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Baseball injuries are a persistent and significant problem, with the greatest injury incidence to the elbow and shoulder. Baseball injuries can be prevented through a stepwise process that enables the identification of injury type, injury risk factors, etiology and injury mechanisms which is dependent upon high quality data. However, current injury risk and prediction research does not quantify the complexities related to athletic injuries. Therefore, the complex interaction of multiple risk factors and injury mechanisms are unclear and inhibits clinical examination and prevention. The primary aim of this thesis was to create an injury prediction model for shoulder and elbow injuries in a cohort of professional baseball pitchers. The secondary aims are to describe the musculoskeletal health and wellbeing of current and former baseball players and assess the clinical utility of the primary injury risk model. I conducted a systematic scoping review of baseball health and wellbeing in 2019. It found that the greatest density of baseball research focused on injury incidence and prevalence. However, there was a paucity of research on the long-term health effect of baseball participation, health and wellbeing across all baseball playing standard, and injury prevention research. I analyzed data of a survey of current and professional baseball players. Both current and former baseball players reported similar health related quality of life compared to the general population, high flourishing, and high physical activity. Former baseball players reported the greatest persistent joint pain prevalence to the shoulder and elbow, and decreased arm function compared to older total shoulder arthroplasty patients. I conducted an interrupted time series analysis to assess the effectiveness of injury risk profiling and education on a five-year cohort of professional baseball players. Injury risk profiling and education decreased injury incidence by 33%. I developed and internally validated an arm injury prediction model on a ten-year cohort of professional baseball pitchers. The prediction model demonstrated good discriminate ability and excellent calibration. I developed and internally validated a humeral torsion prediction model on the same ten-year cohort of professional baseball pitchers. The prediction model demonstrated small error and excellent calibration. I analyzed the clinical net benefit and utility of the developed injury prediction model in comparison to current evidence based practice. The prediction model demonstrated improved net benefit and utility compared to current practice standards. Future research is needed to examine if findings are generalizable to different cohorts and playing standards, and the efficacy of this prediction model in a clinical setting

Additional file 1: Appendix A. Survey questions used to collect pain and non-steroidal anti-inflammatory drug use data

Additional file 2: Appendix B. Missing Data

The IEA Bioenergy Task 42 „Biorefineries“ made the following definition on biorefinery: “Biorefining is the sustainable processing of biomass into a spectrum of bio­based products (food, feed, chemicals, materials) and bioenergy (biofuels, power and/or heat)”. “Energy­driven” biorefineries and “product­driven” biorefineries are distinguished. Based on the ongoing activities in the 12 countries (A, AUS, CA, DK, FR, G, I, IR, NL, T, UK, US) participating in Task 42, the task identifies and assesses the current status and development potential of both “energy­driven” biorefineries (incl. biofuels) and “product­driven” biorefineries. These assessments are based on a “Full Value Chain approach”, covering raw material issues, conversion processes and final product applications in an integrated approach. As a first step the 15 most interesting “energy­driven” biorefinery concepts until 2020 and their value chains, including the integration and deployment options in existing industrial infrastructures, are analysed. These concepts produce the following transportation biofuels: biodiesel, bioethanol, FT­biofuels, biomethane from upgraded biogas and SNG (synthetic natural gas) with the following feedstocks: oil crops, oil residues, sugar and starch crops, wood chips, straw, grass, saw mill residues, (sulfite) liquor, algae. The Task 42 is assessing the sustainability of these concepts by analysing economic, environmental and social aspects in comparison to conventional processes and products., Proceedings of the 19th European Biomass Conference and Exhibition, 6-10 June 2011, Berlin, Germany, pp. 1075-1079

Continuous addition of Aeromonas salmonicida (which causes furunculosis) or Yersinia ruckeri (which causes enteric redmouth disease, or ERM) broth cultures to recirculating aquaculture systems, without fish, resulted in the presence of these pathogens in the fluidized sand biofilters. Disinfection of the recirculating systems, except biofilters, with 200 ppm sodium hypochlorite and flushing biofilters for 24 hours with spring water did not prevent outbreaks of furunculosis or enteric redmouth disease after stocking Arctic char (Salvelinus alpinus) or rainbow trout (Oncorhynchus mykiss), respectively. Disinfection of the entire recirculating systems with 10 ppm Chloramine-T following outbreaks of furunculosis or ERM, or after addition of broth cultures prevented transmission of enteric redmouth in three trials and in two of three trials with furunculosis. Within 75 days of stocking Atlantic salmon (Salmo salar) with subclinical furunculosis in the recirculating system with rainbow trout, A. salmonicida could be cultured from the mucus of rainbow trout and from the fluidized sand biofilters. Removal of salmon and trout and disinfection of the recirculating system with 10 ppm Chloramine-T prevented a furunculosis outbreak when Arctic char were stocked into the system. However, if the recirculating system was only drained and refilled after removal of salmon and trout, furunculosis occurred within seven days of stocking char.

The fate of organic nitrogen and carbon introduced into a swimming pool by pool users has been studied using a 2.2m3 model pool. The study made use of a body fluid analogue, containing the primary endogenous organic amino compounds, and a soiling analogue represented by humic acid. The system was used to examine the effect of organic loading and organic carbon source (i.e. amino or humic acid) on the levels and speciation of the key chlorinated disinfection byproducts (DBPs) of trihalomethanes (THMs) and chloramines under operating conditions representative of those employed on a full-scale pool. Results revealed organic carbon (OC), chloramines and THMs to all attain steady state levels after 200-500 hours of operation, reflecting mineralisation of the dosed OC. Steady state levels of OC were roughly linearly dependent on dose rate over the range of operational conditions investigated and, as with the chloramine levels recorded, were in reasonable agreement with those reported for full-scale pools. THM levels recorded were somewhat lower than those found in real pools, and were dependent on both on pH carbon source: the THM formation propensity for the soling analogue was around eight times than of the body fluid analogue. Of the assayed byproducts, only nitrate was found to accumulate, accounting for 4-28% of the dosed amino nitrogen. Contrary to previous postulations based on the application of Henry's Law, only insignificant amounts of the volatile byproducts were found to be lost to the atmosphere. A mathematical model based on a consideration of equilibrium thermodynamics was shown to accurately predict the formation of chloramines and decay of chlorine for ex-situ closed-bottle experiments. Extension of the model to the pilot pool is problematic, however, since more empirical data from the chlorination of individual BFA constituents is required for this.

Human chronic myelogenous leukemia-blast crisis K562 cells have been demonstrated to be relatively resistant to antileukemic drug-induced apoptosis. This has been attributed to the activity of p210bcr-abl tyrosine kinase present in the K562 cells, which is known to suppress drug-induced apoptosis. Recently, K562 cells have been shown to express the antiapoptosis Bcl-xL but not Bcl-2 proteins. To investigate the contribution of Bcl-xL toward resistance to drug-induced apoptosis, we created K562/Bcl-xS and K562/neo cells by electroporating the expression plasmids pSFFVneo-Bcl-xS and pSFFVneo, containing the bcl-xS and neomycin resistance genes, respectively, into K562 cells. K562/Bcl-xS but not K562/neo cells expressed the bcl-xS mRNA and p19Bcl-xS protein. In contrast, both cell types expressed equivalent levels of Bcl-xL, Bax, Bcl-2, Myc, retinoblastoma, p21cbor-abl, and p145abl proteins. A significant increase in the hemoglobin levels was observed in the K562/Bcl-xS compared with the K562/neo cells (P0.05). In addition, K562/Bcl-xS cells were significantly more sensitive than K562/neo cells to undergoing erythroid differentiation induced by low-dose 1-beta-D-arabinofuranosylcytosine (ara-C) and hexamethyl bisacetamide (P0.05), but not by all-trans-retinoic acid. Low-dose ara-C- or hexamethyl bisacetamide-induced differentiation was not associated with apoptosis of K562/Bcl-xS or K562/neo cells. Low-dose ara-C-induced erythroid differentiation was accompanied by conversion of the retinoblastoma protein to predominantly its underphosphorylated isoform as well as by down-regulation of Myc levels in K562/Bcl-xS and K562/neo cells. Importantly, exposure to high-dose ara-C (HIDAC; 100 microM ara-C for 4 h) caused internucleosomal DNA fragmentation and the morphological features of apoptosis in K562/Bcl-xS cells. These effects were modestly enhanced by cotreatment with HIDAC plus herbimycin A. In contrast, K562/neo cells were completely resistant to HIDAC- and herbimycin A-induced apoptosis. These results indicate that the expression of Bcl-xS induces erythroid differentiation and partially sensitizes chronic myelogenous leukemia-blast crisis-derived K562 cells to ara-C-induced differentiation and apoptosis.

We examined the effects of high intracellular levels of Bcl-2 on the metabolism and DNA incorporation of high-dose Ara-C (HIDAC) as well as on Ara-C-induced DNA strand breaks and apoptosis of human AML HL-60 cells. HL-60/Bcl-2 and HL-60/neo cells were created by retrovirally transfecting the human AML HL-60 cells with the pZip-bcl-2 and pZip-neo plasmids, respectively. As compared to HL-60/neo, HL-60/Bcl-2 cells contained significantly higher (approximately 10-fold) p26Bcl-2, but equivalent levels of Bax and undetectable levels of Bcl-xL. HIDAC (10 or 100 microM for 4 h) produced the kilobase size and internucleosomal DNA fragmentation associated with apoptosis in HL-60/neo but not in HL-60/Bcl-2 cells. Significantly greater loss of survival (by MTT assay) and flowcytometric and morphologically recognizable apoptosis were observed in HL-60/neo cells. HIDAC did not affect Bcl-2 levels in either cell type. The intracellular accumulation of Ara-CTP relative to dCTP, Ara-C DNA incorporation and Ara-C-induced early DNA damage in the form of strand breaks (detected by alkaline elution assay) were not significantly different between HL-60/Bcl-2 and HL-60/neo cells. In addition, HIDAC treatment caused similar DNA synthesis inhibition in the two cell types. These results indicate that high intracellular levels of Bcl-2 operate distally to inhibit the final apototic cell death pathway by preventing the conversion of HIDAC-induced early DNA damage into lethal DNA fragmentation associated with apoptosis.

Taxol-induced polymerization of tubulin into stable microtubules and cell cycle metaphase arrest have been demonstrated to result in internucleosomal DNA fragmentation and morphological features of apoptosis in human leukemia cells. Recent studies have also shown that Taxol-induced apoptosis, but not Taxol-induced microtubular bundling or mitotic arrest, is significantly inhibited in cells that overexpress the bcl-2 gene product p26BCL-2. In the present studies we examined the effects of several modulators of activities of protein kinases on Taxol-induced DNA fragmentation and apoptosis in human pre-B leukemia 697 cells transfected with the cDNA of the bcl-2 gene and expressing high intracellular levels of p26BCL-2 (697/BCL-2 cells). Treatment with 0.1-1.0 microM MTaxol for 24 h produced prolonged mitotic arrest of control 697/neo cells, which had been transfected with the neomycin resistance gene. This resulted in apoptosis-associated large DNA fragments ranging between 5 and 200 kb and internucleosomal DNA fragmentation. Cotreatment with the phorbol ester phorbol dibutyrate (PdBU) significantly reduced Taxol-induced internucleosomal and large DNA fragmentation and inhibited apoptosis of 697/neo cells. In contrast, a combined exposure to Taxol and staurosporine (ST; 5 or 50 ng/ml), a potent inhibitor of protein kinase C and other kinases, significantly increased DNA fragmentation and apoptosis of 697/neo cells. Additionally, in 697/BCL-2 cells, ST partially overcame the suppressive effects of high p26BCL-2 levels on Taxol-induced apoptosis. Cotreatment with the tyrosine kinase inhibitor Genistein (30 microM) markedly inhibited Taxol-induced DNA fragmentation and apoptosis of 697/neo cells. However, it is noteworthy that the modulations of Taxol-induced DNA fragmentation and apoptosis by PdBU, ST, and Genistein occurred without significant effects on Taxol-mediated mitotic arrest of 697/neo cells. These agents also did not affect intracellular p26BCL-2 levels in 697/neo or 697/BCL-2 cells. These findings indicate that Taxol-induced apoptosis can be modulated by agents that affect the activities of protein kinases, and these effects are not mediated by modulations of Taxol-induced mitotic arrest or by alterations of intracellular p26BCL-2 levels.

Previous reports have demonstrated that a variety of anticancer drugs, e.g., 1-beta-D-arabinofuranosylcytosine (ara-C), mitoxantrone, etoposide, camptothecin, and cisplatin, induce the expression of c-jun oncogene in leukemic cells prior to producing internucleosomal DNA fragmentation and the morphological features of apoptosis. This has led to the impression that the induction of c-jun expression may be directly involved in the molecular signaling of the final common pathway of programmed cell death or apoptosis. In the present study, we examined the role of c-jun expression in three different settings of anticancer drug-induced apoptosis in human leukemic cells. First, exposure of human myeloid leukemia HL-60 cells to high-dose ara-C for 4 h produced internucleosomal DNA fragmentation preceded by c-jun induction. However, pretreatment of HL-60 cells with staurosporine, a protein kinase C inhibitor, repressed c-jun yet enhanced DNA fragmentation and apoptosis due to ara-C. Second, in human pre-B leukemia 697/BCL-2 cells which are transfected with the cDNA of the bcl-2 oncogene and overexpress p26BCL-2, although ara-C or mitoxantrone treatment caused greater c-jun induction than in the 697/neo cells, significantly reduced endonucleolytic DNA fragmentation and apoptosis was observed in 697/BCL-2 cells. Finally, taxol-induced internucleosomal DNA fragmentation and morphological features of apoptosis in HL-60 cells were not associated with the induction of c-jun expression. These lines of evidence indicate that the induction of c-jun expression may not have a direct role in the molecular signaling of anticancer drug-induced apoptosis, and that the anticancer drug-induced apoptosis can occur by a mechanism that does not involve the induction of c-jun expression.

Taxol-resistant sublines of HL-60 myeloid leukemia cells (HL-60/TAX100 and HL-60/TAX1000) have been isolated in vitro by subculturing in progressively higher concentrations of taxol. HL-60/TAX100 and HL-60/TAX1000 cells are capable of continuous growth in the presence of 0.1 microM and 1.0 microM taxol, respectively, and the IC50 (50% growth inhibitory dose) values for taxol for the two sublines are 0.34 and 2.44 microM as compared to 3.1 nM for the parent HL-60 cells. HL-60/TAX100 and HL-60/TAX1000 cells display a variable degree of cross-resistance to taxotere, vincristine and doxorubicin, but are sensitive to the antimetabolite Ara-C. Both HL-60/TAX100 and HL-60/TAX1000 cells over-express MDR-1 m-RNA and the membrane efflux multidrug transporter P-glycoprotein (PGP), as determined by Western blot and immunofluorescence labeling with anti-PGP antibodies. Consequently, exposure of the taxol-resistant cells to [3H]taxol or daunomycin results in the accumulation of significantly lower levels of the two drugs. Co-treatment with cyclosporine (0.5 microgram/ml) or verapamil (10 microM) partially overcomes taxol resistance in HL-60/TAX1000 cells. Following treatment with clinically relevant concentration of taxol (1.0 microM for 24 h), HL-60 but not HL-60/TAX1000 cells display intracellular microtubular bundling, markedly enhanced accumulation of the cells in G2/M phase of cell-cycle and internucleosomal DNA fragmentation associated with apoptosis which is independent of bcl-2 gene expression. These taxol-resistant myeloid leukemia cells may serve as in vitro experimental models for examinating strategies which may have potential applicability for overcoming taxol resistance.