was determined to have a critical cooling rate necessary to ensure vitrification of 2.7 °C/min. The following additional solutions were tested: DP6 + 6% (2R, 3R) 2,3-butanediol, DP6 + 6% 1,3-cyclohexanediol, DP6 + 6% (0.175M) sucrose, DP6 + 12% PEG 400, and DP6 + 17.1% (0.5 M) sucrose. The additives decreased the critical cooling rate of the DP6 solution to rates below 1 °C/min that were not quantifiable by the DSC techniques used. The following critical warming rates necessary to avoid devitrification were identified for DP6 and the modified solutions, respectively: 189 °C/min, 5 °C/min, ≈ 1 °C/min, 15 °C/min, <1 °C/min, and <1 °C/min. Glass transition temperatures and melting temperatures were also measured. Sucrose was the least effective additive on a per mass basis, with 1,3-cyclohexanediol appearing to be the most effective additive for suppressing ice formation in DP6.

Isochoric vitrification: An experimental study to establish proof of concept.

Ice-free vitreous cryopreservation (vitrification) is regarded as the principal method for avoiding ice crystallization damage in cryopreserved tissues and organs. We previously established the fundamental thermodynamics of isochoric (constant volume) systems for cryopreservation, and now extend this novel approach to vitrification in an isochoric system. This was achieved by measuring pressure changes in a 2 ml isochoric chamber containing a variety of aqueous solutions of the ubiquitous cryoprotective additives (CPA), dimethyl sulfoxide (Me2SO) and Propane-diol. The CPAs, ranging in concentrations from 0 to 49%(w/v), were prepared in a proprietary preservation solution (Unisol®) in anticipation of future applications to tissue and organ banking. Pressures developed in the system were monitored as a function of CPA concentration and cooling rate when the isochoric chamber was cooled to cryogenic temperature (-160 °C). This study corroborated our previous findings that pressure increases in accordance with the thermodynamics of partially frozen systems of low concentrations of CPAs. A key finding of this study was that in an isochoric system of higher concentrations of CPA, which vitrifies, there is no increase in pressure. In fact, an increase in pressure is a measure of failure to vitrify and a measure of devitrification. Comparison with results from the literature show that the concentration of CPAs needed for vitrification in an isochoric chamber is substantially lower than that needed for vitrification in isobaric systems at 1 atm and hyperbaric systems at 1000 atm. In addition, isochoric chambers are much more effective in promoting vitrification than hyperbaric pressure chambers, and are less expensive, easier to design, and implement.

"Contemplating the Next Maneuver": Functional Neuroimaging Reveals Intraoperative Decision-making Strategies.

OBJECTIVE: To investigate differences in the quality, confidence, and consistency of intraoperative surgical decision making (DM) and using functional neuroimaging expose decision systems that operators use. SUMMARY BACKGROUND DATA: Novices are hypothesized to use conscious analysis (effortful DM) leading to activation across the dorsolateral prefrontal cortex, whereas experts are expected to use unconscious automation (habitual DM) in which decisions are recognition-primed and prefrontal cortex independent. METHODS: A total of 22 subjects (10 medical student novices, 7 residents, and 5 attendings) reviewed simulated laparoscopic cholecystectomy videos, determined the next safest operative maneuver upon video termination (10 s), and reported decision confidence. Video paradigms either declared ("primed") or withheld ("unprimed") the next operative maneuver. Simultaneously, changes in cortical oxygenated hemoglobin and deoxygenated hemoglobin inferring prefrontal activation were recorded using Optical Topography. Decision confidence, consistency (primed vs unprimed), and quality (script concordance) were assessed. RESULTS: Attendings and residents were significantly more certain (P < 0.001), and decision quality was superior (script concordance: attendings = 90%, residents = 78.3%, and novices = 53.3%). Decision consistency was significantly superior in experts (P < 0.001) and residents (P < 0.05) than novices (P = 0.183). During unprimed DM, novices showed significant activation of the dorsolateral prefrontal cortex, whereas this activation pattern was not observed among residents and attendings. During primed DM, significant activation was not observed in any group. CONCLUSIONS: Expert DM is characterized by improved quality, consistency, and confidence. The findings imply attendings use a habitual decision system, whereas novices use an effortful approach under uncertainty. In the presence of operative cues (primes), novices disengage the prefrontal cortex and seem to accept the observed operative decision as correct.

Associations between multimorbidity and additional burden for working-age adults with specific forms of musculoskeletal conditions: a cross-sectional study.

BACKGROUND: Multiple health conditions are increasingly a problem for adults with musculoskeletal conditions. However, multimorbidity research has focused primarily on the elderly and those with a limited subset of musculoskeletal disorders. We sought to determine whether associations between multimorbidity and additional burden differ with specific forms of musculoskeletal conditions among working-age adults. METHODS: Data were sourced from a nationally representative Australian survey. Specific musculoskeletal conditions examined were osteoarthritis; inflammatory arthritis; other forms of arthritis or arthropathies; musculoskeletal conditions not elsewhere specified; gout; back pain; soft tissue disorders; or osteoporosis. Multimorbidity was defined as the additional presence of one or more of the Australian National Health Priority Area conditions. Burden was assessed by self-reported measures of: (i) self-rated health (ii) musculoskeletal-related healthcare and medicines utilisation and, (iii) general healthcare utilisation. Associations between multimorbidity and additional health or healthcare utilisation burden among working-age adults (aged 18 - 64 years of age) with specific musculoskeletal conditions were estimated using logistic regression, adjusting for confounders. Interaction terms were fitted to identify whether there were specific musculoskeletal conditions where multimorbidity was more strongly associated with poorer health or greater healthcare utilisation than in the remaining musculoskeletal group. RESULTS: Among working-age adults, for each of the specified musculoskeletal conditions, multimorbidity was associated with similar, increased likelihood of additional self-rated health burden and certain types of healthcare utilisation. While there were differences in the relationships between multimorbidity and burden for each of the specific musculoskeletal conditions, no one specific musculoskeletal condition appeared to be consistently associated with greater additional health burden in the presence of multimorbidity across the majority of self-rated health burden and healthcare use measures. CONCLUSIONS: For working-age people with any musculoskeletal conditions examined here, multimorbidity increases self-reported health and healthcare utilisation burden. As no one musculoskeletal condition appears consistently worse off in the presence of multimorbidity, there is a need to better understand and identify strategies that acknowledge and address the additional burden of concomitant conditions for working-age adults with a range of musculoskeletal conditions.

Safety and activity of RRx-001 in patients with advanced cancer: a first-in-human, open-label, dose-escalation phase 1 study.

BACKGROUND: Epigenetic alterations have been strongly associated with tumour formation and resistance to chemotherapeutic drugs, and epigenetic modifications are an attractive target in cancer research. RRx-001 is activated by hypoxia and induces the generation of reactive oxygen and nitrogen species that can epigenetically modulate DNA methylation, histone deacetylation, and lysine demethylation. The aim of this phase 1 study was to assess the safety, tolerability, and pharmacokinetics of RRx-001. METHODS: In this open-label, dose-escalation, phase 1 study, we recruited adult patients (aged >18 years) with histologically or cytologically confirmed diagnosis of advanced, malignant, incurable solid tumours from University of California at San Diego, CA, USA, and Sarah Cannon Research Institute, Nashville, TN, USA. Key eligibility criteria included evaluable disease, Eastern Cooperative Group performance status of 2 or less, an estimated life expectancy of at least 12 weeks, adequate laboratory parameters, discontinuation of all previous antineoplastic therapies at least 6 weeks before intervention, and no residual side-effects from previous therapies. Patients were assigned to receive intravenous infusions of RRx-001 at increasing doses (10 mg/m(2), 16·7 mg/m(2), 24·6 mg/m(2), 33 mg/m(2), 55 mg/m(2), and 83 mg/m(2)) either once or twice-weekly for at least 4 weeks, with at least three patients per dose cohort and allowing a 2-week observation period before dose escalation. Samples for safety and pharmacokinetics analysis, including standard chemistry and haematological panels, were taken on each treatment day. The primary objective was to assess safety, tolerability, and dose-limiting toxic effects of RRx-001, to determine single-dose pharmacokinetics, and to identify a recommended dose for phase 2 trials. All analyses were done per protocol. Accrual is complete and follow-up is still on-going. This trial is registered with ClinicalTrials.gov, number NCT01359982. FINDINGS: Between Oct 10, 2011, and March 18, 2013, we enrolled 25 patients and treated six patients in the 10 mg/m(2) cohort, three patients in the 16·7 mg/m(2) cohort, three patients in the 24·6 mg/m(2) cohort, four patients in the 33 mg/m(2) cohort, three patients in the 55 mg/m(2), and six patients in the 83 mg/m(2) cohort. Pain at the injection site, mostly grade 1 and grade 2, was the most common adverse event related to treatment, experienced by 21 (84%) patients. Other common drug-related adverse events included arm swelling or oedema (eight [32%] patients), and vein hardening (seven [28%] patients). No dose-limiting toxicities were observed. Time constraints related to management of infusion pain from RRx-001 resulted in a maximally feasible dose of 83 mg/m(2). Of the 21 evaluable patients, one (5%) patient had a partial response, 14 (67%) patients had stable disease, and six (29%) patients had progressive disease; all responses were across a variety of tumour types. Four patients who had received RRx-001 were subsequently rechallenged with a treatment that they had become refractory to; all four responded to the rechallenge. INTERPRETATION: RRx-001 is a well-tolerated novel compound without clinically significant toxic effects at the tested doses. Preliminary evidence of activity is promising and, on the basis of all findings, a dose of 16·7 mg/m(2) was recommended as the targeted dose for phase 2 trials. FUNDING: EpicentRx (formerly RadioRx).

CSF biomarkers of monocyte activation and chemotaxis correlate with magnetic resonance spectroscopy metabolites during chronic HIV disease.

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist despite combination antiretroviral therapy (cART), supporting the need to better understand HIV neuropathogenesis. Magnetic resonance spectroscopy (MRS) of the brain has demonstrated abnormalities in HIV-infected individuals despite cART. We examined the associations between MRS metabolites and selected cerebrospinal fluid (CSF) biomarkers reflecting monocyte/macrophage activation and chemotaxis. A multicenter cross-sectional study involving five sites in the USA was conducted. The following CSF biomarkers were measured: soluble CD14 (sCD14), monocyte chemotactic protein-1 (MCP-1), interferon inducible protein 10 (IP-10), and stromal cell-derived growth factor 1 alpha (SDF-1α). The following MRS metabolites were measured from basal ganglia (BG), frontal white matter (FWM), and frontal gray matter (FGM): N-acetylaspartate (NAA), myo-inositol (MI), choline (Cho), and creatine (Cr). CSF biomarkers were compared to absolute MRS metabolites as well as metabolite/Cr ratios using linear regression. Eighty-three HIV-infected individuals were included, 78 % on cART and 37 % with HAND. The most robust positive correlations were between MCP-1 and Cho in BG (R (2) 0.179, p < 0.001) as well as MCP-1 and MI in FWM (R (2) 0.137, p = 0.002). Higher Cr levels in FWM were associated with MCP-1 (R (2) 0. 075, p = 0.01) and IP-10 (R (2) 0.106, p = 0.003). Comparing biomarkers to MRS metabolite/Cr ratios impacted some relationships, e.g., higher sCD14 levels were associated with lower Cho/Cr ratios in FGM (R (2) 0.224, p < 0.001), although higher MCP-1 levels remained associated with Cho/Cr in BG. These findings provide evidence that monocyte activation and chemotaxis continue to contribute to HIV-associated brain abnormalities in cART-treated individuals.