Tag: statistics

J Pharmacokinet Pharmacodyn. 2021 Oct 16. doi: 10.1007/s10928-021-09789-2. Online ahead of print.

ABSTRACT

Clinical trials in patients with ulcerative colitis (UC) face the challenge of high and variable placebo response rates. The Mayo Clinical Score (MCS) is used widely as the primary endpoint in clinical trials to describe the clinical status of patients with UC. The MCS is comprised of four subscores, each scored 0, 1, 2 and 3: rectal bleeding (RB), stool frequency (SF), physician’s global assessment (PGA), and endoscopy (ENDO) subscore. Excluding the PGA subscore gives the modified MCS. Quantitative insight on the placebo response, and its impact on the components of the MCS over time, can better inform clinical trial design and interpretation. Longitudinal modeling of the MCS, and the modified MCS, can be challenging due to complex clinical trial design, population heterogeneity, and limited assessments for the ENDO subscore. The current study pooled patient-level placebo/standard of care (SoC) arm data from five clinical trials in the TransCelerate database to develop a longitudinal placebo response model that describes the MCS over time in patients with UC. MCS subscores were modeled using proportional odds models, and the removal of patients from the placebo/SoC arm, or “dropout”, was modeled using logistic regression models. The subscore and dropout models were linked to allow for the prediction of the MCS and the modified MCS. Stepwise covariate modeling identified prior exposure to TNF-α antagonists as a statistically significant predictor on the RB + SF subscore. Patients with prior exposure to TNF-α antagonists had higher post-baseline RB + SF subscores than naive patients.

PMID:34657238 | DOI:10.1007/s10928-021-09789-2

Clin Drug Investig. 2021 Oct 16. doi: 10.1007/s40261-021-01087-6. Online ahead of print.

ABSTRACT

Allogeneic haematopoietic stem cell transplantation (alloHSCT) offers a potentially curative therapy for patients suffering from diseases of the haematopoietic system but requires a high level of expertise and is both resource intensive and expensive. A frequent and life-threatening complication is graft-versus-host disease (GvHD). Acute GvHD (aGvHD) generally causes skin, gastrointestinal and liver symptoms, but chronic GvHD (cGvHD) has a different pathophysiology and may affect nearly every organ or tissue of the body. In Europe, GvHD prophylaxis is generally a calcineurin inhibitor in combination with methotrexate, with high-dose systemic steroids used for advanced GvHD treatment. Between 39% and 59% of alloHSCT patients will develop aGvHD and around 36-37% will develop cGvHD. Steroid response decreases with increasing disease severity, which in turn leads to an increase in non-relapse mortality. GvHD imposes a financial burden on healthcare systems, significantly increasing post-alloHSCT costs. Increased GvHD disease severity magnifies this. Balancing immunosuppression to control the GvHD whilst maintaining a degree of immunocompetence against infection is critical. European GvHD guidelines acknowledge the lack of evidence to support a standard second-line therapy, and improved long-term outcomes and quality-of-life (QoL) remain an unmet need. Evidence generation for potential treatments is challenging. Issues to overcome include choice of comparator (extensive off-label usage); blinding; selection of relevant patient-reported outcome measures (PROMs); and rarity of the condition, which may infeasibly increase timescales to achieve clinical and statistical relevance.

PMID:34657244 | DOI:10.1007/s40261-021-01087-6

Ir J Med Sci. 2021 Oct 16. doi: 10.1007/s11845-021-02783-0. Online ahead of print.

ABSTRACT

INTRODUCTION: Lung cancer is the leading cause of cancer deaths in many Western countries, but its incidence has never been studied in Northern Ireland.

AIMS: Accordingly, the present study was mounted to determine, for the first time, the incidence of the condition in Northern Ireland and to compare the findings with other regions in the British Isles.

METHODS: A notification study of the incidence of lung cancer (ICD 162) was conducted in Northern Ireland during 1991/1992. Notifications from 6 sources were computerised and linked. Incident cases were identified and analysed in relation to Age, Sex and Geographical region-Northern Ireland, England and Wales, Scotland and the Republic of Ireland.

RESULTS: Some 900 incident cases of lung cancer were identified. The incidence rate per 100,000 population was found to be 57.04. Mortality underestimated incidence by 12.5%. ([Formula: see text]). The male to female incidence ratio was 2.1: 1, and this ratio was similar in other regions, except Scotland, where the ratio was 1.7:1. The null hypothesis of a common incidence distribution across regions was formally rejected. A variety of models were fitted and a model in which the log-odds on incidence was a quadratic function of age fitted most of the regional data.

CONCLUSIONS: Northern Ireland had the lowest incidence of lung cancer in the UK, but its overall rate was still 40% higher than that observed in the Republic of Ireland which had the lowest rate in the British Isles. Across regions, the pattern of incidence by age and sex was complicated, but a linear logistic model fitted all of the Irish data and the female data in Scotland, satisfactorily.

PMID:34657234 | DOI:10.1007/s11845-021-02783-0

Prev Vet Med. 2021 Sep 15;196:105494. doi: 10.1016/j.prevetmed.2021.105494. Online ahead of print.

ABSTRACT

Tanzania has the second largest livestock population in Africa and livestock keeping is an integral part of most people’s livelihoods. Foot-and-mouth disease (FMD) is a transboundary disease, affecting cloven-hoofed animals, that is currently endemic in Tanzania. The Tanzania Development Vision 2025 aspires to make the livestock sector more competitive. Part of this plan foresees establishing a FMD-free zone in the Rukwa region to be able to increase the export of animals and animal products. The aim of this study was to assess the economic efficiency and feasibility of establishing such an FMD-free zone and to advise policy makers on the profitability of the investment. A stochastic benefit-cost model, set-up in Palisade @Risk for Excel for a time frame of ten years, was developed to assess whether the benefits of establishing a FMD-free zone would outweigh the costs. Data were collated from reviewing literature, government statistics, and key informant interviews with farmers, traders and veterinarians in Tanzania, and complemented by informed assumptions and expert opinion. Moreover, feasibility aspects including underlying infrastructure, market structures and resource availability were discussed based on key informant interviews, literature review and historical analyses. The net present value for the establishment of a FMD-free zone was negative and the benefit-cost ratio was below one (mean 0.09, min 0.05 – max 0.15 in the scenario considering vaccination of all susceptible domestic animals, and mean 0.11, min 0.06 – max 0.20 when considering vaccinating cattle only), excluding potential benefits from trade. The sensitivity analysis showed that variables related to the cost of vaccination had the largest negative impact on the net present value. The proposed FMD-free zone in Rukwa region is unlikely to be cost-effective with the current FMD status and export trade prospects in Tanzania. Interviews with stakeholders revealed that vaccine availability, funding, farmers’ willingness to participate, and lack of staff continuity in key roles were the main barriers to establish a reliable FMD control programme in the country. Recommendations towards FMD control and potential short and middle term strategies are discussed.

PMID:34656049 | DOI:10.1016/j.prevetmed.2021.105494

Clin Nutr. 2021 Sep 4;40(11):5494-5499. doi: 10.1016/j.clnu.2021.08.022. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Dietary intake of several specific macronutrients has been linked to risk of coronary heart disease (CHD). However, these associations may depend on overall macronutrient composition rather than effects of one single macronutrient. Therefore, we aimed to investigate the associations of macronutrient intake and CHD and its related risk factors, by taking into account different macronutrient substitutions.

METHODS: This study was performed among 5873 participants from the Rotterdam Study, a population-based cohort study. Macronutrient intake was measured using a semi-quantitative food-frequency questionnaire. Cox proportional hazard regression analyses were used to examine associations between intakes of macronutrients and CHD incidence; and linear regression analyses were used to examine associations with the related risk factors, including triglycerides, total, high-density and low-density cholesterol levels, body mass index (BMI), fat mass index (FMI), and fat-free mass index (FFMI).

RESULTS: We documented 669 CHD cases during 74,776 person-years of follow-up. In multivariable-adjusted models we observed no statistically significant associations between macronutrients and CHD incidence. Although non-significant, a higher plant protein intake tended to be associated with a lower risk of CHD when consumed at the expense of any of the other macronutrients. This association was strongest when 5% of energy (5 E%) of plant protein was consumed at the expense of animal protein (HR = 0.61; 95% CI 0.31, 1,21), mono- and disaccharides (HR = 0.62; 95% CI 0.29, 1.35) or saturated fat (HR = 0.61; 95% CI 0.31, 1.20). No consistent associations were observed for risk factors related to CHD.

CONCLUSIONS: Macronutrient composition was not significantly associated with CHD incidence or cardiometabolic risk factors in an adult population. Future studies should further investigate food sources and quality of macronutrients.

PMID:34656031 | DOI:10.1016/j.clnu.2021.08.022

J Affect Disord. 2021 Sep 24;296:514-521. doi: 10.1016/j.jad.2021.09.059. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the mortality risk due to covid-19 with death due to overdose in British Columbia, Canada. The opioid epidemic was declared a public health emergency in 2016.

METHODS: Mortality risk was calculated in micromorts with covid-19 data for January-October 2020, derived from the BC center for Disease Control, and illicit drug toxicity deaths for January 2010-September 2020, derived from the BC Coroners Service. Age-stratified covid-19 incidence and deaths per 100,000 population and age-stratified illicit drug toxicity death rates per 100,000 population were calculated. A micromort is a unit of risk equivalent to a one-in-a-million chance of death.

RESULTS: During the covid-19 pandemic, illicit drug toxicity deaths reached 1.0 micromorts per day, representing an increase of 0.5 micromorts per day relative to 2019 rates. In comparison, covid-19 mortality risk was 0.05 micromorts per day among individuals from the general population living in British Columbia and 21.1 micromorts per day among those infected with covid-19. Covid-related mortality risk was significantly lower among individuals aged <60 years, relative to older adults, whereas drug toxicity-related mortality was highest for individuals aged 30-59 years.

CONCLUSIONS: The mortality associated with covid-19 is apparent and distributed unevenly across subpopulations. The mortality due to overdose has increased during covid-19 and exceeds mortality due to covid-19. Our results instantiate the triple threat caused by covid-19 (i.e., public health crisis, economic crisis and mental health crisis) and quantitatively highlight the externality of increased mortality due to deaths of despair in response to public health efforts to reduce covid-related mortality.

PMID:34656039 | DOI:10.1016/j.jad.2021.09.059

Gait Posture. 2021 Oct 11;91:79-85. doi: 10.1016/j.gaitpost.2021.10.010. Online ahead of print.

ABSTRACT

BACKGROUND: Walking adaptability is an obvious manifestation of Parkinson’s disease (PD). Augmented reality technologies such as interactive walkways may improve walking adaptability in patients with Parkinson’s Disease (PWP).

RESEARCH QUESTION: How effective is C-Mill gait adaptability training in the early and middle stages of PD for improving walking adaptability in motor subtypes of the disease?

METHODS: Fifty-two patients with early- or middle-stage PD were divided into two groups according to motor subtype (postural instability/gait disorder [PIGD] and non-PIGD) and received 7 days of training (0.5 h every day, 2 h after medication) on an augmented reality treadmill with built-in visual targets and obstacles. Functional assessments were performed before and after intervention, including posture control and walking, C-gait assessment, and participant experience. The Parkinson Disease Quality of Life questionnaire was administered at 3-month follow-up.

RESULTS: Both the PIGD (n = 29) and non-PIGD (n = 23) groups showed improved tandem walking, obstacle avoidance, and overall score in C-gait assessment and Timed Up and Go test after C-Mill training. However, there were no differences between the two groups. The PIGD group showed improvement in visually guided stepping and Speed adaptations, whereas the non-PIGD group did not improve. The non-PIGD group reported they could complete the training with less exertion after the intervention and at the 3-month follow-up, these patients reported improvement in quality of life.

SIGNIFICANCE: C-Mill gait adaptation training in the early and middle stages of PD improves walking adaptability in both motor subtypes. Cue strategies are the probable mechanism and may decrease fall risk after training. There was no difference between the groups in the improvements of perceived exertion and quality of life at follow-up. Although PIGD patients showed statistic improvements in visually guided stepping compared with non-PIGD patients, but the difference was not likely to be clinically meaningful. Specific effects of C-mill training for different types of PD were not observed in our study.

PMID:34656008 | DOI:10.1016/j.gaitpost.2021.10.010

Clin Nutr. 2021 Oct 1;40(11):5482-5485. doi: 10.1016/j.clnu.2021.09.040. Online ahead of print.

ABSTRACT

BACKGROUND & AIMS: Immune modulating nutrition (IMN) has been shown to reduce postoperative infectious complications and length of stay in patients with gastrointestinal cancer. Two studies of IMN in patients undergoing surgery for head and neck cancer also suggested that this treatment might improve long-term survival and progression-free survival. In the present study, we analysed follow-up data from our previous randomised controlled trial of IMN, in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer, in order to evaluate the long-term impact on survival of postoperative IMN versus an isocaloric, isonitrogenous control feed.

METHODS: This study included patients undergoing surgery for cancers of the pancreas, oesophagus and stomach, who had been randomised in a double-blind manner to receive postoperative jejunostomy feeding with IMN (Stresson, Nutricia Ltd.) or an isonitrogenous, isocaloric feed (Nutrison High Protein, Nutricia) for 10-15 days. The primary outcome was long-term overall survival.

RESULTS: There was complete follow-up for all 108 patients, with 54 patients randomised to each group. There were no statistically significant differences between groups by demographics [(age, p = 0.63), sex (p = 0.49) or site of cancer (p = 0.25)]. 30-day mortality was 11.1% in both groups. Mortality in the intervention group was 13%, 31.5%, 70.4%, 85.2%, 88.9%, and 96.3% at 90 days, and 1, 5, 10, 15 and 20 years respectively. Corresponding mortality in the control group was 14.8%, 35.2%, 68.6%, 79.6%, 85.2% and 98.1% (p > 0.05 for all comparisons).

CONCLUSION: Early postoperative feeding with arginine-enriched IMN had no impact on long-term survival in patients undergoing surgery for oesophagogastric and pancreaticobiliary cancer.

PMID:34656029 | DOI:10.1016/j.clnu.2021.09.040

Neurobiol Aging. 2021 Sep 17;109:64-77. doi: 10.1016/j.neurobiolaging.2021.09.013. Online ahead of print.

ABSTRACT

In Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that in Tau transgenic mice, human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells. Notably, immunodepletion of ISF phosphorylated Tau, but not Tau fragments, significantly reduces its ability to seed Tau aggregation and only a fraction of Tau, separated by ultracentrifugation, is seeding-competent. These results indicate that ISF seeding competence is driven by a small subset of Tau, which potentially contribute to the propagation of Tau pathology.

PMID:34655982 | DOI:10.1016/j.neurobiolaging.2021.09.013

J Infect Public Health. 2021 Oct 7;14(11):1701-1707. doi: 10.1016/j.jiph.2021.10.002. Online ahead of print.

ABSTRACT

BACKGROUND: Dengue fever is one of the major viral diseases worldwide transmitted by mosquitoes. Depending on the severity of disease it can range from mild fever to severe fatal cases. Rapid decline of platelet levels is one of indicators of clinical worsening. The role of viral factors in dengue pathogenesis and correlation with clinical and laboratory parameters remain unclear.

METHODS: Between September 2017 to December 2018, 102 dengue confirmed paediatric cases were analysed for various viral and host parameters. Based on symptoms, they were classified into dengue without warning signs (DOS), dengue with warning signs (DWS) and severe dengue (SD) as per 2009 WHO classification. Quantitative analysis of NS1, IgM and IgG in were done by ELISA. IgM/IgG ratio revealed primary or secondary dengue infection. Serotyping of virus in serum was done by nested multiplex RT-PCR. Viral load (VL) was determined by quantitative real time polymerase chain reaction. Association between VL and NS1 in patient sera with clinical and laboratory parameters was statistically analysed.

RESULTS: It was found that disease severity (as per 2009 WHO classification) significantly associated with secondary dengue infection. DENV3 was found to be the only serotype detected. The present study reports neither NS1 nor VL significantly associated with disease severity or type of infection (primary or secondary). However, VL positively correlated with haematocrit (p < 0.05). Viral load above 10⁶ copies/mL was found in 61% of patients. Further, high viral load (>10⁶ copies/mL) negatively correlated with platelet levels (p < 0.05).

CONCLUSION: Thus, viral load could be an important predictive parameter in dengue related severe symptoms like thrombocytopenia and elevated hematocrit when it goes above a certain threshold (>10⁶ copies/ mL).

PMID:34655984 | DOI:10.1016/j.jiph.2021.10.002