One of the main elements of dendrochronological standardization is removing the biological trend, i.e. the progressive decline of ring width along a cross-sectional radius that is caused by the corresponding increase in stem size and tree age over time. The ''conservative'' option for removing this biological trend is to fit a modified negative exponential curve (or a straight line with slope # 0) to the ring-width measurements. This method is based on the assumption that, especially for open-grown and/or shade-intolerant species, annual growth rate of mature trees fluctuates around a specific level, expressed by a constant ring width. Because this method has numerical and conceptual drawbacks, we propose an alternative approach based on the assumption that constant growth is expressed by a constant basal area increment distributed over a growing surface. From this starting point, we derive a mathematical expression for the biological trend of ring width, which can be easily calculated and used for dendrochronological standardization. The proposed C-method is compared to other standardization techniques, including Regional Curve Standardization (RCS), of tree-ring width from ponderosa pines (Pinus ponderosa Douglas ex P.Lawson & C.Lawson) located at the Gus Pearson Natural Area (GPNA) in northern Arizona, USA. Master ring-index chronologies built from ring area, RCS, and C-method reproduced stand-wide patterns of tree growth at the GPNA, whereas other standardization options, including the ''conservative'' one, failed to do so. In addition, the C-method has the advantage of calculating an expected growth curve for each tree, whereas RCS is based on applying the same growth curve to all trees. In conclusion, the C-method replaces the purely empirical ''conservative'' option with a theory- based approach, which is applicable to individual ring-width measurement series, does not require fitting a growth curve using nonlinear regression, and can be rigorously tested for improving tree-ring records of environmental changes.

OBJECTIVE: Retrospective clinical data and case studies support a therapeutic effect of ketamine in suppression of spreading depolarization (SD) following brain injury. Preclinical data strongly support efficacy in terms of frequency of SD as well as recovery from electrocorticography (ECoG) depression. The authors present the results of the first prospective controlled clinical trial testing the role of ketamine used for clinical sedation on occurrence of SD.METHODS: Ten patients with severe traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) were recruited for this pilot trial. A standard ECoG strip was placed at the time of craniotomy, and the patients were then placed on an alternating every-6-hour schedule of ketamine or other sedation agent. The order of treatment was randomized. The ketamine dose was adjusted to clinical effect or maintained at a subanesthetic basal dose (0.1 mg/kg/hr) if no sedation was required. SD was scored using standard criteria, blinded to ketamine dosing. Occurrence of SD was compared with the hourly dose of ketamine to determine the effect of ketamine on SD occurrence.RESULTS: Successful ECoG recordings were obtained in all 10 patients: 8 with SAH and 2 with TBI. There were a total of 1642 hours of observations with adequate ECoG: 833 hours off ketamine and 809 hours on ketamine. Analysis revealed a strong dose-dependent effect such that hours off ketamine or on doses of less than 1.15 mg/kg/hr were associated with an increased risk of SD compared with hours on doses of 1.15 mg/kg/hr or more (OR 13.838, 95% CI 1.99–1000). This odds ratio decreased with lower doses of 1.0 mg/kg/hr (OR 4.924, 95% CI 1.337–43.516), 0.85 mg/kg/hr (OR 3.323, 95% CI 1.139–16.074), and 0.70 mg/kg/hr (OR 2.725, 95% CI 1.068–9.898) to a threshold of no effect at 0.55 mg/kg/hr (OR 1.043, 95% CI 0.565–2.135). When all ketamine data were pooled (i.e., on ketamine at any dose vs off ketamine), a nonsignificant overall trend toward less SD during hours on ketamine (χ² = 3.86, p = 0.42) was observed.CONCLUSIONS: Ketamine effectively inhibits SD over a wide range of doses commonly used for sedation, even in nonintubated patients. These data also provide the first prospective evidence that the occurrence of SD can be influenced by clinical intervention and does not simply represent an unavoidable epiphenomenon after injury. These data provide the basis for future studies assessing clinical improvement with SD-directed therapy.Clinical trial registration no.: NCT02501941 (clinicaltrials.gov)

Objective: To assess the risk of new-onset type 1 diabetes mellitus (T1D) diagnosis following COVID-19 diagnosis and the impact of COVID-19 diagnosis on the risk of diabetic ketoacidosis (DKA) in patients with prior T1D diagnosis. Research design and methods: Retrospective data consisting of 27,292,879 patients from the Cerner Real-World Data were used. Odds ratios, overall and stratified by demographic predictors, were calculated to assess associations between COVID-19 and T1D. Odds ratios from multivariable logistic regression models, adjusted for demographic and clinical predictors, were calculated to assess adjusted associations between COVID-19 and DKA. Multiple imputation with multivariate imputation by chained equations (MICE) was used to account for missing data. Results: The odds of developing new-onset T1D significantly increased in patients with COVID-19 diagnosis (OR: 1.42, 95% CI: 1.38, 1.46) compared to those without COVID-19. Risk varied by demographic groups, with the largest risk among pediatric patients ages 0–1 years (OR: 6.84, 95% CI: 2.75, 17.02) American Indian/Alaskan Natives (OR: 2.30, 95% CI: 1.86, 2.82), Asian or Pacific Islanders (OR: 2.01, 95% CI: 1.61, 2.53), older adult patients ages 51–65 years (OR: 1.77, 95% CI: 1.66, 1.88), those living in the Northeast (OR: 1.71, 95% CI: 1.61, 1.81), those living in the West (OR: 1.65, 95% CI: 1.56, 1.74), and Black patients (OR: 1.59, 95% CI: 1.47, 1.71). Among patients with diagnosed T1D at baseline (n = 55,359), 26.7% (n = 14,759) were diagnosed with COVID-19 over the study period. The odds of developing DKA for those with COVID-19 were significantly higher (OR 2.26, 95% CI: 2.04, 2.50) than those without COVID-19, and the largest risk was among patients with higher Elixhauser Comorbidity Index. Conclusions: COVID-19 diagnosis is associated with significantly increased risk of new-onset T1D, and American Indian/Alaskan Native, Asian/Pacific Islander, and Black populations are disproportionately at risk. In patients with pre-existing T1D, the risk of developing DKA is significantly increased following COVID-19 diagnosis.

Aims: This study aimed to estimate the strength of association between prescriptions of glucose‐dependent insulinotropic polypeptide (GIP) and/or glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA) and the incidence of opioid overdose and alcohol intoxication in patients with opioid use disorder (OUD) and alcohol use disorder (AUD), respectively. This study also aimed to compare the strength of the GIP/GLP‐1 RA and substance use‐outcome association among patients with comorbid type 2 diabetes and obesity. Design: A retrospective cohort study analyzing de‐identified electronic health record data from the Oracle Cerner Real‐World Data. Setting: About 136 United States of America health systems, covering over 100 million patients, spanning January 2014 to September 2022. Participants: The study included 503 747 patients with a history of OUD and 817 309 patients with a history of AUD, aged 18 years or older. Measurements: The exposure indicated the presence (one or more) or absence of GIP/GLP‐1 RA prescriptions. The outcomes were the incidence rates of opioid overdose in the OUD cohort and alcohol intoxication in the AUD cohort. Potential confounders included comorbidities and demographic factors. Findings: Patients with GIP/GLP‐1 RA prescriptions demonstrated statistically significantly lower rates of opioid overdose [adjusted incidence rate ratio (aIRR) in OUD patients: 0.60; 95% confidence interval (CI) = 0.43–0.83] and alcohol intoxication (aIRR in AUD patients: 0.50; 95% CI = 0.40–0.63) compared to those without such prescriptions. When stratified by comorbid conditions, the rate of incident opioid overdose and alcohol intoxication remained similarly protective for those prescribed GIP/GLP‐1 RA among patients with OUD and AUD. Conclusions: Prescriptions of glucose‐dependent insulinotropic polypeptide and/or glucagon‐like peptide‐1 receptor agonists appear to be associated with lower rates of opioid overdose and alcohol intoxication in patients with opioid use disorder and alcohol use disorder. The protective effects are consistent across various subgroups, including patients with comorbid type 2 diabetes and obesity.