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Regularized time series of ocean carbon data are necessary for assessing seasonal dynamics, annual budgets, and interannual and climatic variability. There are, however, no standardized methods for filling data gaps and limited evaluation of the impacts on uncertainty in the reconstructed time series when using various imputation methods. Here we present an empirical multivariate linear regression (MLR) model to estimate the concentration of dissolved inorganic carbon (DIC) in the surface ocean, that can utilize remotely sensed and modeled data to fill data gaps. This MLR was evaluated against seven other imputation models using data from seven long-term monitoring sites in a comparative assessment of gap-filling performance and resulting impacts on variability in the reconstructed time series. Methods evaluated included three empirical models – MLR, mean imputation, and multiple imputation by chained equation (MICE) – and five statistical models – linear, spline, and Stineman interpolation; exponential weighted moving average; and Kalman filtering with a state space model. Cross validation was used to determine model error and bias, while a bootstrapping approach was employed to determine sensitivity to varying data gap lengths. A series of synthetic gap filters, including 3-month seasonal gaps (spring, summer, autumn winter), 6-month gaps (centered on summer and winter), and bimonthly (every 2 months) and seasonal (four samples per year) sampling regimes, were applied to each time series to evaluate the impacts of timing and duration of data gaps on seasonal structure, annual means, interannual variability, and long-term trends. All models were fit to time series of monthly mean DIC, with MLR and MICE models also applied to both measured and modeled temperature and salinity with remotely sensed chlorophyll. Our MLR estimated DIC with a mean error of 8.8 µmol kg−1 among five oceanic sites and 20.0 µmol kg−1 for two coastal sites. The MLR performance indicated reanalysis data, such as GLORYS, can be utilized in the absence of field measurements without increasing error in DIC estimates. Of the methods evaluated in this study, empirical models did better than statistical models in retaining observed seasonal structure but led to greater bias in annual means, interannual variability, and trends compared to statistical models. Our MLR proved to be a robust option for imputing data gaps over varied durations and may be trained with either in situ or modeled data depending on application. This study indicates that the number and distribution of data gaps are important factors in selecting a model that optimizes uncertainty while minimizing bias and subsequently enables robust strategies for observational sampling.

Using ancillary datasets and interpolation schemes, 20+ years of the Munida Time Series (MTS) observations were used to evaluate the seasonal to decadal variability in the regional carbon cycle off the southeast coast of New Zealand. The contributions of gas exchange, surface freshwater flux, physical transport processes and biological productivity to mixed layer carbon were diagnostically assessed using a mass-balanced surface ocean model. The seasonal and interannual variability in this region is dominated by horizontal advection of water with higher dissolved inorganic carbon (DIC) concentration primarily transported by the Southland Current, a unique feature in this western boundary current system. The large advection term is primarily balanced by net community production and calcium carbonate production, maintaining a net sink for atmospheric CO 2 with a mean flux of 0.84±0.62 mol C m -2 y -1 . However, surface layer pCO 2 shows significant decadal variability, with the growth rate of 0.53±0.26 μ atm yr -1 during 1998–2010 increasing to 2.24±0.47 μ atm yr -1 during 2010–2019, driven by changes in advection and heat content. Changes in circulation have resulted in the regional sink for anthropogenic CO 2 being 50% higher and pH 0.011±.003 higher than if there had been no long-term changes in circulation. Detrended cross-correlation analysis was used to evaluate correlations between the Southern Annular Mode, the Southern Oscillation Index and various regional DIC properties and physical oceanographic processes over frequencies corresponding the duration of the MTS. The drivers of variability in the regional carbon cycle and acidification rate indicate sensitivity of the region to climate change and associated impacts on the Southern Ocean and South Pacific.

Carbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA. CRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227. 1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45–71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20–28) of these patients had died. Among patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales. National Institutes of Health.

The causes of megafaunal extinctions in North America have been widely debated but remain poorly understood. Mammoths (Mammuthus spp.) in the American Southwest were hunted by Clovis people during a period of rapid climate change, just before the regional onset of Younger Dryas cooling and mammoth extirpation. Thus, these mammoths may provide key insights into late Pleistocene extinction processes. Here we reconstruct the seasonal diet and climatic conditions experienced by mammoths in the San Pedro Valley of Arizona, using the carbon (13C/12C) and oxygen (18O/16O) isotope compositions of tooth enamel. These records suggest that Clovis mammoths experienced a warm, dry climate with sufficient summer rainfall to support seasonal C4 plant growth. Monsoon intensity may have been reduced relative to the preceding time period, but there is no isotopic evidence for severe drought. However, it is possible that the \"Clovis drought\", inferred from stratigraphic evidence, occurred suddenly at the end of the animals’ lives and thus was not recorded in the enamel isotopic compositions. Unlike mammoths that lived before the Last Glacial Maximum, Clovis mammoths regularly increased C4 grass consumption during summer, probably seeking seasonally green grasslands farther from the river valley. This predictable seasonal behavior may have made mammoths easier to locate by Clovis hunters. Furthermore, Clovis mammoths probably had no previous experience of such sudden climatic change as is believed to have occurred at the time of their extinction.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries. In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete. Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2–6] vs 2 [0–4] vs 2 [0–4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2–5] vs 1 [0–3] vs 1 [0–2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42–65) for China versus South America, 50% (41–61) for the USA versus China, and 53% (41–66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8–16; 29 of 246) than in the USA (23%, 16–30; 30 of 130) and South America (28%, 20–37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22–10·50) and the USA (aOR 3·34, 1·50–7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70–2·96). Global CRKP epidemics have important regional differences in patients’ baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. The National Institutes of Health.

BACKGROUND Women demonstrate a memory advantage when cognitively healthy yet lose this advantage to men in Alzheimer's disease. However, the genetic underpinnings of this sex difference in memory performance remain unclear. METHODS We conducted the largest sex‐aware genetic study on late‐life memory to date (Nmales = 11,942; Nfemales = 15,641). Leveraging harmonized memory composite scores from four cohorts of cognitive aging and AD, we performed sex‐stratified and sex‐interaction genome‐wide association studies in 24,216 non‐Hispanic White and 3367 non‐Hispanic Black participants. RESULTS We identified three sex‐specific loci (rs67099044—CBLN2, rs719070—SCHIP1/IQCJ‐SCHIP), including an X‐chromosome locus (rs5935633—EGL6/TCEANC/OFD1), that associated with memory. Additionally, we identified heparan sulfate signaling as a sex‐specific pathway and found sex‐specific genetic correlations between memory and cardiovascular, immune, and education traits. DISCUSSION This study showed memory is highly and comparably heritable across sexes, as well as highlighted novel sex‐specific genes, pathways, and genetic correlations that related to late‐life memory. Highlights Demonstrated the heritable component of late‐life memory is similar across sexes. Identified two genetic loci with a sex‐interaction with baseline memory. Identified an X‐chromosome locus associated with memory decline in females. Highlighted sex‐specific candidate genes and pathways associated with memory. Revealed sex‐specific shared genetic architecture between memory and complex traits.

INTRODUCTION Alzheimer's disease (AD) has genetic and environmental risk factors, including cigarette smoking. Gene–environment interactions may explain AD missing heritability. METHODS Lifetime smoking data from 22,032 European ancestry and 3126 African ancestry participants from the Alzheimer's Disease Genetic Consortium and the Framingham Heart Study were used to conduct genome‐wide single nucleotide polymorphism (SNP)‐by‐smoking interaction and smoking‐stratified association studies. For top‐ranked loci, brain‐derived bulk and single nuclei RNA‐sequencing were used for differential expression and colocalization analyses. RESULTS Among smokers only, there was a genome‐wide significant association in the APAF1/ANKS1B region (rs12368451; odds ratio = 1.19, 95% confidence interval: [1.12, 1.27], p = 3.0 × 10−8). Rs12368451 had expression quantitative trait locus (eQTL) activity that differed by smoking status and brain cell types but showed the most significant posterior probability (PP = 0.15) for being causal via ANKS1B expression in oligodendrocytes among smokers. DISCUSSION Potentially causal in smokers via eQTL activity, the top SNP may alter expression of ANKS1B, which encodes amyloid beta precursor protein intracellular domain associated‐1, known to regulate amyloid beta plaques. Highlights Among smokers only, a novel chromosome 12 single nucleotide polymorphism (SNP) near ANKS1B was associated with Alzheimer's disease. Evidence came from European and African ancestry cohorts. RNA‐sequencing analyses implicated the top SNP as causal via ANKS1B expression in oligodendrocytes. A genome‐wide African ancestry–specific significant SNP–smoking interaction was observed on chromosome 6 in SLC22A23.

INTRODUCTION Although large‐scale genome‐wide association studies (GWAS) have been conducted on AD, few have been conducted on continuous measures of memory performance and memory decline. METHODS We conducted a cross‐ancestry GWAS on memory performance (in 27,633 participants) and memory decline (in 22,365 participants; 129,201 observations) by leveraging harmonized cognitive data from four aging cohorts. RESULTS We found high heritability for two ancestry backgrounds. Further, we found a novel ancestry locus for memory decline on chromosome 4 (rs6848524) and three loci in the non‐Hispanic Black ancestry group for memory performance on chromosomes 2 (rs111471504), 7 (rs4142249), and 15 (rs74381744). In our gene‐level analysis, we found novel genes for memory decline on chromosomes 1 (SLC25A44), 11 (BSX), and 15 (DPP8). Memory performance and memory decline shared genetic architecture with AD‐related traits, neuropsychiatric traits, and autoimmune traits. DISCUSSION We discovered several novel loci, genes, and genetic correlations associated with late‐life memory performance and decline. Highlights Late‐life memory has high heritability that is similar across ancestries. We discovered four novel variants associated with late‐life memory. We identified four novel genes associated with late‐life memory. Late‐life memory shares genetic architecture with psychiatric/autoimmune traits.

Abstract Background Ceftriaxone-resistant (CRO-R) Escherichia coli bloodstream infections (BSIs) are common. Methods This is a prospective cohort of patients with E coli BSI at 14 United States hospitals between November 2020 and April 2021. For each patient with a CRO-R E coli BSI enrolled, the next consecutive patient with a ceftriaxone-susceptible (CRO-S) E coli BSI was included. Primary outcome was desirability of outcome ranking (DOOR) at day 30, with 50% probability of worse outcomes in the CRO-R group as the null hypothesis. Inverse probability weighting (IPW) was used to reduce confounding. Results Notable differences between patients infected with CRO-R and CRO-S E coli BSI included the proportion with Pitt bacteremia score ≥4 (23% vs 15%, P = .079) and the median time to active antibiotic therapy (12 hours [interquartile range {IQR}, 1–35 hours] vs 1 hour [IQR, 0–6 hours]; P < .001). Unadjusted DOOR analyses indicated a 58% probability (95% confidence interval [CI], 52%–63%) for a worse clinical outcome in CRO-R versus CRO-S BSI. In the IPW-adjusted cohort, no difference was observed (54% [95% CI, 47%–61%]). Secondary outcomes included unadjusted and adjusted differences in the proportion of 30-day mortality between CRO-R and CRO-S BSIs (−5.3% [95% CI, −10.3% to −.4%] and −1.8 [95% CI, −6.7% to 3.2%], respectively), postculture median length of stay (8 days [IQR, 5–13 days] vs 6 days [IQR, 4–9 days]; P < .001), and incident admission to a long-term care facility (22% vs 12%, P = .045). Conclusions Patients with CRO-R E coli BSI generally have poorer outcomes compared to patients infected with CRO-S E coli BSI, even after adjusting for important confounders.

INTRODUCTION “SuperAgers” are oldest‐old adults (ages 80+) whose memory performance more closely resembles middle‐aged adults. The present study examined apolipoprotein E (APOE) allele frequency in non‐Hispanic Black (NHB) and non‐Hispanic White (NHW) SuperAgers compared to controls and Alzheimer's disease dementia cases. METHODS In 18,080 participants from eight cohorts, harmonized clinical diagnostics and memory, executive function, and language domain scores were used to identify SuperAgers, cases, and controls across age‐defined bins. RESULTS NHW SuperAgers had significantly lower frequency of APOE‐ε4 alleles and higher frequency of APOE‐ε2 alleles compared to all cases and controls, including oldest‐old controls. Similar patterns were found in a small yet substantial sample of NHB SuperAgers; however, not all comparisons with controls reached significance. DISCUSSION We demonstrated strong evidence that APOE allele frequency relates to SuperAger status. Further research is needed with a larger sample of NHB SuperAgers to determine if mechanisms conferring cognitive resilience differ across race groups. Highlights Apolipoprotein E (APOE) allele frequency differs between SuperAgers and cases APOE allele frequency differs between non‐Hispanic White SuperAgers and controls The relationship of APOE and non‐Hispanic Black SuperAger status is unclear