Cognition and freezing of gait in Parkinson's disease: A systematic review and meta-analysis.

Freezing of gait (FOG) is a common and disabling symptom in people with Parkinson's Disease (PwPD). Although cognition is thought to be worse in PwPD who freeze, a comprehensive analysis of this relationship will inform future research and clinical care. This systematic review and meta-analysis compared cognition between PwPD who do and do not exhibit FOG across a range of cognitive domains and assessed the impact of disease severity and medication status on this relationship. 145 papers (n = 9010 participants) were included in the analysis, with 144 and 138 articles meeting the criteria to assess moderating effects of disease severity and medication status, respectively. PwPD who freeze exhibited worse cognition than PwPD without FOG across global cognition, executive function/attention, language, memory, and visuospatial domains. Greater disease severity and "ON" levodopa medication status moderated the FOG status-cognition relationship in global cognitive performance but not in other cognitive domains. This meta-analysis confirmed that cognition is worse in PwPD with FOG and highlights the importance of disease severity and medication status in this relationship.

Pyrocumulonimbus affect average stratospheric aerosol composition.

Pyrocumulonimbus (pyroCb) are wildfire-generated convective clouds that can inject smoke directly into the stratosphere. PyroCb have been tracked for years, yet their apparent rarity and episodic nature lead to highly uncertain climate impacts. In situ measurements of pyroCb smoke reveal its distinctive and exceptionally stable aerosol properties and define the long-term influence of pyroCb activity on the stratospheric aerosol budget. Analysis of 13 years of airborne observations shows that pyroCb are responsible for 10 to 25% of the black carbon and organic aerosols in the "present-day" lower stratosphere, with similar impacts in both the North and South Hemispheres. These results suggest that, should pyroCb increase in frequency and/or magnitude in future climates, they could generate dominant trends in stratospheric aerosol.

No increase in adverse events with lateral extra-articular tenodesis augmentation of anterior cruciate ligament reconstruction - Results from the stability randomized trial.

OBJECTIVES: Results from the Stability Study suggest that adding a lateral extra-articular tenodesis (LET) to a hamstring tendon autograft reduces the rate of anterior cruciate ligament reconstruction (ACLR) failure in high-risk patients. The purpose of this study is to report adverse events over the 2-year follow-up period and compare groups (ACLR alone vs. ACLR + LET). METHODS: Stability is a randomized clinical trial comparing hamstring tendon ACLR with and without LET. Patients aged 14-25 years with an ACL deficient knee were included. Patients were followed and adverse events documented (type, actions taken, resolution) with visits at 3, 6, 12, and 24 months postoperatively. Adverse events were categorized as none, minor medical, minor surgical, contralateral ACL rupture, or graft rupture. Patient reported outcome measures (PROMs) collected at each visit included the Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee Score (IKDC), and ACL Quality of Life Questionnaire (ACL-QOL). RESULTS: In total, 618 patients were randomized (mean age 18.9 years, 302 (49%) male). Forty-five patients (7%) suffered graft rupture; 34 (11%) in the ACLR group compared to 11 (4%) in the ACLR + LET group (RRR = 0.67, 95% CI 0.36 to 0.83, p < 0.001). There were no differences in effusion or infection rates between groups. The ACLR + LET group experienced an increased number of hardware removals (10 vs. 4). Overall, the rate of minor medical events (11%), minor surgical events (7%), and ipsilateral or contralateral ACL tears (10%) were low considering the high-risk patient profile. Increasing severity of adverse events was associated with lower PROMs at 24 months post-operative. Patients in the ACLR + LET group reported greater degree of pain at 3 months only. There were no clinically significant differences in range of motion between groups. CONCLUSIONS: The addition of LET to hamstring tendon autograft ACLR in young patients at high risk of re-injury resulted in a statistically significant reduction in graft rupture. While the addition of LET may increase rates of hardware irritation, there was no significant increase in overall rates of minor medical adverse events, minor surgical events, or overall re-operation rates. The concerns regarding complications associated with a LET did not materialize in this study. LEVEL OF EVIDENCE: Level I.

The relationship between plantar sensation and muscle onset during automatic postural responses in people with multiple sclerosis and healthy controls.

BACKGROUND: Plantar sensation is critical for balance control in people with multiple sclerosis (PwMS). While previous research has described its impact on standing balance, the influence of plantar sensation during automatic postural responses (APRs) is not well understood in PwMS. The purpose of this study was to characterize the relationship between plantar sensation and APRs in PwMS and controls. A secondary aim was to determine whether the relationship between plantar sensation and APRs is different across PwMS and control groups. METHODS: 122 PwMS and 48 age-matched controls underwent forward and backward support-surface perturbations from stance. The onset of the tibialis anterior (TA) and medial gastrocnemius (MG) were the primary reactive balance outcome measures for backward and forward losses of balance, respectively. Plantar sensation was measured as the vibration sensation threshold (VT). RESULTS: As expected, PwMS had significantly higher (i.e., worse) VT (p<0.001) and an increased MG and TA onset latency (TA: p<0.001, MG: p = 0.01) compared to the control group. A higher VT was related to increased MG (p<0.001) and TA latency (p<0.001) across all participants. However, no moderating effect of group (control or PwMS) was observed for the relationship between VT and muscle onset (MG: p = 0.14; TA: p = 0.34). CONCLUSION: PwMS demonstrated poorer plantar sensation and delayed muscle onset during APRs compared to controls. Plantar sensation was also related to muscle onset after perturbations in all participants. Although this relationship was not moderated by group, this may be related to the lack of dynamic range of VT scores in controls. These results indicate that plantar sensation may be related to reactive balance and provides insight into a potential contributing factor of delayed automatic postural responses in people with MS.

Effects of dual-tasking on time-to-boundary during stance in people with PD: A preliminary study.

BACKGROUND: Quiet stance is impacted by Parkinson's disease and dual-tasking. Recently developed outcomes such as the time-to-boundary provide unique insight into balance by integrating center of pressure position with base of support. However, little is known about the effects of Parkinson's disease on time-to-boundary. In particular, the effects of distracting cognitive tasks, and how people with Parkinson's disease prioritize balance and cognitive tasks are poorly understood. METHODS: 14 people with Parkinson's disease and 13 controls completed quiet standing and cognitive Stroop tasks separately (single-task) and together (dual-task). 2-dimentional, medio-lateral, and anterior-posterior time-to-boundary were calculated via force-plate data. Traditional sway outcomes, including sway area and path length, were also calculated. Cognitive performance was measured as the verbal reaction time after auditory stimulus delivery. Prioritization was assessed by taking the difference between cognitive and postural dual-task interference. FINDINGS: Time-to-boundary was worse in Parkinson's disease compared to controls (2-dimentional: p = .019; anterior-posterior: p = .062; medio-lateral: p = .012). Medio-lateral time-to-boundary, but not anterior-posterior, was significantly worse during dual-tasking than single-tasking (p = .024). Neurotypical adults tended to prioritize cognition over medio-lateral postural outcomes. INTERPRETATION: People with Parkinson's disease exhibit worse time-to-boundary than their neurotypical peers, and medio-lateral outcomes were sensitive to single to dual-task performance changes. Further, participants generally showed cognitive prioritization, such that cognitive performance was less impacted than medio-lateral postural outcomes by dual-tasking.

Using a mobile application to improve pediatric presumptive TB identification in western Kenya.

BACKGROUND: Early recognition of TB symptoms in children is critical in order to link children to appropriate testing and treatment. Healthcare workers (HCWs) in high TB burden countries are often overburdened with competing clinical priorities, leading to incomplete presumptive TB screening. We assessed if implementing a community health volunteer (CHV) led presumptive pediatric TB mobile android application (PPTBMAPP) in pediatric outpatient, primary care clinics in western Kenya would be feasible, appropriate, and effective.METHODS: We used a mixed-methods participatory, iterative approach to design and implement the PPTBMAPP during a 6-month period. We compared the proportion of children identified in presumptive TB and active TB disease registers out of all patients before and after the implementation of the intervention.RESULTS: Of the 1787 children aged ≤15 years screened using the PPTBMAPP, 376 (21%) met the criteria for presumptive TB. There was a statistically significant increase in the proportion of children to all patients in the presumptive TB registers (97/908, 10.7% vs. 160/989, 16.2%; P = 0.0005), and a trend towards an increase in the proportion of children to all patients in the TB case register (17/117, 14.5% vs. 15/83, 18.1%; P = 0.5). HCWs interviewed commented that the application sped up the presumptive TB screening process.CONCLUSION: Our CHV-led mobile screening intervention significantly increased presumptive TB notification. HCWs reported that the mobile screening intervention was feasible, appropriate, and effective.

Beta Decay of Molecular Tritium.

The beta decay of tritium in the form of molecular T_{2} is the basis of sensitive experiments to measure neutrino mass. The final-state electronic, vibrational, and rotational excitations modify the beta spectrum significantly and are obtained from theory. We report measurements of the branching ratios to specific ionization states for the isotopolog HT. Two earlier, concordant measurements gave branching ratios of HT to the bound HHe^{+} ion of 89.5% and 93.2%, in sharp disagreement with the theoretical prediction of 55%-57%, raising concerns about the theory's reliability in neutrino mass experiments. Our result, 56.5(6)%, is compatible with the theoretical expectation and disagrees strongly with the previous measurements.

The Salivary Mycobiome Contains 2 Ecologically Distinct Mycotypes.

A broad range of fungi has been detected in molecular surveys of the oral mycobiome. However, knowledge is still lacking on interindividual variability of these communities and the ecologic and clinical significance of oral fungal commensals. In this cross-sectional study, we use internal transcribed spacer 1 amplicon sequencing to evaluate the salivary mycobiome in 59 subjects, 36 of whom were scheduled to receive cancer chemotherapy. Analysis of the broad population structure of fungal communities in the whole cohort identified 2 well-demarcated genus-level community types (mycotypes), with Candida and Malassezia as the main taxa driving cluster partitioning. The Candida mycotype had lower diversity than the Malassezia mycotype and was positively correlated with cancer and steroid use in these subjects, smoking, caries, utilizing a removable prosthesis, and plaque index. Mycotypes were also associated with metabolically distinct bacteria indicative of divergent oral environments, with aciduric species enriched in the Candida mycotype and inflammophilic bacteria increased in the Malassezia mycotype. Similar to their fungal counterparts, coexisting bacterial communities associated with the Candida mycotype showed lower diversity than those associated with the Malassezia mycotype, suggesting that common environmental pressures affected bacteria and fungi. Mycotypes were also seen in an independent cohort of 24 subjects, in which cultivation revealed Malassezia as viable oral mycobiome members, although the low-abundance Malassezia sympodialis was the only Malassezia species recovered. There was a high degree of concordance between the molecular detection and cultivability of Candida, while cultivation showed low sensitivity for detection of the Malassezia mycotype. Overall, our work provides insights into the oral mycobiome landscape, revealing 2 community classes with apparently distinct ecologic constraints and specific associations with coexisting bacteria and clinical parameters. The utility of mycotypes as biomarkers for oral diseases warrants further study.

The Fate of Ornamental White Fringetree Through the Invasion Wave of Emerald Ash Borer and Implications for Novel Host Use by This Beetle.

Emerald ash borer (EAB, Agrilus planipennis Fairmaire [Coleoptera: Buprestidae]) is a wood boring beetle that is an invasive pest of ash trees (Fraxinus spp.) in North America. In 2014, it was reported that EAB had infested white fringetree (Chionanthus virginicus L. [Lamiales: Oleaceae]) in Ohio and was since found to have infested this species across its invasive range. In 2018, we reexamined 166 white fringetrees in Illinois, Indiana, Ohio, and Pennsylvania that had been previously examined for EAB attack in 2015 to determine their fate. We assessed tree health and EAB infestation in each tree, assigned an infestation status of newly, continuously, not reinfested, or never infested, and compared the trees' current status to their 2015 status. This assessment was done to determine whether their health and infestation status had changed through the EAB invasion wave. We found that attack rates declined: 26% of trees were infested in 2015 whereas only 13% were in 2018, likely coinciding with declining beetle populations in the area. Overall tree health improved for trees that were not reinfested by EAB after a record of attack in 2015, suggesting that they can survive and recover from EAB attack. Conversely, health declined for newly and continuously infested trees, indicating that they became stressed from EAB attack. Although the majority of the trees survived the invasion wave, several were removed from various sites due to EAB attack suggesting that white fringetree varies in its resistance and tolerance to attack. As beetle populations continue to expand geographically, infestation rates will likely increase and health of white fringetrees will decrease with the EAB attack wave, especially as EAB reaches denser populations of fringetrees.

Factors affecting patient flow in a neurosurgery department.

INTRODUCTION: Patient flow is the process by which movement of patients and clinical productivity is achieved. The objectives of this study were to implement and evaluate the NHS Improvement SAFER patient flow bundle, evaluate the impact of the Red2Green initiative, and assess the impact of frailty on patient flow. MATERIALS AND METHODS: All patients admitted to a neurosurgery unit from 1 September to 30 November 2017 were included. Using guidance set out by NHS, data were prospectively collected from daily ward lists and patient notes, including demographics, admission and discharge details, length of stay, anticipated discharge date, red days with reasons and frailty (Rockwood Clinical Frailty Scale). NHS reference costs were used for cost analyses. RESULTS: A total of 420 patients (55% elective) were included, totalling 3909 bed days. All patients received daily senior reviews before midday, and anticipated discharge dates were set at daily multidisciplinary team meetings. Ten per cent of patients were discharged before midday. There were 21% (837) red days, significantly more (76%) for emergency patients (639 vs 198 elective; P < 0.001); 63% red days were attributed to awaiting a bed in a local hospital; 25% (106) patients were classed as frail (50 elective), which was associated with a significantly longer length of stay (17.3 vs 6; P < 0.01), and more red days (615 vs 222; p<0.01). Considering excess bed charges and lost revenue (with penalties), red days cost over £1 million per year. CONCLUSIONS: SAFER has identified areas for improvement in patient flow, with obvious cost implications. It has created a platform for discussion within the referral network and identified a role for a geriatric liaison service.

Designing a therapeutic hepatitis B vaccine to circumvent immune tolerance.

An effective prophylactic hepatitis B virus (HBV) vaccine has long been available but is ineffective for chronic infection. The primary cause of chronic hepatitis B (CHB) and greatest impediment for a therapeutic vaccine is the direct and indirect effects of immune tolerance to HBV antigens. The resulting defective CD4+/CD8+ T cell response, poor cytokine production, insufficient neutralizing antibody (nAb) and poor response to HBsAg vaccination characterize CHB infection. The objective of this study was to develop virus-like-particles (VLPs) that elicit nAb to prevent viral spread and prime CD4+/CD8+ T cells to eradicate intracellular HBV. Eight neutralizing B cell epitopes from the envelope PreS1 region were consolidated onto a species-variant of the HBV core protein, the woodchuck hepatitis core antigen (WHcAg). PreS1-specific B cell epitopes were chosen because of preferential expression on HBV virions. Because WHcAg and HBcAg are not crossreactive at the B cell level and only partially cross-reactive at the CD4+/CD8+ T cell level, CD4+ T cells specific for WHcAg-unique T cell sites can provide cognate T-B cell help for anti-PreS1 Ab production that is not curtailed by immune tolerance. Immunization of immune tolerant HBV transgenic (Tg) mice with PreS1-WHc VLPs elicited levels of high titer anti-PreS1 nAbs equivalent to wildtype mice. Passive transfer of PreS1 nAbs into human-liver chimeric mice prevented acute infection and cleared serum HBV from mice previously infected with HBV in a model of CHB. At the T cell level, PreS1-WHc VLPs and hybrid WHcAg/HBcAg DNA immunogens elicited HBcAg-specific CD4+ Th and CD8+ CTL responses.

Bioimpedance spectroscopy is not associated with a clinical diagnosis of breast cancer-related lymphedema.

The objective of this study was to evaluate the accuracy of bioimpedance spectroscopy measurements (L-Dex) in the diagnosis of breast cancer-related lymphedema. A retrospective review of a prospectively maintained database was performed of all patients that underwent surgical treatment for breast cancer at a tertiary medical center. Patients who had preoperative and postoperative evaluation for possible lymphedema by limb circumference measurements and bioimpedance were eligible for inclusion in the study. No significant demographic differences were found between the group of patients clinically diagnosed with lymphedema (N=134) and those without a clinical diagnosis of lymphedema (N=261). The ability of bioimpedance to diagnose lymphedema based on the manufacturer's criteria demonstrated low sensitivity, which was 7.5% when lymphedema was defined as an absolute L-Dex value greater than 10, and 24.6% when defined as a relative change of >10 between preoperative and postoperative measurements. This corresponded with a positive predictive value of 61-71% and a negative predictive value of 67-70%. We are unable to recommend the use of bioimpedance as a screening tool or for measurement of breast cancer-related lymphedema.

Oral Mucosal Injury Caused by Targeted Cancer Therapies.

Targeted cancer therapies have fundamentally transformed the treatment of many types of cancers over the past decade, including breast, colorectal, lung, and pancreatic cancers, as well as lymphoma, leukemia, and multiple myeloma. The unique mechanisms of action of these agents have resulted in many patients experiencing enhanced tumor response together with a reduced adverse event profile as well. Toxicities do continue to occur, however, and in selected cases can be clinically challenging to manage. Of particular importance in the context of this monograph is that the pathobiology for oral mucosal lesions caused by targeted cancer therapies has only been preliminarily investigated. There is distinct need for novel basic, translational, and clinical research strategies to enhance design of preventive and therapeutic approaches for patients at risk for development of these lesions. The research modeling can be conceptually enhanced by extrapolating "lessons learned" from selected oral mucosal conditions in patients without cancer as well. This approach may permit determination of the extent to which pathobiology and clinical management are either similar to or uniquely distinct from oral mucosal lesions caused by targeted cancer therapies. Modeling associated with oral mucosal disease in non-oncology patients is thus presented in this context as well. This article addresses this emerging paradigm, with emphasis on current mechanistic modeling and clinical treatment. This approach is in turn designed to foster delineation of new research strategies, with the goal of enhancing cancer patient treatment in the future.

Immunological features in pediatric patients with recurrent and severe infection: Identification of Primary Immunodeficiency Diseases in Merida, Venezuela.

INTRODUCTION AND OBJECTIVES: Primary immunodeficiency diseases (PIDs) are disorders associated mainly with recurrent and severe infection and an increase in susceptibility to autoimmune conditions and cancer. In Venezuela, PIDs are underdiagnosed and there is usually a delay in their diagnosis. Hence there are no data concerning the frequency and type of PIDs that occur. The aim of this study was to identify and quantify the types of PIDs that occur in Merida, a population within Venezuela. PATIENTS OR MATERIALS AND METHODS: Following an informative program designed to alert local health professionals to the warning signs for PIDs, patients with a history of recurrent infections were referred to the Instituto de Inmunologia Clinica, Universidad de Los Andes. RESULTS AND CONCLUSIONS: During the three-year period January 2014 to January 2017, thirty-two cases of PIDs were identified in pediatric patients, and 17 different types of PIDs, were identified. Predominantly antibody deficiencies were most frequent (40.6%), followed by immunodeficiencies affecting cellular and humoral immunity (21.8%), congenital defects of phagocyte (18.7%), CID with associated or syndromic features (9.3%), defects in intrinsic and innate immunity (6.4%) and diseases of immune dysregulation (3.2%). These results have important implications not only to the future approach for management of patients in our regions, but add important knowledge concerning PIDs in Latin America and worldwide.

Seasonal variation in equine follicular fluid proteome.

BACKGROUND: Proteomic studies of follicular fluid (FF) exist for several species, including the horse; however, the seasonal influence on FF proteome has not been explored in livestock. The application of high-throughput proteomics of FF in horse has the potential to identify seasonal variations of proteins involved in follicle and oocyte growth. METHODS: This study (i) profiles the proteomes of equine FF collected from dominant growing follicles during the spring anovulatory season (SAN), and spring (SOV), summer (SUM), and fall (FOV) ovulatory seasons; and (ii) identifies season-dependent regulatory networks and associated key proteins. RESULTS: Regardless of season, a total of 90 proteins were identified in FF, corresponding to 63, 72, 69, and 78 proteins detected in the SAN, SOV, SUM, and FOV seasons, respectively. Fifty-two proteins were common to all seasons, a total of 13 were unique to either season, and 25 were shared between two seasons or more. Protein-to-protein interaction (PPI) analysis indicated the likely critical roles of plasminogen in the SAN season, the prothrombin/plasminogen combination in SUM, and plasminogen/complement C3 in both SOV and FOV seasons. The apolipoprotein A1 appeared crucial in all seasons. The present findings show that FF proteome of SUM differs from other seasons, with FF having high fluidity (low viscosity). CONCLUSIONS: The balance between the FF contents in prothrombin, plasminogen, and coagulation factor XII proteins favoring FF fluidity may be crucial at the peak of the ovulatory season (SUM) and may explain the reported lower incidence of hemorrhagic anovulatory follicles during the SUM season.

A systematic review of meta-analyses in orthopaedic surgery between 2000 and 2016.

AIMS: The aims of this systematic review were to describe the quantity and methodological quality of meta-analyses in orthopaedic surgery published during the last 17 years. MATERIALS AND METHODS: MEDLINE, EMBASE, and PubMed, between 1 January 2000 and 31 December 2016, were searched for meta-analyses in orthopaedic surgery dealing with at least one surgical intervention. Meta-analyses were included if the interventions involved a human muscle, ligament, bone or joint. RESULTS: A total of 392 meta-analyses met eligibility criteria, for which the mean AMSTAR quality score was 7.1/11. There was a positive correlation between the year of publication and the quality of the meta-analysis (r = 0.238, p < 0.001). Between 2000 and 2011, the mean AMSTAR score corresponded to that of a medium quality review. However, between 2012 and 2016, the mean scores have been consistently equivalent to those of a high-quality review. The number of meta-analyses published increased 10-fold between 2005 and 2014. CONCLUSION: The quantity and quality of meta-analyses in orthopaedic surgery which have been published has increased, reaching a plateau in 2012. Methodological flaws remain to be addressed in future meta-analyses in order to continue increasing the quality of the orthopaedic literature. Cite this article: Bone Joint J 2018;100-B:1270-4.

Anticipatory postural responses prior to protective steps are not different in people with PD who do and do not freeze.

BACKGROUND: Protective stepping after a loss of balance is related to falls. Anticipatory postural responses (APAs) prior to protective stepping can impact step performance, may be larger in people with PD, and have been suggested to be related to freezing of gait (FOG). However, whether people with PD and FOG (PD + FOG) exhibit larger APAs than people with PD and no FOG (PD-FOG) is unknown. RESEARCH QUESTION: Determine the impact of freezing status on APAs prior to protective steps, thus providing a better understanding of the link between FOG and APAs. METHODS: Twenty-eight people with PD (13 PD + FOG) were exposed to 50 support surface translations (25 forward, 25 backward, random order) resulting in protective steps. The size of medio-lateral weight shifts prior to the protective step (i.e. APAs), and the percentage of trials with an APA were calculated via force-plates. FOG status was assessed at the time of testing as well as 3.25(+/-0.43) years later. Participants without FOG at testing, but with FOG at follow-up were identified as "converters". RESULTS AND SIGNIFICANCE: For both forward and backward protective stepping, size and percentage trials with an APA were not statistically different between PD + FOG and PD-FOG, even after excluding converters from the PD-FOG group (p > 0.27 for all). No group by direction interactions were observed. These data suggest that, in mild to moderate PD, an inability to couple APAs with stepping, rather than an inappropriately sized APA, may be most related to freezing of gait.

T-cell profiles elicited by Toxoplasma gondii in acutely/chronically infected humans.

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that can infect almost all warm-blooded species and induce a chronic infection in human hosts. The aim of this work was to investigate Th1, Th2, Th17 and Treg polarization, induced by four important T. gondii antigens (SAG1, ROP1, GRA8 and MAG1) in acutely and chronically infected patients. For this purpose, SAG1, ROP1, GRA8 and MAG1 were expressed as recombinant proteins, purified, and used to evaluate the proinflammatory and regulatory immune response profiles in seropositive and seronegative individuals. Our results show that SAG1 and ROP1 elicited a proinflammatory profile (INF-γ, IL-12 and IL-17) in individuals in the acute phase, whereas MAG1 and GRA8 induced a regulatory pattern (Treg and TGF-ß) in chronically infected patients. These results reveal fundamental differences in T-cell polarization induced by T. gondii antigens, which could have important implications in the immunopathogenesis of the disease and in future proposals of therapeutic strategies.