Tumor therapy by targeting extracellular hydroxyapatite using novel drugs: A paradigm shift.

BACKGROUND: It has been shown that tumor microenvironment (TME) hydroxyapatite (HAP) is typically associated with many malignancies and plays a role in tumor progression and growth. Additionally, acidosis in the TME has been reported to play a key role in selecting for a more aggressive tumor phenotype, drug resistance and desensitization to immunotherapy for many types of cancers. TME-HAP is an attractive target for tumor detection and treatment development since HAP is generally absent from normal soft tissue. We provide strong evidence that dissolution of hydroxyapatite (HAP) within the tumor microenvironment (TME-HAP) using a novel therapeutic can be used to kill cancer cells both in vitro and in vivo with minimal adverse effects. METHODS: We developed an injectable cation exchange nano particulate sulfonated polystyrene solution (NSPS) that we engineered to dissolve TME-HAP, inducing localized acute alkalosis and inhibition of tumor growth and glucose metabolism. This was evaluated in cell culture using 4T1, MDA-MB-231 triple negative breast cancer cells, MCF10 normal breast cells, and H292 lung cancer cells, and in vivo using orthotopic mouse models of cancer that contained detectable microenvironment HAP including breast (MMTV-Neu, 4T1, and MDA-MB-231), prostate (PC3) and colon (HCA7) cancer using 18 F-NaF for HAP and 18 F-FDG for glucose metabolism with PET imaging. On the other hand, H292 lung tumor cells that lacked detectable microenvironment HAP and MCF10a normal breast cells that do not produce HAP served as negative controls. Tumor microenvironment pH levels following injection of NSPS were evaluated via Chemical Exchange Saturation (CEST) MRI and via ex vivo methods. RESULTS: Within 24 h of adding the small concentration of 1X of NSPS (~7 µM), we observed significant tumor cell death (~ 10%, p < 0.05) in 4T1 and MDA-MB-231 cell cultures that contain HAP but ⟨2% in H292 and MCF10a cells that lack detectable HAP and in controls. Using CEST MRI, we found extracellular pH (pHe) in the 4T1 breast tumors, located in the mammary fat pad, to increase by nearly 10% from baseline before gradually receding back to baseline during the first hour post NSPS administration. in the tumors that contained TME-HAP in mouse models, MMTV-Neu, 4T1, and MDA-MB-231, PC3, and HCA7, there was a significant reduction (p<0.05) in 18 F-Na Fuptake post NSPS treatment as expected; 18 F- uptake in the tumor = 3.8 ± 0.5 %ID/g (percent of the injected dose per gram) at baseline compared to 1.8 ±0.5 %ID/g following one-time treatment with 100 mg/kg NSPS. Of similar importance, is that 18 F-FDG uptake in the tumors was reduced by more than 75% compared to baseline within 24 h of treatment with one-time NSPS which persisted for at least one week. Additionally, tumor growth was significantly slower (p < 0.05) in the mice treated with one-time NSPS. Toxicity showed no evidence of any adverse effects, a finding attributed to the absence of HAP in normal soft tissue and to our therapeutic NSPS having limited penetration to access HAP within skeletal bone. CONCLUSION: Dissolution of TME-HAP using our novel NSPS has the potential to provide a new treatment paradigm to enhance the management of cancer patients with poor prognosis.

Reverse Fragility Index Comparing Rates of Rerupture After Open Achilles Tendon Repair Versus Early Functional Rehabilitation: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Despite similar published rates of rerupture among patients treated with early functional rehabilitation and open repair for acute Achilles tendon rupture, uncertainty still exists regarding the optimal treatment modality. The reverse fragility index (RFI) is a statistical tool that provides an objective measure of the study's neutrality by determining the number of events that need to change for a nonsignificant result to be significant. PURPOSE: The purpose was to utilize the RFI to appraise the strength of neutrality of randomized controlled trials (RCTs) comparing the rerupture rates of acute Achilles tendon ruptures treated with open repair versus early functional rehabilitation. STUDY DESIGN: Systematic review; Level of evidence, 1. METHODS: A systematic review was performed including all RCTs comparing the rerupture rates after operative repair and early functional rehabilitation for acute Achilles tendon ruptures. Studies were included that explicitly used early functional rehabilitation, defined as weightbearing and exercise-based interventions initiated within 2 weeks, as compared with open repair and reported a nonsignificant difference in rerupture rates. The RFI, with rerupture as the primary outcome, was calculated for each study (significance threshold, P < .05). The RFI quantifies a study's strength of neutrality and is defined as the minimum number of event reversals necessary to change a nonsignificant result to statistically significant. RESULTS: Nine RCTs were included, with 713 patients and 46 reruptures. The median (interquartile range) rerupture rate was 7.69% (6.38%-9.64%) overall, 4.00% (2.33%-7.14%) in the operative group, and 10.00% (5.26%-12.20%) in the nonoperative group. The median RFI was 3, indicating that an outcome reversal of 3 patients was necessary to change the results from nonsignificant to statistically significant. The median number of patients lost to follow-up was 6 (3-7). Of 9 studies, 7 (77.8%) had a loss to follow-up greater than or equal to its RFI. CONCLUSION: The statistical nonsignificance of studies reporting equivalent rerupture rates in the management of acute Achilles tendon ruptures with open repair versus nonoperative management with early functional rehabilitation can be reversed by changing the outcome status of only a few patients.

Accidental lipid overdose in a preterm infant: A case report.

BACKGROUND: Intravenous lipid emulsions (ILEs) provide essential fatty acids during parenteral nutrition (PN). Serious adverse events including death can occur from overdose. We report an accidental overdose in a preterm infant. METHOD: On Day 2 of life, a 29-week gestational age (GA) twin was accidentally given 47.5 mL of Intralipid20% (≈3x daily amount) in 50-minutes. RESULTS: No apparent clinical deterioration occurred, although blood samples were lipaemic. Outcomes at 2 years corrected GA were similar to that of his twin. Service changes were made to infusion packaging and administration to avoid similar errors. CONCLUSIONS: Medication errors in neonates are unfortunately common. Published articles usually focus on poor outcomes, which can increase the distress for parents of children where errors have occurred. Publishing the full spectrum of outcomes instead allows parents and professionals to be aware of all possibilities and lessons learnt, even if serious harm was avoided.

A British Society for Haematology Guideline: Diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies.

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

A British Society for haematology guideline: diagnosis and management of thrombotic thrombocytopenic purpura and thrombotic microangiopathies

The objective of this guideline is to provide healthcare professionals with clear, up-to-date and practical guidance on the management of thrombotic thrombocytopenic purpura (TTP) and related thrombotic microangiopathies (TMAs), including complement-mediated haemolytic uraemic syndrome (CM HUS); these are defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Within England, all TTP cases should be managed within designated regional centres as per NHSE commissioning for highly specialised services.

Impingement and perforation of the anterior femoral cortex in cephalomedullary nailing: Systematic review and surgical techniques.

BACKGROUND: Anterior femoral cortical impingement and perforation are known risks of cephalomedullary nailing. The incidence of and risk factors for these findings have not been fully established in the literature. The purpose of this review was to answer: (1) What is the incidence of anterior femoral cortical impingement and perforation associated with cephalomedullary nailing of proximal femur fractures? (2) How does incidence vary by nail radius of curvature (ROC)? (3) What populations are at increased risk of impingement and perforation? (4) What surgical techniques prevent their occurrence? HYPOTHESIS: Our hypothesis was that impingement would be a relatively common finding following cephalomedullary nailing, and perforation would be much less frequent but still an appreciable risk. Secondarily, nails with a larger ROC would have a higher rate of impingement. PATIENTS AND METHODS: In this systematic review, PubMed, MEDLINE, and Cochrane databases were searched for articles from 1990-2020 written in English using the terms "cephalomedullary nail" or "femoral nail" and "perforation" or "impingement", and similar words. Inclusion criteria were studies discussing the complication of anterior femoral cortical impingement or perforation associated with the use of a cephalomedullary nail. Fourteen studies met inclusion criteria. Rates of anterior femoral cortical impingement or perforation, patient demographics, nail type, and ROC were extracted. Surgical techniques to prevent perforation were qualitatively reviewed. RESULTS: The rate of anterior cortical impingement with long cephalomedullary nails was 17.2% (192/1117 patients) and with short nails was 29.2% (176/602). The rate of anterior cortical perforation with long nails was 1.0% (11/1116) and with short nails was 0% (0/234). Long nails with ROC>150cm showed an impingement rate of 10.9% (62/567) and perforation rate of 1.1% (7/617 patients). Nails with ROC 150cm or 100cm had an impingement rate of 1.1% (1/93) and perforation rate of 0% (0/93). DISCUSSION: Impingement and perforation of the anterior femoral cortex during cephalomedullary nailing are appreciable risks that surgeons should anticipate and avoid, especially in certain populations and with nails with larger ROC. Surgeons may consider use of long nails with ROC 150cm and below, given a nearly 10-fold lower incidence of impingement and no reported perforations. LEVEL OF EVIDENCE: Therapeutic, level IV.

Urban Roadway Runoff Is Lethal to Juvenile Coho, Steelhead, and Chinook Salmonids, But Not Congeneric Sockeye.

We compared the sensitivity of closely related Pacific salmon and steelhead (Oncorhynchus spp.) to untreated urban stormwater runoff across three storm events. Juvenile coho, sockeye, steelhead, and Chinook were exposed for 24 h to untreated urban runoff and then transferred to clean water for 48 h. As anticipated from previous studies, coho were highly susceptible to runoff toxicity, with cumulative mortality rates ranging from 92%-100% across the three storms. By contrast, juvenile sockeye were unaffected (100% survival), and cumulative mortality rates were intermediate for steelhead (4%-42%) and Chinook (0%-13%). Furthermore, coho died rapidly following the onset of stormwater exposure (generally <4 h), whereas mortality in Chinook and steelhead was delayed by 1-2 days. Similar to previous findings for coho, steelhead and Chinook did not recover when transferred to clean water. Lastly, significant mortality occurred in coho even when roadway runoff was diluted by 95% in clean water. Our findings extend the urban runoff mortality syndrome in salmonids and point to a near-term need for sublethal studies in steelhead and Chinook to more precisely understand stormwater risks to threatened species recovery efforts in the western United States.

Discovery of a Redox-Activatable Chemical Probe for Detection of Cyclooxygenase-2 in Cells and Animals.

Cyclooxygenase-2 (COX-2) expression is up-regulated in inflammatory tissues and many premalignant and malignant tumors. Assessment of COX-2 protein in vivo, therefore, promises to be a powerful strategy to distinguish pathologic cells from normal cells in a complex disease setting. Herein, we report the first redox-activatable COX-2 probe, fluorocoxib Q (FQ), for in vivo molecular imaging of pathogenesis. FQ inhibits COX-2 selectively in purified enzyme and cell-based assays. FQ exhibits extremely low fluorescence and displays time- and concentration-dependent fluorescence enhancement upon exposure to a redox environment. FQ enters the cells freely and binds to the COX-2 enzyme. FQ exhibits high circulation half-life and metabolic stability sufficient for target site accumulation and demonstrates COX-2-targeted uptake and retention in cancer cells and pathologic tissues. Once taken up, it undergoes redox-mediated transformation into a fluorescent compound fluorocoxib Q-H that results in high signal-to-noise contrast and differentiates pathologic tissues from non-pathologic tissues for real-time in vivo imaging.

Long-term Outcomes Following Temperature-Controlled Radiofrequency Neurolysis for the Treatment of Chronic Rhinitis.

Background: Temperature-controlled radiofrequency neurolysis of the posterior nasal nerve has been shown to reduce the symptom burden of patients with chronic rhinitis. Objectives: To evaluate the long-term safety and effectiveness of temperature-controlled radiofrequency neurolysis of the posterior nasal nerve for the treatment of chronic rhinitis. Methods: A prospective extension of a 12-month single-arm study, where reflective total nasal symptom score (rTNSS) and the responses to a study-specific quality of life questionnaire and patient satisfaction survey were collected at 24 months. Results: Forty-seven patients completed initial 12-month follow-up after treatment with the study device, of which 34 patients were reconsented and completed 24-month follow-up. The mean rTNSS of the long-term follow-up patients improved from 8.4 (95% confidence interval (CI), 7.7 to 9.0) at baseline to 2.9 (95% CI, 2.1 to 3.6), P < .001 at 24 months, a 65.5% improvement. On a 6-point scale (0-5), postnasal drip improved from a mean of 4.1 (95% CI, 3.6 to 4.6) to 2.1 (95% CI, 1.7 to 2.5) and chronic cough improved from 3.2 (95% CI, 2.7 to 3.6) to 0.9 (95% CI, 0.5 to 1.3) from baseline through 24 months; P < .001 for both measures. The proportion of patients achieving a minimal clinically important difference of 30% improvement from baseline at 24 months was 88.2% (95% CI, 73.4%-95.3%). At 24 months, 24% of patients were taking overall fewer and 15% taking overall more rhinitis medication classes than at baseline. Patients reported a higher quality of life in terms of sleep, well-being, and lower oral medication/nasal spray use at 24 months. There were no serious adverse events considered related to the procedure in the 12-24-month period. Conclusion: Temperature-controlled radiofrequency neurolysis results in a significant and durable reduction in the symptom burden of chronic rhinitis and patients reported improved quality of life through 24 months postprocedure.

Where have we come from and where are we going? The paediatric HIV programme in Johannesburg, South Africa, from 2004 to 2018: A retrospective analysis of programme trends.

BACKGROUND: The paediatric HIV treatment programme in South Africa (SA) has grown since its inception in 2004. Despite this impressive scale-up of antiretroviral therapy (ART) in children, the proportion of children started on ART and retained in care remains unacceptably low, with only 47% of the 340 000 HIV-positive children in SA on ART in 2020. Johannesburg is one of the districts in SA with the largest number of children living with HIV who are not on ART, and is a priority district for paediatric case finding and retention. OBJECTIVES: To describe the dynamics of the paediatric HIV programme in Johannesburg, SA. METHODS: A secondary analysis was conducted on patient-level HIV treatment data from TIER.Net, the nationally mandated HIV/ART database. Children aged <15 years who received ART between January 2004 and June 2019 at public health facilities in Johannesburg were included. We reported the number of children on ART and the number who entered and exited the programme by age group over time, and analysed the trends of these indicators. RESULTS: By December 2018, 7 630 children aged <15 years remained in Johannesburg's paediatric ART programme: 82.5% were aged 5 - <15 years, with 54.1% of these being 10 - <15 years old. During the study period, 19 850 children were newly initiated on ART. New initiations slowed from 2013, to range from 1 172 to 1 373 yearly. In 2018, 34.2% of initiators were aged <1 year, 24.2% 1 - <5 years and 41.6% 5 - <15 years. Despite these initiations, the number of children on ART only grew by 97 in 2018, owing to programme losses. In 2018, 924  children (12.1%) aged out, 35 (0.5%) died and 983 (12.9%) were lost to follow-up (LTFU), the latter having increased from 10.7% in 2017. Of children who aged out of the paediatric ART programme, 56.3% remained in care at the same facility. CONCLUSION: Early in the SA ART roll-out, many children were found to be HIV infected and started on ART. This number started to slow in 2013, after which the growth rate of the paediatric HIV programme also began to slow. Scale-up of methods for identifying older children with HIV is needed. While ageing out of the paediatric programme is a consideration, the number of children LTFU remains unacceptably high. Further interrogation of barriers to paediatric retention is needed to help realise the Joint United Nations Programme on HIV and AIDS (UNAIDS) 90:90:90 goals for children in SA.

Temperature-Controlled Radiofrequency Neurolysis for the Treatment of Rhinitis.

BACKGROUND: Chronic rhinitis is a prevalent condition with a significant impact on quality of life. Posterior nasal nerve and vidian neurectomy are surgical options for treating the symptoms of chronic rhinitis but are invasive procedures. OBJECTIVE: To determine the outcomes of patients diagnosed with refractory chronic rhinitis and treated with temperature-controlled radiofrequency neurolysis of the posterior nasal nerve area in a minimally invasive procedure. METHODS: A prospective, single-arm multicenter study with follow-up through 52 weeks. Eligible adult patients had chronic rhinitis symptoms of at least 6 months duration with inadequate response to at least 4 weeks usage of intranasal steroids and an overall 12-h reflective total nasal symptom score (rTNSS) ≥ 6 with subscores 2 to 3 for rhinorrhea, 1 to 3 for nasal congestion, and 0 to 3 for each of nasal itching and sneezing. Temperature-controlled radiofrequency energy was delivered to the nasal cavity mucosa overlying the posterior nasal nerve region with a novel single-use, disposable, handheld device. RESULTS: A total of 50 patients were treated (42.0% male; mean age 57.9 ± 11.9 years), and 47 completed the study through 52 weeks. Mean rTNSS significantly improved from 8.5 (95% CI 8.0, 9.0) at baseline to 3.6 (95% CI 3.0, 4.3) at 52 weeks (P < .001), a 57.6% improvement. Similar trends in improvement were noted for rTNSS subscores (rhinorrhea, nasal congestion, itching, sneezing), postnasal drip scores, and chronic cough scores. Subgroup analysis demonstrated the treatment was effective regardless of rhinitis classification (allergic or nonallergic). No serious adverse events with a relationship to the device/procedure occurred. CONCLUSIONS: Temperature-controlled radiofrequency neurolysis of the posterior nasal nerve area for the treatment of chronic rhinitis is safe and resulted in a durable improvement in the symptoms of chronic rhinitis through a 52-week follow-up. Data suggest that this novel device could be considered a minimally invasive option in the otolaryngologist's armamentarium for the treatment of chronic rhinitis.

Effect of COVID-19 on HIV, tuberculosis, and prevention of mother-to-child transmission of HIV indicators in Mopani district, South Africa.

BACKGROUND: To prevent the spread of SARS-CoV-2, many countries instituted lockdown measures. As the virus was initially slow to spread to rural areas in South Africa, Mopani district in Limpopo Province did not experience a high incidence of COVID-19 until the second wave in December 2020. Until then, lockdown measures were more likely than SARS-CoV-2 infections to have an adverse impact on health services. OBJECTIVES: To analyse HIV, tuberculosis (TB) and prevention of mother-to-child transmission of HIV (PMTCT) indicator trends in Mopani during the COVID-19 lockdown and two COVID-19 waves. METHODS: Using monthly data from the District Health Information System from February 2019 to December 2020, we conducted a retrospective review of data elements and indicators that fall into the following domains: primary healthcare head count (HC), HIV, antiretroviral treatment (ART), PMTCT and TB. Aggregated data were analysed, and an interrupted time series analysis was conducted. We assessed percentage changes between the January - March 2020 and April - June 2020 periods, and differences in means for the period April - December 2019 v. the period April - December 2020 were assessed for statistical significance. RESULTS: At the start of the first wave in April 2020, a statistically significant decline of 10% was recorded for total HC utilisation rates (p=0.1). We also found declines of 665 HIV tests (from 1 608 to 942) and 22 positive HIV tests (from 27 to 4) for children between the ages of 18 months and 14 years (p=0.05), with no recovery. Significant declines were also recorded for children aged <15 years starting (change from 35 to 21) and remaining (change from 4 032 to 3 986) on ART, as well as for adults starting ART (change from 855 to 610) at the onset of the first wave (p=0.01). No significant change was detected in PMTCT and TB indicators during the first wave. Pronounced decreases in HC were recorded in December, during the country's second wave (change from 237 965 to 227 834). CONCLUSION: Declines were recorded for most indicators in Mopani, with HC being affected the most at the start of the first wave and not showing any significant recovery between waves. Strategies are required to mitigate the effects of future COVID-19 waves and encourage positive health-seeking behaviour.

Measurements of Argon-39 from locations near historic underground nuclear explosions.

Measurement of radioactive gas seepage from an underground nuclear explosion is one of the primary methods to confirm whether an event was nuclear in nature. Radioactive noble gas indicators that are commonly targeted by such measurements (e.g. 133Xe, 37Ar) have half-lives of 35 days or less. Argon-39, an activation product similar to 37Ar, is produced by the interaction between neutrons and potassium in the surrounding geology and has a half-life of 269 years. Measurements taken at three sites near three historic underground nuclear test locations at the Nevada National Security Site have all shown highly elevated levels of 39Ar in soil gas decades after the test events. Elevated levels of 39Ar were also detected in atmospheric air collected near two of these sites, and outside the entrance of the one tunnel site. These measurements demonstrate that 39Ar has the potential to be a long-term signature of an underground nuclear event which can be reliably detected at the surface or in the shallow subsurface. This radionuclide detection of an underground nuclear event decades after the event takes place is in contrast to the commonly held assumption that detecting underground nuclear events via radionuclides at the surface needs to be done in a matter of months. Depending upon what further studies show about the robustness of this signature in a variety of geological settings, it may in fact be easy to detect underground nuclear events at the surface for a very long time post-detonation.

Evidence review of physical distancing and partition screens to reduce healthcare acquired SARS-CoV-2.

We review the evidence base for two newly introduced Infection prevention and control strategies within UK hospitals. The new standard infection control precaution of 2 metres physical distancing and the use of partition screens as a means of source control of infection for SARS-CoV-2. Following review of Ovid-MEDLINE and governmental SAGE outputs there is limited evidence to support the use of 2 metres physical distancing and partition screens within healthcare.

Primary healthcare workers at risk during COVID-19: An analysis of infections in HIV service providers in five districts of South Africa.

BACKGROUND: Protecting healthcare workers (HCWs) from COVID-19 is a global priority. Anova Health Institute (Anova) is the PEPFAR (US President's Emergency Plan for AIDS Relief) District Support Partner for the Johannesburg, Cape Town, Sedibeng, Capricorn and Mopani districts in South Africa, operating in public sector primary healthcare facilities. At the time of the emergence of COVID-19, Anova employed close to 4 000 people: 41% community health workers (CHWs), 23% data staff, 20% nurses and doctors, 12% management/support and 5% allied HCWs. OBJECTIVES: To describe rates of COVID-19 diagnosis in Anova-employed HCWs in five districts. METHODS: Employees exposed to, tested for or diagnosed with COVID-19 were required to report the event. These reports were compiled into a database to monitor the impact of COVID-19 on the workforce. We kept a timeline of key events occurring at national and district level, including Anova's policies and their implementation, that was used to describe organisational response. We described the number of confirmed cases, cumulative incidence rates and testing rates, broken down by district and job category. We estimated expected deaths and the effect on time off work. RESULTS: Of Anova employees, 14% (n=562) were diagnosed with COVID-19 by the end of September 2020. Cumulative incidence was highest in Sedibeng (29%) and lowest in Mopani (5%). All HCWs experienced high incidences: data staff 17%, allied HCWs 16%, CHWs 14%, nurses and doctors 13%, and management/support 11%. At the peak of the epidemic, for 5 weeks, >5% of employees were unable to work owing to exposure or infection, significantly disrupting service delivery. The additional administrative burden on managers was substantial. CONCLUSIONS: It is critical that all cadres of HCWs are protected in the workplace, including in primary care settings, where better structuresare needed to perform risk assessments and conduct outbreak investigations. CHWs and data staff may be at higher risk owing to poor infrastructure, limited power to negotiate working conditions, and limited experience of infection prevention and control. Their working conditions must be improved to reduce their risk.

Distinct adaptation patterns between grip dynamics and arm kinematics when the body is upside-down.

In humans, practically all movements are learnt and performed in a constant gravitational field. Yet, studies on arm movements and object manipulation in parabolic flight have highlighted very fast sensorimotor adaptations to altered gravity environments. Here, we wondered if the motor adjustments observed in those altered gravity environments could also be observed on Earth in a situation where the body is upside-down. To address this question, we asked participants to perform rhythmic arm movements in two different body postures (right-side-up and upside-down) while holding an object in precision grip. Analyses of grip-load force coordination and of movement kinematics revealed distinct adaptation patterns between grip and arm control. Grip force and load force were tightly synchronized from the first movements performed in upside-down posture, reflecting a malleable allocentric grip control. In contrast, velocity profiles showed a more progressive adaptation to the upside-down posture and reflected an egocentric planning of arm kinematics. In addition to suggesting distinct mechanisms between grip dynamics and arm kinematics for adaptation to novel contexts, these results also suggest the existence of general mechanisms underlying gravity-dependent motor adaptation that can be used for fast sensorimotor coordination across different postures on Earth and, incidentally, across different gravitational conditions in parabolic flights, in human centrifuges, or in Space.NEW & NOTEWORTHY During rhythmic arm movements performed in an upside-down posture, grip control adapted very quickly, but kinematics adaptation was more progressive. Our results suggest that grip control and movement kinematics planning might operate in different reference frames. Moreover, by comparing our results with previous results from parabolic flight studies, we propose that a common mechanism underlies adaptation to unfamiliar body postures and adaptation to altered gravity.

Evaluation of Knee Cartilage Diurnal, Activity, and BMI-Related Variations Using Quantitative T2 Mapping MRI and Fitbit Activity Tracking.

The aim of this study is to evaluate diurnal variation in knee cartilage 3 Tesla magnetic resonance imaging (MRI) T2 mapping relaxation times, as well as activity- and body mass index (BMI)-dependent variability, using quantitative analysis of T2 values from segmented regions of the weight-bearing articular surfaces of the medial and lateral femoral condyles and tibial plateaus. Ten healthy volunteers' daily activity (steps) were tracked with Fitbit pedometers. Sagittal MRI T2 maps were obtained in the morning and afternoon on days 2 and 3. Mean T2 values were analyzed for variation related to the number of steps taken (activity), time of day (diurnal variation), and BMI using mixed effect model. Significant (albeit small) differences in the medial femoral and medial tibial cartilage regions were identified between morning and afternoon scans (diurnal variation). Daily activity did not result in significant changes and increasing BMI only demonstrated a slight increase in T2 values for the lateral tibial plateau. These findings suggest that it may be necessary to control diurnal variation when using quantitative MRI T2 mapping to assess articular cartilage longitudinally in healthy participants. Further investigation is needed to confirm these findings and determine if they also apply to symptomatic patients.

Molecular Imaging of Inflammation in Osteoarthritis Using a Water-Soluble Fluorocoxib.

Clinical imaging approaches to detect inflammatory biomarkers, such as cyclooxygenase-2 (COX-2), may facilitate the diagnosis and therapy of inflammatory diseases. To this end, we report the discovery of N-[(rhodamin-X-yl)but-4-yl]-2-[1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]acetamide chloride salt (fluorocoxib D), a hydrophilic analog of fluorocoxib A. Fluorocoxib D inhibits COX-2 selectively in purified enzyme preparations and cells. It exhibits adequate photophysical properties to enable detection of COX-2 in intact cells, in a mouse model of carrageenan-induced acute footpad inflammation and inflammation in a mouse model of osteoarthritis. COX-2-selectivity was verified either by blocking the enzyme's active site with celecoxib or by molecular imaging with nontargeted 5-carboxy-X-rhodamine dye. These data indicate that fluorocoxib D is an ideal candidate for early detection of inflammatory or neoplastic lesions expressing elevated levels of COX-2.