Motor skill competence and moderate- and vigorous-intensity physical activity: a linear and non-linear cross-sectional analysis of eight pooled trials.

BACKGROUND: Few studies have examined the relationship between motor skill competence and device-measured physical activity in large samples and none have used non-linear modelling. This study assessed the linear and non-linear associations between motor skill competence and physical activity in children using pooled data from eight studies. METHODS: Cross-sectional ActiGraph accelerometer and motor skills competence data from 988 children (50.8% boys) aged 3-11 years were included. Total, object control and locomotor skill competence were assessed using the Test of Gross Motor Skill Development. Linear mixed models were fitted to examine linear associations between motor skill competence and physical activity. Then, restricted cubic splines models were used to assess potential non-linear relationships. Interactions by sex and age were assessed. RESULTS: There was evidence of positive linear associations between total skill, and object control and locomotor skills, with moderate- and vigorous-intensity physical activity; however, the associations with total skill competence and object control better fitted a non-linear model. Non-linear models indicated associations were positive but relatively weak in the low to mid ranges of TGMD/object control scores but at high ranges (~ > 70 out of 100/ and ~ 35 out of 50) the association strength increased for both moderate- and vigorous-intensity physical activity. There were sex interactions for locomotor skills only, specifically for vigorous activity with boys having a stronger positive association than girls. CONCLUSIONS: There appears to be a threshold for object control skill proficiency that children need to reach to enhance their physical activity levels which provides support for a motor skill "proficiency barrier". This provides a tangible benchmark for children to achieve in motor competence programs.

The moment of tooth: rate, fate and pattern of Pacific lingcod dentition revealed by pulse-chase.

Tooth replacement rates of polyphyodont cartilaginous and bony fishes are hard to determine because of a lack of obvious patterning and maintaining specimens long enough to observe replacement. Pulse-chase is a fluorescent technique that differentially colours developing mineralized tissue. We present in situ tooth replacement rate and position data for the oral and pharyngeal detentions of Ophiodon elongatus (Pacific lingcod). We assessed over 10 000 teeth, in 20 fish, and found a daily replacement rate of about two teeth (3.6% of the dentition). The average tooth is in the dental battery for 27 days. The replacement was higher in the lower pharyngeal jaw (LPJ). We found no difference between replacement rates of feeding and non-feeding fish, suggesting feeding was not a driver of tooth replacement. Lingcod teeth have both a size and location fate; smaller teeth at one spot will not grow into larger teeth, even if a large tooth nearby is lost. We also found increased rates of replacement at the posterior of the LPJ relative to the anterior. We propose that lingcod teeth do not migrate in the jaw as they develop; their teeth are fated in size and location, erupting in their functional position.

Essential medicine selection during the COVID-19 pandemic: Enabling access in uncharted territory.

The COVID-19 pandemic requires urgent decisions regarding treatment policy in the face of rapidly evolving evidence. In response, the South African Essential Medicines List Committee established a subcommittee to systematically review and appraise emerging evidence, within very short timelines, in order to inform the National Department of Health COVID-19 treatment guidelines. To date, the subcommittee has reviewed 14 potential treatments, and made recommendations based on local context, feasibility, resource requirements and equity. Here we describe the rapid review and evidence-to-decision process, using remdesivir and dexamethasone as examples. Our experience is that conducting rapid reviews is a practical and efficient way to address medicine policy questions under pandemic conditions.

Optical skyrmion lattice in evanescent electromagnetic fields.

Topological defects play a key role in a variety of physical systems, ranging from high-energy to solid-state physics. A skyrmion is a type of topological defect that has shown promise for applications in the fields of magnetic storage and spintronics. We show that optical skyrmion lattices can be generated using evanescent electromagnetic fields and demonstrate this using surface plasmon polaritons, imaged by phase-resolved near-field optical microscopy. We show how the optical skyrmion lattice exhibits robustness to imperfections while the topological domain walls in the lattice can be continuously tuned, changing the spatial structure of the skyrmions from bubble type to Néel type. Extending the generation of skyrmions to photonic systems provides various possibilities for applications in optical information processing, transfer, and storage.

The thyroid hormone-αvß3 integrin axis in ovarian cancer: regulation of gene transcription and MAPK-dependent proliferation.

Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvß3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvß3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvß3) and A2780 (low αvß3) cells promoted αv and ß3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvß3 antibodies, excluding T3-induced ß3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of ß3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvß3-deficient HEK293 cells treated with αvß3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the ß3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvß3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.

Strengthening pharmacovigilance in South Africa.

This report outlines findings and recommendations of a national pharmacovigilance workshop held in August 2012 in South Africa (SA). A survey of current pharmacovigilance activities, conducted in preparation for the meeting, identified multiple programmes collecting drug safety data in SA, with limited co-ordination at national level. The meeting resolved that existing pharmacovigilance programmes need to be strengthened and consolidated to ensure that important local safety issues are addressed, data can be pooled and compared and outputs shared more widely. Pharmacovigilance activities should inform treatment guidelines with the goal of improving patient care. A variety of pharmaco-epidemiological approaches should be employed, including nesting drug safety studies within existing sentinel cohorts and the creation of a pregnancy exposure registry. The attendees agreed on key principles that will inform a national pharmacovigilance plan and compiled a list of priority pharmacovigilance issues facing public health programmes in SA.

Vascular distribution of glioblastoma multiforme at diagnosis.

Treatment of high-grade gliomas with selective intra-arterial (IA) administration of chemotherapies has been proposed, and utilized as a therapeutic modality. This approach offers the conceptual benefit of providing maximal delivery of the agent to the tumor bed, while potentially reducing systemic exposure to the agent. This retrospective study was designed to determine the vascular distribution of glioblastoma multiforme (GBM) at the time of diagnosis in an effort to determine what proportion of patients would likely be candidates for this approach. The preoperative MRI scans of 50 patients with GBM were analyzed and compared to published normative data of intracranial vascular distribution. Vascular distribution was determined by analyzing post-gadolinium axial and coronal T1 images, axial T2 images, and axial T2 images with an additional 1 cm margin (T2 + 1 cm) added in all dimensions. T1 analysis demonstrated 60% of tumors in a single vascular distribution. T2 analysis of these tumors reduced that number to 34%. When the T2 + 1 cm margin was utilized, only 6% of tumors were in a single vascular distribution. 66% of tumors were limited to the anterior circulation on T1 imaging but only 34% on T2 + 1 cm imaging. 30% of tumors were also within the distribution of the anterior choroidal artery. These findings suggest that the use of selective IA administration of agents is necessarily limited to a fraction of presenting patients or will require administration via multiple cerebral arteries.

Transoral robotic surgery alone for oropharyngeal cancer: an analysis of local control.

OBJECTIVE: To evaluate local control following transoral robotic surgery (TORS) with the da Vinci Surgical System (Intuitive Surgical Inc) as a single treatment modality for oropharyngeal squamous cell carcinoma (OSCC). DESIGN: Prospective, single-center, observational study. SETTING: Academic university health system and tertiary referral center. PATIENTS: Thirty adults with previously untreated OSCC. INTERVENTION: Transoral robotic surgery with staged neck dissection as indicated. MAIN OUTCOME MEASURES: Local control and margin status. RESULTS: Thirty patients were enrolled with previously untreated OSCC and no prior head and neck radiation therapy. Follow-up duration was at least 18 months. At the time of diagnosis, 9 tumors were T1 (30%); 16 were T2 (53%); 4 were T3 (13%); and 1 was T4a (3%). The anatomic sites of these primary tumors were tonsil in 14 (47%), tongue base in 9 (30%), glossotonsillar sulcus in 3 (10%), soft palate in 3 (10%), and oropharyngeal wall in 1 (3%). There was only 1 patient (3%) who had a positive margin after primary resection; further resection achieved a final negative margin. Perineural invasion was noted in 3 tumors (10%). No patient received postoperative adjuvant therapy. At a mean follow-up of 2.7 years (range, 1.5-5.1 years), there was 1 patient with local failure (3%). CONCLUSION: As the only modality used for treatment of pathologically low-risk OSCCs, TORS provides high local control and is associated with low surgical morbidity.

Onset of adreno-leukodystrophy after medulloblastoma therapy: causal connection or coincidence?

X-linked adreno-leukodystrophy (ALD) is a peroxisomal disorder affecting the white matter of the central nervous system and the adrenal cortex. It is caused by mutations in the ABCD1 gene encoding for a peroxisomal membrane protein. The absent genotype-phenotype correlation implies a contribution by environmental factors to explain the phenotypical heterogeneity. We report on a 4-year-old boy with a biochemically confirmed diagnosis of ALD after birth. At the age of 32 months, the additional diagnosis of a medulloblastoma was made. After treatment of the medulloblastoma, he developed active areas of demyelination representing the characteristic neuroimaging features of ALD. The clinical history of our patient supports the hypothesis that external factors, like neurosurgical intervention as part of medulloblastoma treatment, may accelerate or initiate cerebral ALD-related demyelination. A postsurgical inflammatory reaction may facilitate the inclusion of abnormal fatty acids in myelin. The opening of the blood-brain barrier following neurosurgery may enhance the recognition of previously sequestered antigens considered to play a role in ALD onset. Consequently, neurosurgical disruption of the BBB can precipitate the immune-mediated inflammatory process, which progressively destroys myelin in ALD patients. Tumor-related chemotherapy and/or radiotherapy may also play a contributing role. We suggest that X-ALD patients who undergo neurosurgical intervention need close follow-up imaging to identify active demyelination early.

Low cerebellar vermis volumes and impaired neuropsychologic performance in children treated for brain tumors and leukemia.

BACKGROUND AND PURPOSE: Injury of the cerebellar vermis may occur in children with brain malignancies. Because the vermis is involved in motor and cognitive functioning, the goal of this prospective longitudinal study was to evaluate treatment-related changes in vermal volumes and neuropsychologic performance in children receiving brain radiation of the cerebellum. MATERIALS AND METHODS: Ten patients (mean age, 11.6 years) and 10 healthy children (mean age, 12.1 years) were examined. Lobar vermal volumes and performance on neuropsychologic tests evaluating motor, visual, verbal, attention, memory, and executive functions were assessed at baseline and at 6-month follow-up visits. RESULTS: At baseline, lower mean vermal volumes and impaired performance on visual-spatial and fine-motor tasks were detected in patients. At 6-month follow-up, further decrease in vermal volumes was detected only in patients with medulloblastoma, who received the largest radiation doses to the entire vermis. The volume decrease was not associated with reduction in neuropsychologic performance compared with baseline. At 6-month follow-up, data from all subjects revealed an association between smaller vermal volumes and slower fine-motor speed and lower visual-spatial skills. CONCLUSIONS: Reduced brain-tissue volumes following radiation have been reported previously in pediatric patients. In this study, lower vermal volumes were detected even earlier, before radiation treatment was initiated or completed. Six months postradiation, vermal volume decreases detected in patients with medulloblastoma were not accompanied by declines in already poor neuropsychologic performance. In addition to radiation, the presence of brain malignancies and preradiation treatment may be important factors affecting cerebellar vermis tissue.

Impact of nepafenac 0.1% on macular thickness and postoperative visual acuity after cataract surgery in patients at low risk for cystoid macular oedema.

PURPOSE: To evaluate the use of topical nepafenac 0.1% after routine phacoemulsification in patients at low risk for cystoid macular oedema (CME) using optical coherence tomography (OCT) measurement of macular thickness. METHODS: Seventy-nine subjects with no risk factors for CME had uncomplicated bimanual micro-incision cataract surgery by an experienced surgeon. All subjects received preoperative nepafenac. Subjects were randomised to postoperative standard of care, consisting of a topical antibiotic for 10 days and topical corticosteroid for 1 month (control), or standard of care plus nepafenac for 1 month (treatment). OCT and ETDRS best-corrected visual acuity were measured preoperatively and 2 months postoperatively. Primary endpoints were comparison of changes in macular thickness between groups and the relationship of that change to postoperative vision. RESULTS: All subjects had excellent visual outcomes, with mean visual improvement of 15 letters. Cataract surgery was very efficient with a mean effective phaco time (EPT) of 4.99 and 6.90 s in the control and treatment groups, respectively. There were small increases in the central macular thickness in both the control (2.78 microm) and treatment (5.60 microm) groups. The change in macular thickness was statistically similar between groups and did not correlate with the final visual outcome. DISCUSSION: The small increase in macular thickness after routine cataract surgery is probably not clinically significant. In subjects undergoing routine cataract surgery, and at low risk for CME, the routine use of preoperative nepafenac may be all that is necessary to achieve excellent visual recovery.

Silencing p21(Waf1/Cip1/Sdi1) expression increases gene transduction efficiency in primitive human hematopoietic cells.

Adult hematopoietic and other tissue stem cells have highly constrained cell cycling that limits their susceptibility to standard gene therapy vectors, which depend upon chromosomal integration. Using cytokine cocktails to increase transduction efficiency often compromises subsequent stem cell function in vivo. We previously showed that p21(Waf1/Cip1/Sdi1) (p21) mediates stem cell quiescence in vivo and decreasing its expression ex vivo leads to an expansion of stem cell pool in vivo. Here, we report that application of p21 specific siRNA increased the gene transduction efficiency in hematopoietic stem cells while preserving cell multipotentiality. Both types of siRNA, synthesized siRNA and transcribed shRNA, reduced p21 expression in target cells by 85-98%. The effect of RNAi in these cells was transient and the level of p21 mRNA returned to base line 14-28 days after siRNA treatment. This brief interval of reduction, however, was sufficient to increase transduction efficiency to two- to four-fold in cell cultures, and followed by a seven- to eight-fold increase in mice. The RNAi treated, lentivector-transduced CD34+ cells retained multipotentiality as assessed in vitro by colony formation assay and in vivo by NOD/SCID mouse transplantation assay. Reduction of p21 resulted in an increased chromosomal integration of lentivector into target cellular DNA. Taken together, both synthesized and transcribed siRNA knocked down p21 expression in human CD34+ hematopoietic stem/progenitor cells. Silencing p21 expression increased gene transduction efficiency and vector integration while retaining stem cell multipotentiality. Thus, RNAi targeting of p21 is a useful strategy to increase stem cell gene transfer efficiency. Decreasing p21 expression transiently while increasing gene-transfer vector integration may ultimately facilitate clinical applications of gene therapy.

Inaccuracy of intraocular lens power calculation after traumatic corneal laceration and cataract.

A 53-year-old man sustained a perforating, central corneal injury with a nail in his right eye. After primary repair of the laceration, a traumatic cataract was removed and a Multiflex-style intraocular lens (IOL) was inserted. A 4.00 diopter surprise resulted, probably due to calculation of the IOL power using measurements from the contralateral normal eye. Inability to wear a contact lens for visual correction resulted in IOL exchange surgery in which a sulcus-sutured IOL was implanted. The IOL power was calculated using simulated keratometry from videokeratoscopy and axial length measurements of the injured eye. This resulted in an IOL power closer to emmetropia, allowing for a best spectacle-corrected visual acuity of 20/20 and comfortable wearing of spectacles.

Second surgery for recurrent pilocytic astrocytoma in children.

Pilocytic astrocytoma (PA) is the most common childhood brain tumor. In cases where the tumor progresses or recurs following primary surgical resection, the appropriate treatment is unclear. Options include chemotherapy, radiation therapy, surgical resection or a combination thereof. To analyze the utility of further surgery, we performed a retrospective, single-institution review of pediatric patients with recurrent PAs from 1990 to 1999 who were treated with a second surgical resection. Patients were excluded if they received adjuvant chemotherapy or radiation therapy. Twenty cases were identified. Tumor locations included: cerebral hemisphere (3), cerebellum (7), optic pathway/hypothalamus (5), thalamus (1) and brainstem (4). The indication for 4 surgeries included an enlarging tumor-associated cyst. At second surgery, 10 of 20 patients had a gross total resection (GTR), 2 a near total resection (NTR), and the remaining 8 patients had a subtotal resection (STR). No patients have died. Two of 10 tumors after GTR, 0 of 2 tumors after NTR, and 7 of 8 tumors after STR had second recurrence/progression at a mean of 15 months (range 4-33 months) following second surgery. The remaining 11 patients are recurrence/progression-free at a mean of 40.7 months (range 19-119 months). Surgery for tumors or midline structures rarely resulted in a GTR (1 of 10 cases). Surgery for tumors located in the cerebral hemispheres or cerebellum resulted in GTR or NTR in all cases and can result in long periods of progression-free survival without further adjuvant treatment.

Microwave thermal keratoplasty for myopia: keratoscopic evaluation in porcine eyes.

PURPOSE: Microwave thermal keratoplasty applies microwave energy to elevate the temperature of the paracentral stroma of the cornea to its thermal shrinkage temperature of about 60 degrees C. A suitable pattern of shrinkage in the paracentral cornea can flatten the central cornea. A surface cooling system preserves the epithelium during the procedure. METHODS: Fourteen enucleated porcine eyes were treated with a prototype microwave thermal keratoplasty applicator that heated in a ring pattern with inner diameter of 3.2 mm and width of 0.7 mm. The change in corneal power was quantified by a videokeratoscope. Slit-lamp microscope examinations and histological assessments were made. RESULTS: The 3-mm simulated keratometry reading showed an average of 6.60+/-6.00 D (standard deviation) of flattening. The region of opacity associated with shrinkage extended to 62% (+/-26%) of the corneal thickness. The epithelium was intact in all eyes. CONCLUSIONS: Microwave thermal keratoplasty applied in the paracentral cornea may flatten the central cornea.

Factors influencing mammography use among women in Medicare managed care.

This article presents findings about the mammography screening experience of Medicare members of a health maintenance organization (HMO). Based on a mail survey of 309 women, we assessed factors that may be facilitators or barriers to this service for older women. The results indicate that these respondents generally are receiving timely mammograms; over three-quarters (79 percent) reported having a mammogram in the past 2 years. Multivariate analysis showed that women who were younger (under 75 years of age), believed in the importance of screening, had been told by a physician to obtain a mammogram, and were more satisfied with their physician and more likely to report mammography use.

Pediatric glial tumors.

Glial neoplasms in children comprise many heterogeneous tumors that include pilocytic and fibrillary astrocytomas, ependymomas, and the diffuse intrinsic pontine gliomas. In contrast to adults, most of whom present with high-grade fibrillary neoplasms, alternate histologies represent most cases seen in the pediatric setting. In addition, although most adult gliomas are supratentorial in location, in pediatrics infratentorial tumors (posterior fossa and brain stem) predominate. We discuss three specific tumors: diffuse intrinsic pontine gliomas; pilocytic astrocytomas; and ependymomas. Maximal surgical resection is the mainstay of therapy for both pilocytic astrocytomas and ependymomas. Failure to achieve an optimal resection often results in progression and the need for further therapy for patients with pilocytic astrocytomas, and is ultimately fatal in most children with subtotally resected ependymomas. Surgical resection has no role in the treatment of pontine gliomas. Focal radiation therapy is included routinely in the treatment of ependymomas, and it has been shown to improve event-free survival. This therapy also is used in the treatment of pontine gliomas because radiation treatment appears to slow inevitable tumor progression. Radiation therapy in pilocytic astrocytomas is generally reserved for patients who progress after an initial surgical resection or for those patients with midline tumors; these patients are poor candidates for aggressive surgical resection. The role of chemotherapy in these tumors is in evolution. Chemotherapy for pilocytic astrocytomas, particularly in young children (for whom radiation therapy is avoided), appears to be effective in the treatment of a subset of patients. Up-front chemotherapy is generally reserved for the youngest children who present with ependymoma. In the recurrence setting, chemotherapy has shown some activity, although this approach is never curative. Despite the application of various chemotherapeutics and other biologic agents, none of these therapies has improved the prognosis for patients with the uniformly lethal pontine glioma.

Pathology of diencephalic astrocytomas.

Pediatric gliomas span a spectrum of neoplasms ranging from the well-circumscribed, slowly growing lesions that can be totally removed by surgery to highly infiltrating, nonexcisable, rapidly growing tumors that resist any form of postoperative therapy. As part of this symposium, we discuss selected members of this group in the diencephalon, where lesions of both extremes are common in children. The report illustrates and contrasts the clinical, radiographic and pathological features of the two classic regional astrocytomas, pilocytic and fibrillary, as well as two less common but distinctive lesions, pilomyxoid astrocytoma and bithalamic astrocytoma.

Astroblastoma: clinicopathologic features and chromosomal abnormalities defined by comparative genomic hybridization.

Astroblastomas are uncommon brain tumors whose classification and histogenesis have been debated. Precise criteria for diagnosis have been described only recently, but have not found wide acceptance. We report the clinical, radiographic, and histopathologic features of 20 astroblastomas, and the chromosomal alterations in seven cases as detected by comparative genomic hybridization (CGH). The tumors occurred both in children and young adults (average age, 14 years), most often as well circumscribed, peripheral, cerebral hemispheric masses. Radiographically, the lesions were contrast-enhancing and solid, often with a cystic component. All were characterized histologically by astroblastic pseudorosettes, and most displayed prominent perivascular hyalinization, regional hyaline changes, and pushing borders in regard to adjacent brain. Tumor cells were strongly immunoreactive for S-100 protein, GFAP, and vimentin. Staining for EMA was focal. Ten of 20 astroblastomas were classified as "well differentiated" and 10 were classified as "malignant," largely on the basis of hypercellular zones with increased mitotic indices, vascular proliferation, and necrosis with pseudopalisading. All 10 well differentiated lesions and 8 of 10 malignant lesions were completely resected. None of the well differentiated astroblastomas recurred within the limited follow-up period. Three malignant astroblastomas recurred, including two incompletely resected tumors, and one that had been totally resected. One patient died of disease following recurrence. The most frequent chromosomal alterations detected by CGH were gains of chromosome arm 20q (4/7 tumors) and chromosome 19 (3/7). The combination of these gains occurred in three, including two well differentiated and one malignant astroblastoma. Other alterations noted in two tumors each were losses on 9q, 10, and X. These chromosomal alterations are not typical of ependymoma or infiltrating astrocytic neoplasms, and suggest that astroblastomas may have a characteristic cytogenetic profile in addition to their distinctive clinical, radiographic, and histopathologic features.