Master of Science

thesisThe downward influence of stratospheric sudden warmings (SSWs) can create significant tropospheric circulation anomalies that last for several weeks. It is therefore of interest to understand the month of the year during which SSWs are most likely to occur and the controlling factors of their temporal distribution. Conceivably, the distribution is controlled by the interplay between decreasing stratospheric wave driving and weakening stratospheric vortex strength. General circulation models (GCMs) tend to produce their SSW maximum later in winter than observations, which is considered a model deficiency. However, the observed record is short, suggesting that under-sampling of SSWs may contribute to this discrepancy. Here, we study the distribution of SSWs and related events in a long control simulation with a stratosphere resolving GCM. Further, we create a simple statistical model to determine the primary factors controlling the SSW distribution. The model is based on the daily climatological mean, standard deviation, and autocorrelation of stratospheric winds and assumes that the winds follow a normal distribution. Results indicate that we cannot reject the null hypothesis that model and observations stem from the same distribution suggesting that the mid-winter SSW maximum seen in the observations is due to sampling uncertainty. We conclude that the late SSW distribution seen in models is not unrealistic and that it is likely that future observations will show more late winter SSWs. We further find that the statistical model reproduces the seasonal evolution of SSWs well and that the decreasing climatological strength of the vortex is the primary factor in controlling the SSW distribution. This supports the idea that stratospheric winds are approximately normally distributed and that SSWs simply form the tail of this monotonic and unimodal distribution

Marjolin\u27s Tumor Complicating Chronic Periprosthetic Infection of a Total Knee Arthroplasty

Marjolin\u27s tumor is a term used to describe a malignancy developing in the setting of a chronic wound, infection, or other tissue subject to chronic inflammatory changes. These malignancies usually present after many years of chronicity, and can range from lower grade basal cell carcinomas to high-grade sarcomas. We present the case of a squamous cell carcinoma that developed within a chronic periprosthetic infection of a total knee arthroplasty of 7 years duration. The intra-articular location, association with an orthopaedic implant, and brief latency period are all unique features of this case

Haptic technology for micro-robotic cell injection training systems — a review

Currently, the micro-robotic cell injection procedure is performed manually by expert human bio-operators. In order to be proficient at the task, lengthy and expensive dedicated training is required. As such, effective specialized training systems for this procedure can prove highly beneficial. This paper presents a comprehensive review of haptic technology relevant to cell injection training and discusses the feasibility of developing such training systems, providing researchers with an inclusive resource enabling the application of the presented approaches, or extension and advancement of the work. A brief explanation of cell injection and the challenges associated with the procedure are first presented. Important skills, such as accuracy, trajectory, speed and applied force, which need to be mastered by the bio-operator in order to achieve successful injection, are then discussed. Then an overview of various types of haptic feedback, devices and approaches is presented. This is followed by discussion on the approaches to cell modeling. Discussion of the application of haptics to skills training across various fields and haptically-enabled virtual training systems evaluation are then presented. Finally, given the findings of the review, this paper concludes that a haptically-enabled virtual cell injection training system is feasible and recommendations are made to developers of such systems

The cost of a primary care-based childhood obesity prevention intervention

Background: United States pediatric guidelines recommend that childhood obesity counseling be conducted in the primary care setting. Primary care-based interventions can be effective in improving health behaviors, but also costly. The purpose of this study was to evaluate the cost of a primary care-based obesity prevention intervention targeting children between the ages of two and six years who are at elevated risk for obesity, measured against usual care. Methods: High Five for Kids was a cluster-randomized controlled clinical trial that aimed to modify children’s nutrition and TV viewing habits through a motivational interviewing intervention. We assessed visit-related costs from a societal perspective, including provider-incurred direct medical costs, provider-incurred equipment costs, parent time costs and parent out-of-pocket costs, in 2011 dollars for the intervention (n = 253) and usual care (n = 192) groups. We conducted a net cost analysis using both societal and health plan costing perspectives and conducted one-way sensitivity and uncertainty analyses on results. Results: The total costs for the intervention group and usual care groups in the first year of the intervention were $65,643 (95$64,522, $66,842]) and$12,192 (95% CI [$11,393,$13,174]). The mean costs for the intervention and usual care groups were $259 (95$255, $264]) and$63 (95% CI [$59,$69]) per child, respectively, for a incremental difference of $196 (95$191, $202]) per child. Children in the intervention group attended a mean of 2.4 of a possible 4 in-person visits and received 0.45 of a possible 2 counseling phone calls. Provider-incurred costs were the primary driver of cost estimates in sensitivity analyses. Conclusions: High Five for Kids was a resource-intensive intervention. Further studies are needed to assess the cost-effectiveness of the intervention relative to other pediatric obesity interventions. Trial registration ClinicalTrials.gov Identifier: NCT00377767

Induction of Lrp5 HBM-causing mutations in Cathepsin-K expressing cells alters bone metabolism

High-bone-mass (HBM)-causing missense mutations in the low density lipoprotein receptor-related protein-5 (Lrp5) are associated with increased osteoanabolic action and protection from disuse- and ovariectomy-induced osteopenia. These mutations (e.g., A214V and G171V) confer resistance to endogenous secreted Lrp5/6 inhibitors, such as sclerostin (SOST) and Dickkopf homolog-1 (DKK1). Cells in the osteoblast lineage are responsive to canonical Wnt stimulation, but recent work has indicated that osteoclasts exhibit both indirect and direct responsiveness to canonical Wnt. Whether Lrp5-HBM receptors, expressed in osteoclasts, might alter osteoclast differentiation, activity, and consequent net bone balance in the skeleton, is not known. To address this, we bred mice harboring heterozygous Lrp5 HBM-causing conditional knock-in alleles to Ctsk-Cre transgenic mice and studied the phenotype using DXA, μCT, histomorphometry, serum assays, and primary cell culture. Mice with HBM alleles induced in Ctsk-expressing cells (TG) exhibited higher bone mass and architectural properties compared to non-transgenic (NTG) counterparts. In vivo and in vitro measurements of osteoclast activity, population density, and differentiation yielded significant reductions in osteoclast-related parameters in female but not male TG mice. Droplet digital PCR performed on osteocyte enriched cortical bone tubes from TG and NTG mice revealed that ~8–17% of the osteocyte population (depending on sex) underwent recombination of the conditional Lrp5 allele in the presence of Ctsk-Cre. Further, bone formation parameters in the midshaft femur cortex show a small but significant increase in anabolic action on the endocortical but not periosteal surface. These findings suggest that Wnt/Lrp5 signaling in osteoclasts affects osteoclastogenesis and activity in female mice, but also that some of the changes in bone mass in TG mice might be due to Cre expression in the osteocyte population

Expression of a Degradation‐Resistant β‐Catenin Mutant in Osteocytes Protects the Skeleton From Mechanodeprivation‐Induced Bone Wasting

Mechanical stimulation is a key regulator of bone mass, maintenance, and turnover. Wnt signaling is a key regulator of mechanotransduction in bone, but the role of β‐catenin—an intracellular signaling node in the canonical Wnt pathway—in disuse mechanotransduction is not defined. Using the β‐catenin exon 3 flox (constitutively active [CA]) mouse model, in conjunction with a tamoxifen‐inducible, osteocyte‐selective Cre driver, we evaluated the effects of degradation‐resistant β‐catenin on bone properties during disuse. We hypothesized that if β‐catenin plays an important role in Wnt‐mediated osteoprotection, then artificial stabilization of β‐catenin in osteocytes would protect the limbs from disuse‐induced bone wasting. Two disuse models were tested: tail suspension, which models fluid shift, and botulinum‐toxin (botox)‐induced muscle paralysis, which models loss of muscle force. Tail suspension was associated with a significant loss of tibial bone mass and density, reduced architectural properties, and decreased bone formation indices in uninduced (control) mice, as assessed by dual‐energy X‐ray absorptiometry (DXA), micro‐computed tomography (µCT), and histomorphometry. Activation of the βcatCA allele in tail‐suspended mice resulted in little to no change in those properties; ie, these mice were protected from bone loss. Similar protective effects were observed among botox‐treated mice when the βcatCA was activated. RNAseq analysis of altered gene regulation in tail‐suspended mice yielded 35 genes, including Wnt11, Gli1, Nell1, Gdf5, and Pgf, which were significantly differentially regulated between tail‐suspended β‐catenin stabilized mice and tail‐suspended nonstabilized mice. Our findings indicate that selectively targeting/blocking of β‐catenin degradation in bone cells could have therapeutic implications in mechanically induced bone disease

Does Concomitant CABG Influence the Outcomes of Post-Myocardial Infarction Ventricular Septal Defect Repair?

Introduction: Ventricular septal defect (VSD) following myocardial infarction (MI) is a relatively infrequent complication with high mortality. Over time, understanding of the pathology and its management has resulted in improved outcomes; however, controversies remain. Objective: We sought to investigate the effect of concomitant coronary artery bypass graft (CABG) on outcomes following post-MI VSD repair. Methods: Electronic search was performed to identify all relevant studies published from 2000 to 2018. After assessment for inclusion and exclusion criteria, 66 studies were selected for the analysis. Data were extracted and pooled for systematic review and meta-analysis. Results: Average age was 68.7 years (95% CI 67.3-70.1) with 57% (95% CI 54-60) males. Coronary angiogram was available preoperatively in 94% (95% CI 92-96) of patients. Single-vessel disease was most common (47%, 95% CI 42-52) with left anterior descending coronary artery the most commonly involved vessel (55%, 95% CI 46-63). Concomitant CABG was performed in 52% (95% CI 46-57) of patients. Of these, infarcted territory was revascularized in 54% (95% CI 23-82). No significant survival difference was observed between those who had concomitant CABG versus those without CABG at 30 days (65%, 95% CI 58-72) vs (60%, 95% CI 47-72), 1 year (59%, 95% CI 50-68) vs (51%, 95% CI 41-61), and 5 years (46%, 95% CI 38-54) vs (39%, 95% CI 27-52) respectively. Discussion: Overall, concomitant CABG did not have a significant effect on survival following VSD repair, therefore, decision on revascularization should be weighed against the risks associated with prolonged cardiopulmonary bypass

Co-deletion of Lrp5 and Lrp6 in the skeleton severely diminishes bone gain from sclerostin antibody administration

The cysteine knot protein sclerostin is an osteocyte-derived secreted inhibitor of the Wnt co-receptors LRP5 and LRP6. LRP5 plays a dominant role in bone homeostasis, but we previously reported that Sost/sclerostin suppression significantly increased osteogenesis regardless of Lrp5 presence or absence. Those observations suggested that the bone forming effects of sclerostin inhibition can occur through Lrp6 (when Lrp5 is suppressed), or through other yet undiscovered mechanisms independent of Lrp5/6. To distinguish between these two possibilities, we generated mice with compound deletion of Lrp5 and Lrp6 selectively in bone, and treated them with sclerostin monoclonal antibody (Scl-mAb). All mice were homozygous flox for both Lrp5 and Lrp6 (Lrp5f/f; Lrp6f/f), and varied only in whether or not they carried the Dmp1-Cre transgene. Positive (Cre+) and negative (Cre−) mice were injected with Scl-mAb or vehicle from 4.5 to 14 weeks of age. Vehicle-treated Cre+ mice exhibited significantly reduced skeletal properties compared to vehicle-treated Cre− mice, as assessed by DXA, μCT, pQCT, and histology, indicating that Lrp5/6 deletions were effective and efficient. Scl-mAb treatment improved nearly every bone-related parameter among Cre− mice, but the same treatment in Cre+ mice resulted in little to no improvement in skeletal properties. For the few endpoints where Cre+ mice responded to Scl-mAb, it is likely that antibody-induced promotion of Wnt signaling occurred in cell types earlier in the mesenchymal/osteoblast differentiation pathway than the Dmp1-expressing stage. This latter conclusion was supported by changes in some histomorphometric parameters. In conclusion, unlike with the deletion of Lrp5 alone, the bone-selective late-stage co-deletion of Lrp5 and Lrp6 significantly impairs or completely nullifies the osteogenic action of Scl-mAb, and highlights a major role for both Lrp5 and Lrp6 in the mechanism of action for the bone-building effects of sclerostin antibody

Feasibility and impact of Creciendo Sanos, a clinic-based pilot intervention to prevent obesity among preschool children in Mexico City

Background: Mexico has the highest adult overweight and obesity prevalence in the Americas; 23.8% of children <5 years old are at risk for overweight and 9.7% are already overweight or obese. Creciendo Sanos was a pilot intervention to prevent obesity among preschoolers in Instituto Mexicano del Seguro Social (IMSS) clinics. Methods: We randomized 4 IMSS primary care clinics to either 6 weekly educational sessions promoting healthful nutrition and physical activity or usual care. We recruited 306 parent-child pairs: 168 intervention, 138 usual care. Children were 2-5 years old with WHO body mass index (BMI) z-score 0-3. We measured children’s height and weight and parents reported children’s diet and physical activity at baseline and 3 and 6-month follow-up. We analyzed behavioral and BMI outcomes with generalized mixed models incorporating multiple imputation for missing values. Results: 93 (55%) intervention and 96 (70%) usual care families completed 3 and 6-month follow-up. At 3 months, intervention v. usual care children increased vegetables by 6.3 servings/week (95% CI, 1.8, 10.8). In stratified analyses, intervention participants with high program adherence (5-6 sessions) decreased snacks and screen time and increased vegetables v. usual care. No further effects on behavioral outcomes or BMI were observed. Transportation time and expenses were barriers to adherence. 90% of parents who completed the post-intervention survey were satisfied with the program. Conclusions: Although satisfaction was high among participants, barriers to participation and retention included transportation cost and time. In intention to treat analyses, we found intervention effects on vegetable intake, but not other behaviors or BMI. Trial registration ClinicalTrials.gov NCT01539070. Comisión Nacional de Investigación Científica del IMSS: 2009-785-120