Tag: statistics

Lancet Neurol. 2021 Apr;20(4):294-303. doi: 10.1016/S1474-4422(21)00024-7.

ABSTRACT

BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk.

METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602.

FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models.

INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted.

FUNDING: British Heart Foundation and Stroke Association.

PMID:33743239 | DOI:10.1016/S1474-4422(21)00024-7

Knee. 2021 Mar 17;29:478-485. doi: 10.1016/j.knee.2021.02.025. Online ahead of print.

ABSTRACT

BACKGROUND: The bone healing in open-wedge high tibial osteotomy (OWHTO) proceeds gradually by a filling of the osteotomy gap. This can comprise several risk factors.

METHODS: A retrospective study analysed the clinical and radiological course of 101 consecutive OWHTOs in 96 patients. The following risk factors were considered: age, body mass index, tobacco consumption, amount of tobacco consumption, severity of comorbidities, infection of the surgical area, occurrence of a lateral hinge fracture and the degree of correction. The bone healing was evaluated by using the modified Radiographic Union Score for Tibial fractures (RUST).

RESULTS: A disturbance in bone healing was observed in 16 of the 101 osteotomies. Binary logistic regression analysis showed a correlation between the angle of the opening wedge and the development of a disturbance in bone healing (P = 0.002). The odds ratio indicated an increase in the risk of a disturbance in bone healing of 56% with each additional degree of correction. For the risk factor ‘age’ a statistical trend was recognizable (P = 0.077) with the risk of a disturbance in bone healing in higher age.

CONCLUSION: Lateral hinge fractures seem not to have a detrimental effect on the filling of the osteotomy gap. An increase in the opening wedge bears the risk of a disturbance in bone healing.

PMID:33743262 | DOI:10.1016/j.knee.2021.02.025

Clin Nutr. 2021 Feb 27;40(4):1537-1545. doi: 10.1016/j.clnu.2021.02.033. Online ahead of print.

ABSTRACT

AIMS: To study whether the consumption of ultra-processed foods and drinks is associated with breast, colorectal, and prostate cancers.

METHODS: Multicentric population-based case-control study (MCC-Spain) conducted in 12 Spanish provinces. Participants were men and women between 20 and 85 years of age with diagnoses of colorectal (n = 1852), breast (n = 1486), or prostate cancer (n = 953), and population-based controls (n = 3543) frequency-matched by age, sex, and region. Dietary intake was collected using a validated food frequency questionnaire. Foods and drinks were categorized according to their degree of processing based on the NOVA classification. Unconditional multivariable logistic regression was used to evaluate the association between ultra-processed food and drink consumption and colorectal, breast, and prostate cancer.

RESULTS: In multiple adjusted models, consumption of ultra-processed foods and drinks was associated with a higher risk of colorectal cancer (OR for a 10% increase in consumption: 1.11; 95% CI 1.04-1.18). The corresponding odds for breast (OR 1.03; 95% CI 0.96-1.11) and prostate cancer (OR 1.02; 95% CI 0.93-1.12) were indicative of no association.

CONCLUSIONS: Results of this large population-based case-control study suggest an association between the consumption of ultra-processed foods and drinks and colorectal cancer. Food policy and public health should include a focus on food processing when formulating dietary guidelines.

PMID:33743289 | DOI:10.1016/j.clnu.2021.02.033

Cell Stem Cell. 2021 Mar 16:S1934-5909(21)00108-9. doi: 10.1016/j.stem.2021.03.002. Online ahead of print.

ABSTRACT

Age-related clonal hematopoiesis (CH) is a risk factor for malignancy, cardiovascular disease, and all-cause mortality. Somatic mutations in DNMT3A are drivers of CH, but decades may elapse between the acquisition of a mutation and CH, suggesting that environmental factors contribute to clonal expansion. We tested whether infection provides selective pressure favoring the expansion of Dnmt3a mutant hematopoietic stem cells (HSCs) in mouse chimeras. We created Dnmt3a-mosaic mice by transplanting Dnmt3a^-/- and WT HSCs into WT mice and observed the substantial expansion of Dnmt3a^-/- HSCs during chronic mycobacterial infection. Injection of recombinant IFNγ alone was sufficient to phenocopy CH by Dnmt3a^-/- HSCs upon infection. Transcriptional and epigenetic profiling and functional studies indicate reduced differentiation associated with widespread methylation alterations, and reduced secondary stress-induced apoptosis accounts for Dnmt3a^-/- clonal expansion during infection. DNMT3A mutant human HSCs similarly exhibit defective IFNγ-induced differentiation. We thus demonstrate that IFNγ signaling induced during chronic infection can drive DNMT3A-loss-of-function CH.

PMID:33743191 | DOI:10.1016/j.stem.2021.03.002

Lancet. 2021 Mar 17:S0140-6736(21)00575-4. doi: 10.1016/S0140-6736(21)00575-4. Online ahead of print.

ABSTRACT

BACKGROUND: The degree to which infection with SARS-CoV-2 confers protection towards subsequent reinfection is not well described. In 2020, as part of Denmark’s extensive, free-of-charge PCR-testing strategy, approximately 4 million individuals (69% of the population) underwent 10·6 million tests. Using these national PCR-test data from 2020, we estimated protection towards repeat infection with SARS-CoV-2.

METHODS: In this population-level observational study, we collected individual-level data on patients who had been tested in Denmark in 2020 from the Danish Microbiology Database and analysed infection rates during the second surge of the COVID-19 epidemic, from Sept 1 to Dec 31, 2020, by comparison of infection rates between individuals with positive and negative PCR tests during the first surge (March to May, 2020). For the main analysis, we excluded people who tested positive for the first time between the two surges and those who died before the second surge. We did an alternative cohort analysis, in which we compared infection rates throughout the year between those with and without a previous confirmed infection at least 3 months earlier, irrespective of date. We also investigated whether differences were found by age group, sex, and time since infection in the alternative cohort analysis. We calculated rate ratios (RRs) adjusted for potential confounders and estimated protection against repeat infection as 1 – RR.

FINDINGS: During the first surge (ie, before June, 2020), 533 381 people were tested, of whom 11 727 (2·20%) were PCR positive, and 525 339 were eligible for follow-up in the second surge, of whom 11 068 (2·11%) had tested positive during the first surge. Among eligible PCR-positive individuals from the first surge of the epidemic, 72 (0·65% [95% CI 0·51-0·82]) tested positive again during the second surge compared with 16 819 (3·27% [3·22-3·32]) of 514 271 who tested negative during the first surge (adjusted RR 0·195 [95% CI 0·155-0·246]). Protection against repeat infection was 80·5% (95% CI 75·4-84·5). The alternative cohort analysis gave similar estimates (adjusted RR 0·212 [0·179-0·251], estimated protection 78·8% [74·9-82·1]). In the alternative cohort analysis, among those aged 65 years and older, observed protection against repeat infection was 47·1% (95% CI 24·7-62·8). We found no difference in estimated protection against repeat infection by sex (male 78·4% [72·1-83·2] vs female 79·1% [73·9-83·3]) or evidence of waning protection over time (3-6 months of follow-up 79·3% [74·4-83·3] vs ≥7 months of follow-up 77·7% [70·9-82·9]).

INTERPRETATION: Our findings could inform decisions on which groups should be vaccinated and advocate for vaccination of previously infected individuals because natural protection, especially among older people, cannot be relied on.

FUNDING: None.

PMID:33743221 | DOI:10.1016/S0140-6736(21)00575-4

Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6.

ABSTRACT

BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.

METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10¹⁴ vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).

FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).

INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.

FUNDING: Novartis Gene Therapies.

PMID:33743238 | DOI:10.1016/S1474-4422(21)00001-6

Jpn J Radiol. 2021 Mar 20. doi: 10.1007/s11604-021-01110-y. Online ahead of print.

ABSTRACT

PURPOSE: To evaluate the diagnostic performance of ultrafast and standard dynamic contrast-enhanced (DCE)-MRI in evaluating the residual disease after neoadjuvant chemotherapy (NAC) for breast cancer.

MATERIALS AND METHODS: Sixty-seven consecutive patients underwent MRI after NAC. Visual analysis of enhancement was performed on ultrafast and standard DCE-MRI, and compared between no residual disease and residual disease groups. The lesion diameters measured on the last phase of ultrafast DCE-MRI and early and delayed phases of standard DCE-MRI were compared with pathological diameter of entire residual cancer and residual invasive ductal carcinoma (IDC).

RESULTS: The visual analysis in the delayed phase of standard DCE-MRI exhibited the highest sensitivity (90%), whereas ultrafast DCE-MRI revealed the highest positive predictive value (92%). There were no significant differences between the diameters in the delayed phase of the standard DCE-MRI and the pathological entire residual cancer (p = 0.97), and the diameters in ultrafast DCE-MRI and the pathological residual IDC (p = 0.97).

CONCLUSION: The delayed phase of standard DCE-MRI may be effective for detecting the residual disease and evaluating the extension of entire residual cancer. Enhancement in ultrafast DCE-MRI may be strongly suggestive of the presence of residual disease, and effective for evaluating the extension of residual IDC.

PMID:33743147 | DOI:10.1007/s11604-021-01110-y

Jpn J Radiol. 2021 Mar 20. doi: 10.1007/s11604-021-01107-7. Online ahead of print.

ABSTRACT

BACKGROUND: Multiple prominent hypointense vessels on susceptibility-weighted image (SWI) have been found in the ischemic territory of patients with acute ischemic stroke. SWI is suitable for venous imaging.

PURPOSE: To evaluate the conditions of prominent hypointense vessel (PHV) in hyperacute and acute cerebral infarctions using susceptibility-weighted image (SWI).

MATERIALS AND METHODS: Magnetic resonance images, including SWI, of 284 patients with acute infarction were evaluated. Based on lesion size, the infarction was classified as a small (< 3 cm) or a large (> 3 cm) infarction. Stage of infarction was classified as hyperacute (< 6 h) or acute (> 6 h, < 1 week) on the basis of the onset of stroke. The site of infarction was categorised as a deep grey matter or a mixed (cortical and/or deep grey matter) infarction. The venous structures were analysed qualitatively for the calibre difference between ipsilateral and contralateral hemispheres. We quantitatively analysed the relationship between the size of areas with PHV on SWI and the abnormalities on MR angiography, apparent diffusion coefficient value, and signal intensity on T2WI in the 271 patients.

RESULTS: PHV over the infarction site was observed in 54.1% (137/253) of the large infarctions, and 19.3% (6/31) of the small infarctions on SWI. PHV was demonstrated in 63.1% (118/187) of mixed infarctions and 25.8% (25/97) of deep grey matter infarctions, and 59.2% (58/98) in hyperacute and 45.7% (85/186) of acute infarctions. The presence of PHV was statistically significant in the size and region of cerebral infarction (p < 0.05), and was not significant in the stage of infarction (p = 0.137). Quantitative analysis revealed significant differences in the MRA abnormalities and ADC values in the PHV ( +) group (p < 0.05) and no significant difference in the T2WI SI ratio in the PHV ( +) group (p = 0.086), compared with PHV (-) group.

CONCLUSION: PHV on SWI was more prominent at the portions with the large and mixed infarctions. PHV was observed both in hyperacute and acute infarction.

PMID:33743148 | DOI:10.1007/s11604-021-01107-7

Hum Cell. 2021 Mar 20. doi: 10.1007/s13577-021-00520-4. Online ahead of print.

ABSTRACT

The polymorphism rs2853669 in the telomerase reverse transcriptase gene (TERT) promoter region is widely investigated for the risk of different cancers. However, previous results remained inconclusive. Thus, we performed this updated meta-analysis to comprehensively evaluate the association between rs2853669 and the susceptibility of human cancer. A systematic literature search via PubMed, EMBASE, Cochrane Library, and Web of Science databases was conducted that produced a total of 19 eligible studies containing 23,085 subjects. The relationship was calculated with the odds ratio (OR) and 95% confidence intervals (CIs). Statistical analyses were performed using the RevMan 5.4 software. The analysis indicated that rs2853669 is associated with an enhanced risk of overall cancer risk. From subgroup analysis, a significantly increased association in five genetic models (p < 0.05) was found among Asians, but no association was observed in Caucasians. Although we did not find any significant correlation between rs2853669 and breast cancer, an increased and statistically significant association was found for both lung cancer and acute myeloid leukemia. We did not find any association in other cancer types during stratified analysis. Our meta-analysis suggests that rs2853669 polymorphism in TERT gene is associated with an increased risk of overall cancer susceptibility, particularly in the Asian population. Moreover, rs2853669 is significantly associated with lung cancer and acute myeloid lymphoma. However, large-scale studies are needed to confirm our findings.

PMID:33743166 | DOI:10.1007/s13577-021-00520-4

Hernia. 2021 Mar 20. doi: 10.1007/s10029-021-02392-x. Online ahead of print.

ABSTRACT

PURPOSE: The primary goal of this study was to determine the incidence of occult paraumbilical hernias during open primary umbilical hernia repair. The secondary objective was to further characterize the clinical features of these patients and hernias.

METHODS: This was a retrospective chart review of patients undergoing primary umbilical hernia repair at Shouldice Hospital, from 2007 to 2017. Inclusion criteria were utilized to elucidate patients, where a concomitant occult paraumbilical hernia was found. Descriptive statistics were used throughout.

RESULTS: 5850 patients underwent primary umbilical hernia repair, 459 (7.85%) patients had concomitant primary umbilical and paraumbilical hernias. There was a preoperative suspicion/diagnosis of a paraumbilical hernia in 166 (2.8%) of these patients. In 293 (5.01%) patients who had open primary umbilical hernia repair, at least one associated occult paraumbilical defect was found during surgery. Most of umbilical and concomitant occult paraumbilical hernias were small and medium size defects. The great majority of the reported occult paraumbilical hernias were found in the supraumbilical position at a distance of 3 cm or less from the top of the umbilical defect.

CONCLUSION: The incidence of concomitant occult paraumbilical hernias in patients mildly overweight undergoing primary umbilical hernia repair is 5.01%, relevant to surgical decision-making. Since the great majority of these paraumbilical defects are superior to the umbilical defect, an adequate incision and dissection for at least 3 cm above the umbilical hernia may reduce the number of missed concomitant hernias and result in less presumed recurrences.

PMID:33743094 | DOI:10.1007/s10029-021-02392-x