Long Term Gait, Mobility, and Daily Living Outcomes after Orthopedic Surgery for Youth with Cerebral Palsy: Influence of Rehabilitation Dose and Setting

Background/Purpose: Cerebral palsy (CP) is a broad diagnostic description of early brain insult causing motor impairment. To help correct gait abnormalities, many children with CP undergo an orthopedic single event multi-level surgery (SEMLS). After surgery and most importantly SEMLS, rehabilitation is important to recovery. The purpose of this study was to examine the effects of post-op therapy setting and dose on functional mobility outcomes for youth with CP. Methods: Outcome measures included gait deviation index (GDI), walking speed, Pediatrics Outcomes Data Collection Instrument (PODCI), Gross Motor Function Mobility-D (GMFM-D). Data on post-op rehab therapy were retrieved from electronic medical records. Multiple Regression, Two-Way ANOVA, and Welch’s t-tests were used. Patient Sample: 74 cases were eligible. Average age at baseline gait analysis was 11.5, at surgery was 12, and at post-op gait analysis was 13.3 years old, with Gross Motor Function Classification System (GMFCS) levels I (9%), II (53%), III (34%), and IV (4%). Results: There was variability in therapy setting, with 33 different therapy centers. Higher burden of surgery was associated with more therapy sessions. Patients with low burden surgeries tended to improve in PODCI scores, but patients with high burden surgeries did not. These trends were not related to therapy dose, however, patients receiving Nemours Outpatient therapy had a positive association with PODCI gains. Similarly, patients who had low burden surgery improved GMFM-D and those with high burden did not. A minimal threshold of therapy dose was identified for cases with low burden surgery. Patients who attended 46 sessions or more saw GMFM-D improvements and patients who attended 25 sessions or fewer did not improve. Conclusion: Clinical practice recommends rehab therapy after SEMLS, but implementation is inconsistent. Post-op therapy varied widely by setting and number of sessions. As expected, youth who had low-burden surgery had less post-op therapy. Those above a minimum threshold and those at Nemours settings tended to show improvement at one-year post-op. At one year post-op, youth with high burden surgery demonstrated less gains, which is likely related to ongoing recovery in year two

One-pot three-step thioconjugate addition-oxidation-Diels–Alder reactions of ethyl propiolate

Ethyl propiolate undergoes one-pot three-step thioconjugate addition-oxidation-Diels–Alder cycloaddition when treated with a variety of thiols in the presence of catalytic base, meta-chloroperbenzoic acid, lithium perchlorate, and cyclopentadiene. The reaction of S‑aryl thiols is catalyzed by trialkylamines, and the reaction of aliphatic thiols requires catalytic alkoxide base. Yields of the major diastereomer of the conveniently functionalized bicyclic products range from 47 to 81% depending upon the thiol reactant, which compares favorably to yields observed when the entire synthesis is performed step by step

Anthropometric cut-offs to identify hyperglycemia in an Afro-Caribbean population: a cross-sectional population-based study from Barbados.

INTRODUCTION: Body mass index (BMI) and waist circumference (WC) cut-offs associated with hyperglycemia may differ by ethnicity. We investigated the optimal BMI and WC cut-offs for identifying hyperglycemia in the predominantly Afro-Caribbean population of Barbados. RESEARCH DESIGN AND METHODS: A cross-sectional study of 865 individuals aged ≥25 years without known diabetes or cardiovascular disease was conducted. Hyperglycemia was defined as fasting plasma glucose ≥5.6 mmol/L or hemoglobin A1c ≥5.7% (39 mmol/mol). The Youden index was used to identify the optimal cut-offs from the receiver operating characteristic (ROC) curves. Further ROC analysis and multivariable log binomial regression were used to compare standard and data-derived cut-offs. RESULTS: The prevalence of hyperglycemia was 58.9% (95% CI 54.7% to 63.0%). In women, optimal BMI and WC cut-offs (27 kg/m2 and 87 cm, respectively) performed similarly to standard cut-offs. In men, sensitivities of the optimal cut-offs of BMI ≥24 kg/m2 (72.0%) and WC ≥86 cm (74.0%) were higher than those for standard BMI and WC obesity cut-offs (30.0% and 25%-46%, respectively), although with lower specificity. Hyperglycemia was 70% higher in men above the data-derived WC cut-off (prevalence ratio 95% CI 1.2 to 2.3). CONCLUSIONS: While BMI and WC cut-offs in Afro-Caribbean women approximate international standards, our findings, consistent with other studies, suggest lowering cut-offs in men may be warranted to improve detection of hyperglycemia. Our findings do, however, require replication in a new data set.The project was supported by the Ministry of Health of the Government of Barbados. ANW is supported by the Fogarty International Center of the National Institutes of Health under Award Number K43TW010698. This paper describes the views of the authors and does not necessarily represent the official views of the National Institutes of Health (USA)

One-pot synthesis of (Z)-B-sulfonyl enoates from ethyl propiolate

B-Sulfonyl enoates may be synthesized through a one-pot two-step sequence from ethyl propiolate with good to excellent selectivity for the Z isomer. Trialkylamines catalyze thioconjugate additions of aryl thiols, and alkoxides catalyze the addition of aliphatic thiols. Addition of meta-chloroperbenzoic acid (mCPBA) and LiClO4 to the reaction mixture provides rapid access to the sulfonyl enoates. Yields of the pure Z isomer range from 51 – 90%

Factors affecting consistency and accuracy in identifying modern macroperforate planktonic foraminifera

Planktonic foraminifera are widely used in biostratigraphic, palaeoceanographic and evolutionary studies, but the strength of many study conclusions could be weakened if taxonomic identifications are not reproducible by different workers. In this study, to assess the relative importance of a range of possible reasons for among-worker disagreement in identification, 100 specimens of 26 species of macroperforate planktonic foraminifera were selected from a core-top site in the subtropical Pacific Ocean. Twenty-three scientists at different career stages – including some with only a few days experience of planktonic foraminifera – were asked to identify each specimen to species level, and to indicate their confidence in each identification. The participants were provided with a species list and had access to additional reference materials. We use generalised linear mixed-effects models to test the relevance of three sets of factors in identification accuracy: participant-level characteristics (including experience), species-level characteristics (including a participant’s knowledge of the species) and specimen-level characteristics (size, confidence in identification). The 19 less experienced scientists achieve a median accuracy of 57 %, which rises to 75 % for specimens they are confident in. For the 4 most experienced participants, overall accuracy is 79 %, rising to 93 % when they are confident. To obtain maximum comparability and ease of analysis, everyone used a standard microscope with only 35× magnification, and each specimen was studied in isolation. Consequently, these data provide a lower limit for an estimate of consistency. Importantly, participants could largely predict whether their identifications were correct or incorrect: their own assessments of specimen-level confidence and of their previous knowledge of species concepts were the strongest predictors of accuracy

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

How the 22q11.2 deletion predisposes to psychiatric disease is unclear. Here, the authors examine living human neuronal cells and show that 22q11.2 regulates the expression of genes linked to autism during early development, and genes linked to schizophrenia and synaptic biology in neurons. It is unclear how the 22q11.2 deletion predisposes to psychiatric disease. To study this, we generated induced pluripotent stem cells from deletion carriers and controls and utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Here, we show that upon differentiation into neural progenitor cells, the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including autism. In excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common and rare variants. To understand how the deletion contributed to these changes, we defined the minimal protein-protein interaction network that best explains gene expression alterations. We found that many genes in 22q11.2 interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways. Our findings suggest that the 22q11.2 deletion impacts genes that may converge with psychiatric risk loci to influence disease manifestation in each deletion carrier.Peer reviewe

The dental calculus metabolome in modern and historic samples.

INTRODUCTION: Dental calculus is a mineralized microbial dental plaque biofilm that forms throughout life by precipitation of salivary calcium salts. Successive cycles of dental plaque growth and calcification make it an unusually well-preserved, long-term record of host-microbial interaction in the archaeological record. Recent studies have confirmed the survival of authentic ancient DNA and proteins within historic and prehistoric dental calculus, making it a promising substrate for investigating oral microbiome evolution via direct measurement and comparison of modern and ancient specimens. OBJECTIVE: We present the first comprehensive characterization of the human dental calculus metabolome using a multi-platform approach. METHODS: Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) quantified 285 metabolites in modern and historic (200 years old) dental calculus, including metabolites of drug and dietary origin. A subset of historic samples was additionally analyzed by high-resolution gas chromatography-MS (GC-MS) and UPLC-MS/MS for further characterization of metabolites and lipids. Metabolite profiles of modern and historic calculus were compared to identify patterns of persistence and loss. RESULTS: Dipeptides, free amino acids, free nucleotides, and carbohydrates substantially decrease in abundance and ubiquity in archaeological samples, with some exceptions. Lipids generally persist, and saturated and mono-unsaturated medium and long chain fatty acids appear to be well-preserved, while metabolic derivatives related to oxidation and chemical degradation are found at higher levels in archaeological dental calculus than fresh samples. CONCLUSIONS: The results of this study indicate that certain metabolite classes have higher potential for recovery over long time scales and may serve as appropriate targets for oral microbiome evolutionary studies

Prevention of Morbidity in Sickle Cell Disease (POMS2a)-overnight auto-adjusting continuous positive airway pressure compared with nocturnal oxygen therapy: a randomised crossover pilot study examining patient preference and safety in adults and children.

DESIGN: This randomised crossover trial compared nocturnal auto-adjusting continuous positive airway pressure (APAP) and nocturnal oxygen therapy (NOT) in adults and children with sickle cell anaemia, with patient acceptability as the primary outcome. Secondary outcomes included pulmonary physiology (adults), safety, and daily pain during interventions and washout documented using tablet technology. METHODS: Inclusion criteria were age > 8 years and the ability to use an iPad to collect daily pain data. Trial participation was 4 weeks; week 1 involved baseline data collection and week 3 was a washout between interventions, which were administered for 7 days each during weeks 2 and 4 in a randomised order. Qualitative interviews were transcribed verbatim and analysed for content using a funnelling technique, starting generally and then gaining more detailed information on the experience of both interventions. Safety data included routine haematology and median pain days between each period. Missing pain day values were replaced using multiple imputation. RESULTS: Ten adults (three female, median age 30.2 years, range 18-51.5 years) and eleven children (five female, median age 12 years, range 8.7-16.9 years) enrolled. Nine adults and seven children completed interviews. Qualitative data revealed that the APAP machine was smaller, easier to handle, and less noisy. Of 16 participants, 10 preferred APAP (62.5%, 95% confidence interval (CI) 38.6-81.5%). Haemoglobin decreased from baseline on APAP and NOT (mean difference -3.2 g/L (95% CI -6.0 to -0.2 g/L) and -2.5 g/L (95% CI -4.6 to 0.3 g/L), respectively), but there was no significant difference between interventions (NOT versus APAP, 1.1 (-1.2 to 3.6)). Pulmonary function changed little. Compared with baseline, there were significant decreases in the median number of pain days (1.58 for APAP and 1.71 for NOT) but no significant difference comparing washout with baseline. After adjustment for carry-over and period effects, there was a non-significant median difference of 0.143 (95% CI -0.116 to 0.401) days additional pain with APAP compared with NOT. CONCLUSION: In view of the point estimate of patient preference for APAP, and no difference in haematology or pulmonary function or evidence that pain was worse during or in washout after APAP, it was decided to proceed with a Phase II trial of 6 months APAP versus standard care with further safety monitoring for bone marrow suppression and pain. TRIAL REGISTRATION: ISRCTN46078697 . Registered on 18 July 2014

Relative sea-level rise around East Antarctica during Oligocene glaciation

During the middle and late Eocene (∼48-34 Myr ago), the Earth's climate cooled and an ice sheet built up on Antarctica. The stepwise expansion of ice on Antarcticainduced crustal deformation and gravitational perturbations around the continent. Close to the ice sheet, sea level rosedespite an overall reduction in the mass of the ocean caused by the transfer of water to the ice sheet. Here we identify the crustal response to ice-sheet growth by forcing a glacial-hydro isostatic adjustment model with an Antarctic ice-sheet model. We find that the shelf areas around East Antarctica first shoaled as upper mantle material upwelled and a peripheral forebulge developed. The inner shelf subsequently subsided as lithosphere flexure extended outwards from the ice-sheet margins. Consequently the coasts experienced a progressive relative sea-level rise. Our analysis of sediment cores from the vicinity of the Antarctic ice sheet are in agreement with the spatial patterns of relative sea-level change indicated by our simulations. Our results are consistent with the suggestion that near-field processes such as local sea-level change influence the equilibrium state obtained by an icesheet grounding line

Human Cytomegalovirus IE1 Protein Elicits a Type II Interferon-Like Host Cell Response That Depends on Activated STAT1 but Not Interferon-γ

Human cytomegalovirus (hCMV) is a highly prevalent pathogen that, upon primary infection, establishes life-long persistence in all infected individuals. Acute hCMV infections cause a variety of diseases in humans with developmental or acquired immune deficits. In addition, persistent hCMV infection may contribute to various chronic disease conditions even in immunologically normal people. The pathogenesis of hCMV disease has been frequently linked to inflammatory host immune responses triggered by virus-infected cells. Moreover, hCMV infection activates numerous host genes many of which encode pro-inflammatory proteins. However, little is known about the relative contributions of individual viral gene products to these changes in cellular transcription. We systematically analyzed the effects of the hCMV 72-kDa immediate-early 1 (IE1) protein, a major transcriptional activator and antagonist of type I interferon (IFN) signaling, on the human transcriptome. Following expression under conditions closely mimicking the situation during productive infection, IE1 elicits a global type II IFN-like host cell response. This response is dominated by the selective up-regulation of immune stimulatory genes normally controlled by IFN-γ and includes the synthesis and secretion of pro-inflammatory chemokines. IE1-mediated induction of IFN-stimulated genes strictly depends on tyrosine-phosphorylated signal transducer and activator of transcription 1 (STAT1) and correlates with the nuclear accumulation and sequence-specific binding of STAT1 to IFN-γ-responsive promoters. However, neither synthesis nor secretion of IFN-γ or other IFNs seems to be required for the IE1-dependent effects on cellular gene expression. Our results demonstrate that a single hCMV protein can trigger a pro-inflammatory host transcriptional response via an unexpected STAT1-dependent but IFN-independent mechanism and identify IE1 as a candidate determinant of hCMV pathogenicity