Effects of sodium glucose cotransporter-2 inhibitors on serum uric acid in type 2 diabetes mellitus: A systematic review with an indirect comparison meta-analysis

To describe the effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid (SUA) in patients with type 2 diabetes mellitus (T2DM). PubMed, EMBASE, and CENTRAL were searched for randomized controlled trials of SGLT2 inhibitors in patients with T2DM up to Aug 10, 2017, without language or date restrictions. Thirty-one studies totaling 13,650 patients were included. SGLT2 inhibitors significantly decreased SUA levels compared with placebo, canagliflozin WMD –37.02?μmol/L, 95% CI [–38.41, –35.63], dapagliflozin WMD –38.05?μmol/L, 95% CI [–44.47, –31.62], empagliflozin WMD –42.07?μmol/L, 95% CI [–46.27, –37.86]. The drug class effect of SUA reduction suggesting SGLT2 inhibitors might be beneficial for diabetic patients with hyperuricemia.     

Variant rs2237892 of KCNQ1 Is Potentially Associated with Hypertension and Macrovascular Complications in Type 2 Diabetes Mellitus in A Chinese Han Population

KCNQ1 has been identified as a susceptibility gene of type 2 diabetes mellitus(T2DM) in Asian populations through genome-wide association studies. However, studies on the association between gene polymorphism of KCNQ1 and T2 DM complications remain unclear. To further analyze the association between different alleles at the single nucleotide polymorphism(SNP) rs2237892 within KCNQ1 and TD2 M and its complications, we conducted a case-control study in a Chinese Han population. The C allele of rs2237892 variant contributed to susceptibility to T2DM(odds ratio [OR], 1.45; 95% confidence interval [CI], 1.20–1.75). Genotypes CT(OR, 1.97; 95% CI,1.24–3.15) and CC(OR, 2.49; 95% CI, 1.57–3.95) were associated with an increased risk of T2 DM. Multivariate regression analysis was performed with adjustment of age, gender, and body mass index. We found that systolic blood pressure(P = 0.015), prevalence of hypertension(P = 0.037), and risk of macrovascular disease(OR, 2.10; CI, 1.00–4.45) were significantly higher in subjects with the CC genotype than in the combined population with genotype either CT or     

Molecular approaches reveal weak sibship aggregation and a high dispersal propensity in a non‐native fish parasite

Inferring parameters related to the aggregation pattern of parasites and to their dispersal propensity are important for predicting their ecological consequences and evolutionary potential. Nonetheless, it is notoriously difficult to infer these parameters from wildlife parasites given the difficulty in tracking these organisms. Molecular‐based inferences constitute a promising approach that has yet rarely been applied in the wild. Here, we combined several population genetic analyses including sibship reconstruction to document the genetic structure, patterns of sibship aggregation, and the dispersal dynamics of a non‐native parasite of fish, the freshwater copepod ectoparasite Tracheliastes polycolpus. We collected parasites according to a hierarchical sampling design, with the sampling of all parasites from all host individuals captured in eight sites spread along an upstream–downstream river gradient. Individual multilocus genotypes were obtained from 14 microsatellite markers, and used to assign parasites to full‐sib families and to investigate the genetic structure of T. polycolpus among both hosts and sampling sites. The distribution of full‐sibs obtained among the sampling sites was used to estimate individual dispersal distances within families. Our results showed that T. polycolpus sibs tend to be aggregated within sites but not within host individuals. We detected important upstream‐to‐downstream dispersal events of T. polycolpus between sites (modal distance: 25.4 km; 95% CI [22.9, 27.7]), becoming scarcer as the geographic distance from their family core location increases. Such a dispersal pattern likely contributes to the strong isolation‐by‐distance observed at the river scale. We also detected some downstream‐to‐upstream dispersal events (modal distance: 2.6 km; 95% CI [2.2–23.3]) that likely result from movements of infected hosts. Within each site, the dispersal of free‐living infective larvae among hosts likely contributes to increasing genetic diversity on hosts, possibly fostering the evolutionary potential of T. polycolpus.     

Even patients with mild COVID‐19 symptoms after SARS‐CoV‐2 infection show prolonged altered red blood cell morphology and rheological parameters

Infection with the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) and the associated coronavirus disease‐19 (COVID‐19) might affect red blood cells (RBC); possibly altering oxygen supply. However, investigations of cell morphology and RBC rheological parameters during a mild disease course are lacking and thus, the aim of the study. Fifty individuals with mild COVID‐19 disease process were tested after the acute phase of SARS‐CoV‐2 infection (37males/13 females), and the data were compared to n = 42 healthy controls (30 males/12 females). Analysis of venous blood samples, taken at rest, revealed a higher percentage of permanently elongated RBC and membrane extensions in COVID‐19 patients. Haematological parameters and haemoglobin concentration, MCH and MCV in particular, were highly altered in COVID‐19. RBC deformability and deformability under an osmotic gradient were significantly reduced in COVID‐19 patients. Higher RBC‐NOS activation was not capable to at least in part counteract these reductions. Impaired RBC deformability might also be related to morphological changes and/or increased oxidative state. RBC aggregation index remained unaffected. However, higher shear rates were necessary to balance the aggregation‐disaggregation in COVID‐19 patients which might be, among others, related to morphological changes. The data suggest prolonged modifications of the RBC system even during a mild COVID‐19 disease course.     

Assessing the risk of ketoacidosis due to sodium-glucose cotransporter (SGLT)-2 inhibitors in patients with type 1 diabetes: A meta-analysis and meta-regression

BackgroundSodium-glucose cotransporter-2 (SGLT2) inhibitors (SGLT2i) showed benefits in type 1 diabetes mellitus (T1DM), but the risk of diabetic ketoacidosis (DKA) limits their use. Ability to predict DKA risk and therapeutic responses would enable appropriate patient selection for SGLT2i. We conducted a meta-analysis and meta-regression of randomized controlled trials (RCTs) evaluating SGLT2i in T1DM to assess moderators of the relative risk (RR) of DKA, of glycemic (HbA1c, fasting plasma glucose, continuous glucose monitoring parameters, insulin dose, and insulin sensitivity indices) and non-glycemic (body mass index (BMI), systolic BP, renal function, albuminuria, and diabetic eye disorders) efficacy, and of other safety outcomes (including hypoglycemia, infections, major adverse cardiovascular events, and death).Methods and findingsWe searched MEDLINE, Cochrane Library, EMBASE, ClinicalTrials.gov, Cochrane CENTRAL Register of Controlled Trials, and other electronic sources through August 30, 2020, for RCTs comparing SGLT2i with active comparators or placebo in adult patients with T1DM. Reviewers extracted data for relevant outcomes, performed random effects meta-analyses, subgroup analyses, and multivariable meta-regression. The strength of evidence was summarized with the GRADE approach. Among 9,914 records identified, 18 placebo-controlled RCTs (7,396 participants, 50% males, mean age 42 y (range 23 to 55 y), 5 different SGLT2i evaluated), were included. Main outcome measures were effect sizes and moderators of glycemic and non-glycemic efficacy and of safety outcomes. In a multivariable meta-regression model, baseline BMI (β = 0.439 [95% CI: 0.211, 0.666], p < 0.001) and estimated glucose disposal rate (eGDR) (β = −0.766 [−1.276, −0.256], p = 0.001) were associated with the RR of DKA (RR: 2.81; 95% CI:1.97, 4.01; p < 0.001, R² = 61%). A model including also treatment-related parameters (insulin dose change-to-baseline insulin sensitivity ratio and volume depletion) explained 86% of variance across studies in the risk of DKA (R² = 86%). The association of DKA with a BMI >27 kg/m² and with an eGDR <8.3 mg/kg/min was confirmed also in subgroup analyses. Among efficacy outcomes, the novel findings were a reduction in albuminuria (WMD: −9.91, 95% CI: −16.26, −3.55 mg/g, p = 0.002), and in RR of diabetic eye disorders (RR: 0.27[0.11, 0.67], p = 0.005) associated with SGLT2i. A SGLT2i dose-response gradient was consistently observed for main efficacy outcomes, but not for adverse events (AEs). Overall, predictors of DKA and of other AEs differed substantially from those of glycemic and non-glycemic efficacy. A limitation of our analysis was the relatively short (≤52 weeks) duration of included RCTs. The potential relevance for clinical practice needs also to be confirmed by real-world prospective studies.ConclusionsIn T1DM, the risk of DKA and main therapeutic responses to SGLT2i are modified by baseline BMI and insulin resistance, by total insulin dose reduction-to-baseline insulin sensitivity ratio, and by volume depletion, which may enable the targeted use of these drugs in patients with the greatest benefit and the lowest risk of DKA.

Giovanni Musso and colleagues conduct a meta-analysis to identify risk factors of diabetic ketoacidosis in patients with Type 1 diabetes taking SGLT2 inhibitors.     

Association between IGF‐1 levels ranges and all‐cause mortality: A meta‐analysis

The association between IGF‐1 levels and mortality in humans is complex with low levels being associated with both low and high mortality. The present meta‐analysis investigates this complex relationship between IGF‐1 and all‐cause mortality in prospective cohort studies. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, and Cochrane Library up to September 2019. Published studies were eligible for the meta‐analysis if they had a prospective cohort design, a hazard ratio (HR) and 95% confidence interval (CI) for two or more categories of IGF‐1 and were conducted among adults. A random‐effects model with a restricted maximum likelihood heterogeneity variance estimator was used to find combined HRs for all‐cause mortality. Nineteen studies involving 30,876 participants were included. Meta‐analysis of the 19 eligible studies showed that with respect to the low IGF‐1 category, higher IGF‐1 was not associated with increased risk of all‐cause mortality (HR = 0.84, 95% CI = 0.68–1.05). Dose–response analysis revealed a U‐shaped relation between IGF‐1 and mortality HR. Pooled results comparing low vs. middle IGF‐1 showed a significant increase of all‐cause mortality (HR = 1.33, 95% CI = 1.14–1.57), as well as comparing high vs. middle IGF‐1 categories (HR = 1.23, 95% CI = 1.06–1.44). Finally, we provide data on the association between IGF‐1 levels and the intake of proteins, carbohydrates, certain vitamins/minerals, and specific foods. Both high and low levels of IGF‐1 increase mortality risk, with a specific 120–160 ng/ml range being associated with the lowest mortality. These findings can explain the apparent controversy related to the association between IGF‐1 levels and mortality.     

Sodium-glucose cotransporter 2 inhibitors: a practical guide for the Dutch cardiologist based on real-world experience

Sodium-glucose cotransporter 2 (SGLT2) inhibitors include a relatively new class of glucose-lowering drugs that reduce plasma glucose concentrations by inhibiting proximal tubular reabsorption of glucose in the kidney, while increasing its excretion in urine. Recent large randomised controlled trials have demonstrated that many of these agents reduce the occurrence of major adverse cardiovascular events, hospitalisation for heart failure, cardiovascular death and/or chronic kidney disease progression in patients with and without type 2 diabetes mellitus (DM2). Given their unique insulin-independent mode of action and favourable efficacy and adverse-event profile, SGLT2 inhibitors are promising and they offer an interesting therapeutic approach for the cardiologist to incorporate into routine practice. However, despite accumulating data supporting this class of therapy, cardiologists infrequently prescribe SGLT2 inhibitors, potentially due to a lack of familiarity with their use and the reticence to change DM medication. Here, we provide an up-to-date practical guide highlighting important elements of treatment initiation based on real-world evidence and expert opinion. We describe how to change DM medication, including insulin dosing when appropriate, and how to anticipate any adverse events based on real-world experience in patients with DM2 in the Meander Medical Centre in Amersfoort, the Netherlands. This includes a simple algorithm showing how to initiate SGLT2 inhibitor treatment safely, while considering the consequence of the glucosuric effects of these inhibitors for the individual patient.Supplementary InformationThe online version of this article (10.1007/s12471-021-01580-9) contains supplementary material, which is available to authorized users.     

Contributions of PARP‐1 rs1136410 C>T polymorphism to the development of cancer

Poly(ADP‐ribose) polymerase‐1 (PARP‐1) is a nuclear chromatin‐associated enzyme involved in the DNA damage response. SNP rs1136410 C>T, the most studied polymorphism in PARP‐1 gene, is highly implicated in the susceptibility of cancer. However, the roles of PARP‐1 rs1136410 C>T on cancer risk vary from different studies. We comprehensively screened all qualified publications from several databases, including PubMed, EMBASE, MEDLINE, CNKI and Wanfang. The searching was updated to April 2020. Our meta‐analysis included 60 articles with 65 studies, comprised of a total of 23 996 cases with cancer and 33 015 controls. Overall, pooled data showed that the PARP‐1 rs1136410 C>T polymorphism was significantly but a border‐line associated with an increased risk of overall cancer (CC vs. TT/TC: OR = 1.11, 95% CI = 1.00‐1.24; C vs T: OR = 1.07, 95% CI = 1.01‐1.14). Subgroup analysis indicated that rs1136410 C allele contributed to high risk among gastric, thyroid, and cervical cancer, but lower risk among brain cancer. Furthermore, increased cancer risk was detected in the subgroups of Asian, controls from population‐based design studies, and HWE ≤ 0.05 studies. Sensitivity analysis and Egger''s test showed that results of the meta‐analysis were fairly stable. The current study indicated that PARP1 rs1136410 C>T polymorphism may have an impact on certain types of cancer susceptibility.     

Neutralization of SARS‐CoV‐2 by highly potent,hyperthermostable, and mutation‐tolerant nanobodies

Monoclonal anti‐SARS‐CoV‐2 immunoglobulins represent a treatment option for COVID‐19. However, their production in mammalian cells is not scalable to meet the global demand. Single‐domain (VHH) antibodies (also called nanobodies) provide an alternative suitable for microbial production. Using alpaca immune libraries against the receptor‐binding domain (RBD) of the SARS‐CoV‐2 Spike protein, we isolated 45 infection‐blocking VHH antibodies. These include nanobodies that can withstand 95°C. The most effective VHH antibody neutralizes SARS‐CoV‐2 at 17–50 pM concentration (0.2–0.7 µg per liter), binds the open and closed states of the Spike, and shows a tight RBD interaction in the X‐ray and cryo‐EM structures. The best VHH trimers neutralize even at 40 ng per liter. We constructed nanobody tandems and identified nanobody monomers that tolerate the K417N/T, E484K, N501Y, and L452R immune‐escape mutations found in the Alpha, Beta, Gamma, Epsilon, Iota, and Delta/Kappa lineages. We also demonstrate neutralization of the Beta strain at low‐picomolar VHH concentrations. We further discovered VHH antibodies that enforce native folding of the RBD in the E. coli cytosol, where its folding normally fails. Such “fold‐promoting” nanobodies may allow for simplified production of vaccines and their adaptation to viral escape‐mutations.     

Dual deficiency of angiotensin‐converting enzyme‐2 and Mas receptor enhances angiotensin II‐induced hypertension and hypertensive nephropathy

Angiotensin‐converting enzyme‐2 (ACE2) and Mas receptor are the major components of the ACE2/Ang 1‐7/Mas axis and have been shown to play a protective role in hypertension and hypertensive nephropathy individually. However, the effects of dual deficiency of ACE2 and Mas (ACE2/Mas) on Ang II‐induced hypertensive nephropathy remain unexplored, which was investigated in this study in a mouse model of hypertension induced in either ACE2 knockout (KO) or Mas KO mice and in double ACE2/Mas KO mice by subcutaneously chronic infusion of Ang II. Compared with wild‐type (WT) animals, mice lacking either ACE2 or Mas significantly increased blood pressure over 7‐28 days following a chronic Ang II infusion (P < .001), which was further exacerbated in double ACE2/Mas KO mice (P < .001). Furthermore, compared to a single ACE2 or Mas KO mice, mice lacking ACE2/Mas developed more severe renal injury including higher levels of serum creatinine and a further reduction in creatinine clearance, and progressive renal inflammation and fibrosis. Mechanistically, worsen hypertensive nephropathy in double ACE2/Mas KO mice was associated with markedly enhanced AT1‐ERK1/2‐Smad3 and NF‐κB signalling, thereby promoting renal fibrosis and renal inflammation in the hypertensive kidney. In conclusion, ACE2 and Mas play an additive protective role in Ang II‐induced hypertension and hypertensive nephropathy. Thus, restoring the ACE2/Ang1‐7/Mas axis may represent a novel therapy for hypertension and hypertensive nephropathy.     

Efficacy and safety of combination PD‐1/PD‐L1 checkpoint inhibitors for malignant solid tumours: A systematic review

Treatment of multiple malignant solid tumours with programmed death (PD)‐1/PD ligand (PD‐L) 1 inhibitors has been reported. However, the efficacy and immune adverse effects of combination therapies are controversial. This meta‐analysis was performed with PubMed, Web of Science, Medline, EMBASE and Cochrane Library from their inception until January 2020. Random‐effect model was adopted because of relatively high heterogeneity. We also calculated hazard ratio (HR) of progression‐free survival (PFS), overall survival (OS) and risk ratio (RR) of adverse events (AEs), the incidence of grade 3‐5 AEs by tumour subgroup, therapeutic schedules and therapy lines. Nineteen articles were selected using the search strategy for meta‐analysis. Combined PD‐1/PD‐L1 inhibitors prolonged OS and PFS (HR 0.72, P < 0.001) and (HR 0.66, P < 0.001). In addition, incidence of all‐grade and grade 3‐5 AEs was not significant in the two subgroup analyses (HR 1.01, P = 0.31) and (HR 1.10, P = 0.07), respectively. Our meta‐analysis indicated that combination therapy with PD‐1/PD‐L1 inhibitors had greater clinical benefits and adverse events were not increased significantly.     

Kinetics and persistence of cellular and humoral immune responses to SARS‐CoV‐2 vaccine in healthcare workers with or without prior COVID‐19

SARS‐CoV‐2 vaccines are highly efficient against severe forms of the disease, hospitalization and death. Nevertheless, insufficient protection against several circulating viral variants might suggest waning immunity and the need for an additional vaccine dose. We conducted a longitudinal study on the kinetics and persistence of immune responses in healthcare workers vaccinated with two doses of BNT162b2 mRNA vaccine with or without prior SARS‐CoV‐2 infection. No new infections were diagnosed during follow‐up. At 6 months, post‐vaccination or post‐infection, despite a downward trend in the level of anti‐S IgG antibodies, the neutralizing activity does not decrease significantly, remaining higher than 75% (85.14% for subjects with natural infection, 88.82% for vaccinated after prior infection and 78.37% for vaccinated only). In a live‐virus neutralization assay, the highest neutralization titres were present at baseline and at 6 months follow‐up in persons vaccinated after prior infection. Anti‐S IgA levels showed a significant descending trend in vaccinated subjects (p < 0.05) after 14 weeks. Cellular immune responses are present even in vaccinated participants with declining antibody levels (index ratio 1.1–3) or low neutralizing activity (30%–40%) at 6 months, although with lower T‐cell stimulation index (p = 0.046) and IFN‐γ secretion (p = 0.0007) compared to those with preserved humoral responses.     

Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: A community-based case–control study

Objectives

There are no data regarding the possible role of the single nucleotide polymorphism (SNP) of class I histone deacetylases (HDACs) in type 2 diabetes mellitus (DM). We designed this study to examine whether polymorphisms of HDACs can be implicated in that disease.

Methods

A community-based, case–control study was conducted, with a total of 568 subjects (284 patients and 284 controls) enrolled. Four polymorphisms of HDAC1 (rs1741981) and HDAC3 (rs11741808, rs2547547, rs2530223) were examined by the use of TaqMan technology.

Results

We found a significant association with risk of type 2 DM for three SNPs of HDAC3, including rs11741808 [odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.35–0.81], rs2547547 [OR = 1.72, 95% CI: 1.13–2.64], and rs2530223 [OR = 1.39; 95% CI: 1.01–1.91]. Subgroup analysis showed that BMI ≥ 23 kg/m², high triglyceride and high blood pressure, together with the rs11741808AG genotype, were associated with a significantly decreased risk for type 2 DM, with ORs of 0.50 (95% CI: 0.27–0.91), 0.38 (95% CI: 0.20–0.71) and 0.43 (95% CI: 0.24–0.76) compared with the AA genotype, respectively. In a population with normal total cholesterol, the AG genotype yielded a significantly decreased risk of type 2 DM risk, with an OR of 0.42 (95% CI: 0.25–0.70) when compared with the persons of the AA genotype. For rs2547547, in a population with normal total cholesterol and triglyceride, the AG genotype was associated with a significantly increased risk of type 2 DM, with ORs of 1.92 (95% CI: 1.17–3.15) and 2.24 (95% CI: 1.28–3.94) when compared with the population carrying the AA genotype.

Conclusions

The results suggest that variants of HDAC3 contribute to an increased prevalence of type 2 DM in the Chinese Han population.     

Telomere length and metabolic syndrome traits: A Mendelian randomisation study

Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty‐two independent variants identified at FDR<0.05 from a genome‐wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary‐level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two‐sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR‐Egger, weighted‐median and MR‐PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist‐to‐hip ratio adjusted for body mass index (β = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (β = 1.529 mmHg, SE = 0.332, p = 4x10⁻⁶) and diastolic (β = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057–1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper‐body fat distribution and raised blood pressure.     

Mortality in people with schizophrenia: a systematic review and meta‐analysis of relative risk and aggravating or attenuating factors

People with schizophrenia die 15‐20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and random‐effects meta‐analysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was all‐cause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specific‐cause mortality. Publication bias, subgroup and meta‐regression analyses, and quality assessment (Newcastle‐Ottawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), all‐cause mortality was increased in people with schizophrenia versus any non‐schizophrenia control group (RR=2.52, 95% CI: 2.38‐2.68, n=79), with the largest risk in first‐episode (RR=7.43, 95% CI: 4.02‐13.75, n=2) and incident (i.e., earlier‐phase) schizophrenia (RR=3.52, 95% CI: 3.09‐4.00, n=7) versus the general population. Specific‐cause mortality was highest for suicide or injury‐poisoning or undetermined non‐natural cause (RR=9.76‐8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79‐7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardio‐cerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). All‐cause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001‐0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased all‐cause and suicide‐related mortality compared to those ≥40 years old, and a higher percentage of females increased suicide‐related mortality risk in incident schizophrenia samples. All‐cause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased all‐cause mortality (RR=1.62, 95% CI: 1.47‐1.80, n=3). Antipsychotics were protective against all‐cause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59‐0.84, n=11), with largest effects for second‐generation long‐acting injectable anti­psychotics (SGA‐LAIs) (RR=0.39, 95% CI: 0.27‐0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34‐0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39‐0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44‐0.63, n=4). Antipsychotics were also protective against natural cause‐related mortality, yet first‐generation antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust the analyses moderated larger natural‐cause mortality risk, and more recent study year moderated larger protective effects of antipsychotics. These results indicate that the excess mortality in schizophrenia is associated with several modifiable factors. Targeting comorbid substance abuse, long‐term maintenance antipsychotic treatment and appropriate/earlier use of SGA‐LAIs and clozapine could reduce this mortality gap.     

Killer whale (Orcinus orca) population dynamics in response to a period of rapid ecosystem change in the eastern North Atlantic

This study investigates survival and abundance of killer whales (Orcinus orca) in Norway in 1988–2019 using capture–recapture models of photo‐identification data. We merged two datasets collected in a restricted fjord system in 1988–2008 (Period 1) with a third, collected after their preferred herring prey shifted its wintering grounds to more exposed coastal waters in 2012–2019 (Period 2), and investigated any differences between these two periods. The resulting dataset, spanning 32 years, comprised 3284 captures of 1236 whales, including 148 individuals seen in both periods. The best‐supported models of survival included the effects of sex and time period, and the presence of transients (whales seen only once). Period 2 had a much larger percentage of transients compared to Period 1 (mean = 30% vs. 5%) and the identification of two groups of whales with different residency patterns revealed heterogeneity in recapture probabilities. This caused estimates of survival rates to be biased downward (females: 0.955 ± 0.027 SE, males: 0.864 ± 0.038 SE) compared to Period 1 (females: 0.998 ± 0.002 SE, males: 0.985 ± 0.009 SE). Accounting for this heterogeneity resulted in estimates of apparent survival close to unity for regularly seen whales in Period 2. A robust design model for Period 2 further supported random temporary emigration at an estimated annual probability of 0.148 (± 0.095 SE). This same model estimated a peak in annual abundance in 2015 at 1061 individuals (95% CI 999–1127), compared to a maximum of 731 (95% CI 505–1059) previously estimated in Period 1, and dropped to 513 (95% CI 488–540) in 2018. Our results indicate variations in the proportion of killer whales present of an undefined population (or populations) in a larger geographical region. Killer whales have adjusted their distribution to shifts in key prey resources, indicating potential to adapt to rapidly changing marine ecosystems.