Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Creation of an Open-Access, Mutation-Defined Fibroblast Resource for Neurological Disease Research

Our understanding of the molecular mechanisms of many neurological disorders has been greatly enhanced by the discovery of mutations in genes linked to familial forms of these diseases. These have facilitated the generation of cell and animal models that can be used to understand the underlying molecular pathology. Recently, there has been a surge of interest in the use of patient-derived cells, due to the development of induced pluripotent stem cells and their subsequent differentiation into neurons and glia. Access to patient cell lines carrying the relevant mutations is a limiting factor for many centres wishing to pursue this research. We have therefore generated an open-access collection of fibroblast lines from patients carrying mutations linked to neurological disease. These cell lines have been deposited in the National Institute for Neurological Disorders and Stroke (NINDS) Repository at the Coriell Institute for Medical Research and can be requested by any research group for use in in vitro disease modelling. There are currently 71 mutation-defined cell lines available for request from a wide range of neurological disorders and this collection will be continually expanded. This represents a significant resource that will advance the use of patient cells as disease models by the scientific community

Mortality Risk of Hypnotics: Strengths and Limits of Evidence

Sleeping pills, more formally defined as hypnotics, are sedatives used to induce and maintain sleep. In a review of publications for the past 30 years, descriptive epidemiologic studies were identified that examined the mortality risk of hypnotics and related sedative-anxiolytics. Of the 34 studies estimating risk ratios, odds ratios, or hazard ratios, excess mortality associated with hypnotics was significant (p < 0.05) in 24 studies including all 14 of the largest, contrasted with no studies at all suggesting that hypnotics ever prolong life. The studies had many limitations: possibly tending to overestimate risk, such as possible confounding by indication with other risk factors; confusing hypnotics with drugs having other indications; possible genetic confounders; and too much heterogeneity of studies for meta-analyses. There were balancing limitations possibly tending towards underestimates of risk such as limited power, excessive follow-up intervals with possible follow-up mixing of participants taking hypnotics with controls, missing dosage data for most studies, and over-adjustment of confounders. Epidemiologic association in itself is not adequate proof of causality, but there is proof that hypnotics cause death in overdoses; there is thorough understanding of how hypnotics euthanize animals and execute humans; and there is proof that hypnotics cause potentially lethal morbidities such as depression, infection, poor driving, suppressed respiration, and possibly cancer. Combining these proofs with consistent evidence of association, the great weight of evidence is that hypnotics cause huge risks of decreasing a patient's duration of survival

Exendin-4 Ameliorates Motor Neuron Degeneration in Cellular and Animal Models of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS

Treatment of Acute Uncomplicated Colonic Diverticulitis

The overall aim of this thesis was to evaluate the clinical management of AUD with regard to the no-antibiotic policy and its long-term effect, treatment on an outpatient basis and the potential health-care cost savings Study I:  a retrospective study at Västmanlands Hospital that evaluated and confirmed the adherence to the no-antibiotic policy in patients with AUD and its safety regarding complications and recurrences. A total of 246 patients with acute diverticulitis were identified, of which 195 had computed tomography (CT) confirmed AUD. In total, 91.3% of these patients did not receive any antibiotics and only two developed complications. Study II: a retrospective study with the aim to conduct a long-term follow-up of all Swedish patients who participated in the AVOD trial in terms of recurrences, complications, surgery and quality of life. The medical records of 96% of the patients were reviewed with a mean follow up of 11 years. Quality of life questionnaires were sent out to all patients. There were no differences regarding the rates of recurrence, complications or surgery for diverticulitis. There were no differences in the quality of life between groups according to the EQ-5D questionnaire. Study III: a prospective study where 155 patients with CT-verified AUD as were treated as outpatients without antibiotics. On day 3, patients reported an average pain score of 1.8 of 10 on the VAS scale and only 30% of patients were using analgesia. Four patients returned to hospital because of treatment failure. Study IV: a retrospective cohort study at Västmanland’s Hospital evaluated the impact on admissions, complication rates and health-care costs of the policy of outpatient treatment without using antibiotics. Medical records of all patients diagnosed with AUD in the year before (2011) and after (2014) the implementation of outpatient management without antibiotics were reviewed. Overall 494 episodes of AUD were identified: 254 in 2011 and 240 in 2014. Three patients developed complications in 2011 and four in 2014. The proportion of patients managed as outpatients was 20% in 2011 compared with 61% in 2014. The hospital admissions, total length of stay of and total health-care costs were almost halved. In conclusion, these studies confirm the low complication and recurrence rates of AUD and strengthens findings that antibiotics have no benefit in the treatment of this disease. The no-antibiotic policy had no impact on short- or long-term outcomes regarding the rates of recurrence, complications, surgery or quality of life. Outpatient management was found to be feasible and safe, and significantly reduced admissions, which led to large health-care cost savings

Treatment of Acute Uncomplicated Colonic Diverticulitis

The overall aim of this thesis was to evaluate the clinical management of AUD with regard to the no-antibiotic policy and its long-term effect, treatment on an outpatient basis and the potential health-care cost savings Study I:  a retrospective study at Västmanlands Hospital that evaluated and confirmed the adherence to the no-antibiotic policy in patients with AUD and its safety regarding complications and recurrences. A total of 246 patients with acute diverticulitis were identified, of which 195 had computed tomography (CT) confirmed AUD. In total, 91.3% of these patients did not receive any antibiotics and only two developed complications. Study II: a retrospective study with the aim to conduct a long-term follow-up of all Swedish patients who participated in the AVOD trial in terms of recurrences, complications, surgery and quality of life. The medical records of 96% of the patients were reviewed with a mean follow up of 11 years. Quality of life questionnaires were sent out to all patients. There were no differences regarding the rates of recurrence, complications or surgery for diverticulitis. There were no differences in the quality of life between groups according to the EQ-5D questionnaire. Study III: a prospective study where 155 patients with CT-verified AUD as were treated as outpatients without antibiotics. On day 3, patients reported an average pain score of 1.8 of 10 on the VAS scale and only 30% of patients were using analgesia. Four patients returned to hospital because of treatment failure. Study IV: a retrospective cohort study at Västmanland’s Hospital evaluated the impact on admissions, complication rates and health-care costs of the policy of outpatient treatment without using antibiotics. Medical records of all patients diagnosed with AUD in the year before (2011) and after (2014) the implementation of outpatient management without antibiotics were reviewed. Overall 494 episodes of AUD were identified: 254 in 2011 and 240 in 2014. Three patients developed complications in 2011 and four in 2014. The proportion of patients managed as outpatients was 20% in 2011 compared with 61% in 2014. The hospital admissions, total length of stay of and total health-care costs were almost halved. In conclusion, these studies confirm the low complication and recurrence rates of AUD and strengthens findings that antibiotics have no benefit in the treatment of this disease. The no-antibiotic policy had no impact on short- or long-term outcomes regarding the rates of recurrence, complications, surgery or quality of life. Outpatient management was found to be feasible and safe, and significantly reduced admissions, which led to large health-care cost savings

Treatment of Acute Uncomplicated Colonic Diverticulitis

The overall aim of this thesis was to evaluate the clinical management of AUD with regard to the no-antibiotic policy and its long-term effect, treatment on an outpatient basis and the potential health-care cost savings Study I:  a retrospective study at Västmanlands Hospital that evaluated and confirmed the adherence to the no-antibiotic policy in patients with AUD and its safety regarding complications and recurrences. A total of 246 patients with acute diverticulitis were identified, of which 195 had computed tomography (CT) confirmed AUD. In total, 91.3% of these patients did not receive any antibiotics and only two developed complications. Study II: a retrospective study with the aim to conduct a long-term follow-up of all Swedish patients who participated in the AVOD trial in terms of recurrences, complications, surgery and quality of life. The medical records of 96% of the patients were reviewed with a mean follow up of 11 years. Quality of life questionnaires were sent out to all patients. There were no differences regarding the rates of recurrence, complications or surgery for diverticulitis. There were no differences in the quality of life between groups according to the EQ-5D questionnaire. Study III: a prospective study where 155 patients with CT-verified AUD as were treated as outpatients without antibiotics. On day 3, patients reported an average pain score of 1.8 of 10 on the VAS scale and only 30% of patients were using analgesia. Four patients returned to hospital because of treatment failure. Study IV: a retrospective cohort study at Västmanland’s Hospital evaluated the impact on admissions, complication rates and health-care costs of the policy of outpatient treatment without using antibiotics. Medical records of all patients diagnosed with AUD in the year before (2011) and after (2014) the implementation of outpatient management without antibiotics were reviewed. Overall 494 episodes of AUD were identified: 254 in 2011 and 240 in 2014. Three patients developed complications in 2011 and four in 2014. The proportion of patients managed as outpatients was 20% in 2011 compared with 61% in 2014. The hospital admissions, total length of stay of and total health-care costs were almost halved. In conclusion, these studies confirm the low complication and recurrence rates of AUD and strengthens findings that antibiotics have no benefit in the treatment of this disease. The no-antibiotic policy had no impact on short- or long-term outcomes regarding the rates of recurrence, complications, surgery or quality of life. Outpatient management was found to be feasible and safe, and significantly reduced admissions, which led to large health-care cost savings

Optimering av distribution av COVID-19 vaccin

This paper explores how to optimally distribute vaccines by deciding what middle warehouses to use for storage. For this purpose, a network has been designed with a central warehouse, a set of middle warehouses and a set of local hospitals. The supply has been defined by two different types of vaccines to incorporate their logistical requirements, and the demand has been defined by the elderly population of Sweden. The model was constructed as a mixed-integer program in the optimisation programming language GAMS. The results was a set of 13 middle warehouses allocated such that the total distances when distributing the vaccines are minimised. It was also identified how much of each type of vaccines that was being shipped. The integer program was then relaxed to test whether the optimal value was in fact a global optima. Both the objective value for the original problem and for the relaxed problem was 10189.8 km, which means that it could be identified as a global optima. Furthermore, this paper explored ways to mitigate the supply chain risks with the help of mathematical methods and supply chain management literature. This paper presents scenario-based stochastic programming, how to construct a supplier portfolio, reliability engineering and distribution-based stochastic programming as useful methods when dealing with the risks.  In essence, the purpose of this paper was to evaluate modeling opportunities for distributions of vaccines rather than the quantitative results since the data was limited. The aim was to present a general model that could be used with different sets of data, and provide the most optimal allocation of warehouses. Recommended improvements to the paper are greater accuracy in data, in probability distributions and expansion of model with consideration of time.Detta arbete utforskar hur man kan optimera distributionen av vaccin genom att bestämma placering av en mängd mellanlager. I detta syfte har ett nätverk designats med ett centrallager, en utspridd mängd mellanlager och en mängd lokala sjukhus. Utbudet har definerats som två olika typer av vaccin för att ta hänsyn till deras olika logistiska krav och efterfrågan har definerats som Sveriges äldre befolkning. Modellen var konstruerad som ett blandat heltalsproblem i programmeringsspråket GAMS. Resultatet blev 13 mellanlager som är optimala för en så effektiv distribution av vaccin som möjligt. Resultaten visar också vilken typ av vaccin som ska skickas var. Heltalsprogrammet använder sedan relaxation för att undersöka om resultatet är ett globalt optimum och inte endast ett lokalt optimum. Målfunktionens värde är 10189,8 km både för det ordinarie problemet och för det relaxerade, vilket inneär att man kan dra slutsaten att värdet är ett globalt optimum. Dessutom utforskars sätt att mildra försörjningskedjans risker med hjälp av matematiska metoder och litteratur inom logistik av försörjningskedjor. Denna uppsats presenterar scenariobaserad och distributionbaserad stokastisk programmering, konstruktion av leverantörsportföljer och tillförlitlighetsteknik som användbara metoder för att hantera riskerna.  Sammanfattningsvis är detta ett arbete som utforskar möjligheter med modelleringen av vaccindistribution snarare än en rigid kvantitativ analys eftersom datan är begränsad. Syftet var därför att utveckla en generell modell som med olika dataset kan ge den optimala allokeringen av mellanlager. De förbättringar av arbetet som rekommenderas är mer noggrann data, exakthet kring sannolikhetsfördelningarna och en expansion av modellen som tar hänsyn till tid

Optimering av distribution av COVID-19 vaccin

This paper explores how to optimally distribute vaccines by deciding what middle warehouses to use for storage. For this purpose, a network has been designed with a central warehouse, a set of middle warehouses and a set of local hospitals. The supply has been defined by two different types of vaccines to incorporate their logistical requirements, and the demand has been defined by the elderly population of Sweden. The model was constructed as a mixed-integer program in the optimisation programming language GAMS. The results was a set of 13 middle warehouses allocated such that the total distances when distributing the vaccines are minimised. It was also identified how much of each type of vaccines that was being shipped. The integer program was then relaxed to test whether the optimal value was in fact a global optima. Both the objective value for the original problem and for the relaxed problem was 10189.8 km, which means that it could be identified as a global optima. Furthermore, this paper explored ways to mitigate the supply chain risks with the help of mathematical methods and supply chain management literature. This paper presents scenario-based stochastic programming, how to construct a supplier portfolio, reliability engineering and distribution-based stochastic programming as useful methods when dealing with the risks.  In essence, the purpose of this paper was to evaluate modeling opportunities for distributions of vaccines rather than the quantitative results since the data was limited. The aim was to present a general model that could be used with different sets of data, and provide the most optimal allocation of warehouses. Recommended improvements to the paper are greater accuracy in data, in probability distributions and expansion of model with consideration of time.Detta arbete utforskar hur man kan optimera distributionen av vaccin genom att bestämma placering av en mängd mellanlager. I detta syfte har ett nätverk designats med ett centrallager, en utspridd mängd mellanlager och en mängd lokala sjukhus. Utbudet har definerats som två olika typer av vaccin för att ta hänsyn till deras olika logistiska krav och efterfrågan har definerats som Sveriges äldre befolkning. Modellen var konstruerad som ett blandat heltalsproblem i programmeringsspråket GAMS. Resultatet blev 13 mellanlager som är optimala för en så effektiv distribution av vaccin som möjligt. Resultaten visar också vilken typ av vaccin som ska skickas var. Heltalsprogrammet använder sedan relaxation för att undersöka om resultatet är ett globalt optimum och inte endast ett lokalt optimum. Målfunktionens värde är 10189,8 km både för det ordinarie problemet och för det relaxerade, vilket inneär att man kan dra slutsaten att värdet är ett globalt optimum. Dessutom utforskars sätt att mildra försörjningskedjans risker med hjälp av matematiska metoder och litteratur inom logistik av försörjningskedjor. Denna uppsats presenterar scenariobaserad och distributionbaserad stokastisk programmering, konstruktion av leverantörsportföljer och tillförlitlighetsteknik som användbara metoder för att hantera riskerna.  Sammanfattningsvis är detta ett arbete som utforskar möjligheter med modelleringen av vaccindistribution snarare än en rigid kvantitativ analys eftersom datan är begränsad. Syftet var därför att utveckla en generell modell som med olika dataset kan ge den optimala allokeringen av mellanlager. De förbättringar av arbetet som rekommenderas är mer noggrann data, exakthet kring sannolikhetsfördelningarna och en expansion av modellen som tar hänsyn till tid