Author Correction: Emerging trends in global freshwater availability.

In Fig. 2 of this Analysis, the tick-mark labels on the colour bars in the second and third images from the top were inadvertently swapped. In addition, the citation at the end of the sentence, "On a monthly basis GRACE can resolve TWS changes with sufficient accuracy over scales that range from approximately 200,000 km2 at low latitudes to about 90,000 km2 near the poles" should be to ref. 4 not ref. 1. These errors have been corrected online.

Emerging trends in global freshwater availability.

Freshwater availability is changing worldwide. Here we quantify 34 trends in terrestrial water storage observed by the Gravity Recovery and Climate Experiment (GRACE) satellites during 2002-2016 and categorize their drivers as natural interannual variability, unsustainable groundwater consumption, climate change or combinations thereof. Several of these trends had been lacking thorough investigation and attribution, including massive changes in northwestern China and the Okavango Delta. Others are consistent with climate model predictions. This observation-based assessment of how the world's water landscape is responding to human impacts and climate variations provides a blueprint for evaluating and predicting emerging threats to water and food security.

CLOCK 3111T/C genetic variant influences the daily rhythm of autonomic nervous function: relevance to body weight control.

BACKGROUND/OBJECTIVES: Humans carrying the genetic risk variant C at the circadian CLOCK (Circadian Locomotor Output Cycles Kaput) 3111T/C have been shown to have more difficulties to achieve desired weight loss than TT carriers. We tested the hypothesis that the daily rhythm of autonomic nervous function differs in CLOCK 3111C carriers, leading to reduced effectiveness in weight control. SUBJECTS/METHODS: We recruited 40 overweight/obese Caucasian women (body mass index>25), 20 carrying CLOCK 3111C (CC and TC) and 20 non-carriers with matched age and body mass index who participated in a dietary obesity treatment program of up to 30 weeks. Following the treatment, ambulatory electrocardiography was continuously monitored for up to 3.5 days when subjects underwent their normal daily activities. To assess autonomic function, heart rate variability analysis (HRV) was performed hourly to obtain mean inter-beat interval between two consecutive R waves (mean RR) and s.d. of normal-to-normal heartbeat intervals (SDNN), and two parasympathetic measures, namely, proportion of differences between adjacent NN intervals that are >50 ms (pNN50), and high-frequency (HF: 0.15-0.4 Hz) power. RESULTS: In the TT carriers, all tested HRV indices showed significant daily rhythms (all P-values <0.0001) with lower mean RR, SDNN, pNN50, and HF during the daytime as compared with the nighttime. The amplitudes of these rhythms except for SDNN were reduced significantly in the C carriers (mean RR: ~19.7%, P=0.001; pNN50: 58.1%, P=0.001; and HF: 41.1%, P=0.001). In addition, subjects with less weight loss during the treatment program had smaller amplitudes in the rhythms of mean RR (P<0.0001), pNN50 (P=0.007) and HF (P=0.003). Furthermore, the rhythmicity-weight loss associations were much stronger in the C carriers as compared to the TT carriers (mean RR: P=0.028, pNN50: P=0.0002; HF: P=0.015). CONCLUSIONS: The daily rhythm of parasympathetic modulation may play a role in the influence of the CLOCK variation on body weight control.

Association of dementia in patients with benign paroxysmal positional vertigo.

OBJECTIVE: We conducted a cohort study to investigate whether benign paroxysmal positional vertigo (BPPV) is correlated with an increased risk of dementia. METHODS: We established a case cohort comprising 7818 patients aged over 20 years who were diagnosed with BPPV from 2000 to 2010. In addition, we formed a control cohort by randomly selecting 31,272 people without BPPV and matched them with the BPPV patients according to gender, age, and index year. Cox proportional hazard regressions were performed to compute the hazard ratio (HR) of dementia after we adjusted for demographic characteristics and comorbidity. RESULTS: The prevalence of comorbidity was higher among patients with BPPV than among those without BPPV. In addition, patients with BPPV exhibited a 1.24-fold (95% confidence interval, CI 1.09-1.40; P < 0.001) higher risk of dementia than those without BPPV after we adjusted for age, gender, and comorbidity. An analysis stratified according to demographic factors revealed that women with BPPV exhibited a 1.36-fold (95% CI 1.16-1.59; P < 0.001) higher risk of dementia. Patients with BPPV aged over 65 years exhibited a significantly higher risk of dementia (adjusted HR: 1.26; 95% CI 1.10-1.43; P < 0.001) than those without BPPV. CONCLUSIONS: Patients with BPPV exhibited a higher risk of dementia than those without BPPV.

Acclimation potential of Arctic cod (Boreogadus saida) from the rapidly warming Arctic Ocean.

As a consequence of the growing concern about warming of the Arctic Ocean, this study quantified the thermal acclimation responses of Boreogadus saida, a key Arctic food web fish. Physiological rates for cardio-respiratory functions as well as critical maximum temperature (Tc,max) for loss of equilibrium (LOE) were measured. The transition temperatures for these events (LOE, the rate of oxygen uptake and maximum heart rate) during acute warming were used to gauge phenotypic plasticity after thermal acclimation from 0.5°C up to 6.5°C for 1 month (respiratory and Tc,max measurements) and 6 months (cardiac measurements). Tc,max increased significantly by 2.3°C from 14.9°C to 17.1°C with thermal acclimation, while the optimum temperature for absolute aerobic scope increased by 4.5°C over the same range of thermal acclimation. Warm acclimation reset the maximum heart rate to a statistically lower rate, but the first Arrhenius breakpoint temperature during acute warming was unchanged. The hierarchy of transition temperatures was quantified at three acclimation temperatures and was fitted inside a Fry temperature tolerance polygon to better define ecologically relevant thermal limits to performance of B. saida We conclude that B. saida can acclimate to 6.5°C water temperatures in the laboratory. However, at this acclimation temperature 50% of the fish were unable to recover from maximum swimming at the 8.5°C test temperature and their cardio-respiratory performance started to decline at water temperatures greater than 5.4°C. Such costs in performance may limit the ecological significance of B. saida acclimation potential.

Immunotherapy for peanut allergy.

Peanut allergy is one of the commonest food hypersensitivities causing fatal or near-fatal reactions. There is, currently, no preventive treatment and the incidence of severe allergic reactions during peanut desensitisation has limited its clinical use. Anti-immunoglobulin E therapy has been shown to be effective in preventing peanut-induced reactions but it does not result in long-term tolerance. Two important advances have recently been reported. One involves gradual oral introduction of peanut protein to desensitise, whereas the other approach uses a combination of anti-immunoglobulin E and oral peanut immunotherapy. Both approaches could offer a way to desensitise with a far greater margin of safety than has, hitherto, been reported. This article provides an overview of the literature on peanut immunotherapy and describes the experience in a small group of children in Hong Kong who were treated successfully using anti-immunoglobulin E combined with oral peanut desensitisation.

Drug reaction with eosinophilia and systemic symptoms syndrome associated myocarditis: a survival experience after extracorporeal membrane oxygenation support.

WHAT IS KNOWN AND OBJECTIVE: Myocarditis that develops because of the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a life-threatening disease. We report a case of DRESS-associated myocarditis with cardiac failure that required extracorporeal membrane oxygenation (ECMO) for cardiovascular support. CASE SUMMARY: A 14-year-old boy experienced DRESS-associated myocarditis after anticonvulsive therapy with carbamazepine, clonazepam and phenytoin. The clinical signs included hypotension, cardiac arrhythmia and poor left ventricular (LV) performance. Laboratory investigations showed elevated levels of cardiac enzymes. Systemic corticosteroid pulse therapy for 3 days was administered for treating the DRESS syndrome. The patient required inotropic drugs including dopamine, dobutamine and milrinone because of refractory hypotension and poor LV function. He was placed on ECMO support, and intra-aortic balloon pumping was initiated because of poor response to inotropic drugs and stasis of blood flow in the ventricle on hospital day 17. Plasma exchanges for four separate times over 8 days were also performed during ECMO support on day 22. His condition stabilized 13 days after ECMO support was initiated. The patient was discharged on hospital day 50, and the seizure was controlled by the oral form clonazepam, phenobarbital, topiramate and levetiracetam. Three months later, an echocardiogram showed mild dilated cardiomyopathy. WHAT IS NEW AND CONCLUSION: Drug reaction with eosinophilia and systemic symptoms-associated fulminant myocarditis is a life-threatening disease. Traditionally, systemic corticosteroid administration, plasmapheresis, intravenous immunoglobulin infusion and ventricular assist device implantation have been used for the treatment of this disease. To our knowledge, this is the first case of DRESS-associated fulminant myocarditis treated successfully with ECMO support. However, echocardiogram should be followed regularly because dilated cardiomyopathy may be the late sequela.

A restructuring of microbiome niche space is associated with Elexacaftor-Tezacaftor-Ivacaftor therapy in the cystic fibrosis lung.

BACKGROUND: Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). METHODS: We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics. RESULTS: The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications. CONCLUSIONS: ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug's effects take hold. FUNDING: This project was funded by a National Institute of Allergy and Infectious Disease Grant R01AI145925.

Acute increase of complexity in the neurocardiovascular dynamics following carotid stenting.

OBJECTIVE: Percutaneous carotid angioplasty and stenting (CAS) has been used to improve cerebral circulation and autoregulation. However, whether CAS ameliorates the autonomic regulatory dynamics remains unclear. This prospective study examines the neurocardiovascular dynamics following carotid stenting. METHODS: Thirty minutes electrocardiograms were recorded at three different time points (pre-operative, 1-h post-operative, 1-day post-operative) on twelve male patients (mean age 70.8 ± 9.6 years) receiving unilateral primary CAS. The HR data were analyzed by the conventional heart rate variability (HRV) and the multiscale entropy (MSE) methods; the former associates with autonomic activities and the latter quantifies the regulatory complexity of heart beat intervals. Loss of complexity at multiple scales has been associated with decoupled regulatory network in vivo. RESULTS: Conventional HRV indices showed no difference after CAS. Complexity indices increased significantly on scales 2-8 at 1-h and on scales 2-3 1-day post-treatment. The lower scale MSE (1-5) correlated with the frequency components of conventional HRV indices. The increased complexity could imply a restoration of the neurocardiovascular dynamics on the path to a healthier state. CONCLUSIONS: Primary CAS can induce a recovery in the neurocardiovascular regulatory dynamics in patients with high-grade carotid stenosis.

Hmong participants' reactions to return of individual and community pharmacogenetic research results: "A positive light for our community".

Pharmacogenetic research has historically lacked racial and ethnic diversity, limiting the application of findings to minority populations. Recent studies, including the Hmong, have gauged communities' interest in participating in genomic research and receiving their individual results. This study was conducted to create a culturally and linguistically appropriate format to return pharmacogenomic results and identify Minnesota Hmong research participants' reactions to their personal and collective results. Using a community-based participatory research approach, researchers collaborated with Hmong community members to format the pharmacogenetic disclosure process. Three focus groups were completed with 24 Hmong participants and three major themes emerged using thematic analysis. Many Hmong focus group participants viewed the results positively, finding them useful for themselves and their community as a means to optimize responses to and avoid harms from medicines. However, some participants expressed concerns about harms that the pharmacogenetic information could bring, including anxiety, misunderstanding, discrimination, exploitation, and lack of a clinician involvement in interpreting and applying the result. Many participants interpreted their results through an experiential lens, trusting their experience of medicines more than trusting genetic information, and through a cultural lens, expressing the belief that environmental factors may influence how people's bodies respond to medicines by influencing their inherited flesh and blood (roj ntsha). Lastly, participants stressed the importance of disseminating the information while acknowledging the complex linguistic, educational, and cultural factors that limit understanding of the results. Researchers, genetic counselors, pharmacists, and healthcare providers should strive to return results in meaningful ways to all members of society.

Disseminated histoplasmosis associated with hemophagocytic lymphohistiocytosis in kidney transplant recipients.

Transplant patients are susceptible to infectious complications due to chronic immunosuppression. We present two cases of persistent fever, weight loss and pancytopenia in kidney transplant recipients (originally concerning for posttransplant lymphoproliferative disease) that were later diagnosed with disseminated histoplasmosis on bone marrow and lymph node biopsy. In both patients, pancytopenia was due to hemophagocytic lymphohistiocytosis (HLH) which has rarely been described in association with histoplasmosis and not previously reported in kidney transplant recipients with this fungal infection. The diagnosis of histoplasmosis can be complex due to nonspecific symptomatology, delays in isolating histoplasma by fungal culture and false-negative antibody titers in immunocompromised patients. A review of the literature including the clinical features of histoplasmosis in immunosuppressed patients (prevalence, current diagnostic testing and treatment options) as well as the association of HLH in immunocompromised states are discussed.

Polymorphisms of cytotoxic T lymphocyte-associated antigen-4 and cytokine genes in Taiwanese patients with ankylosing spondylitis.

Cytokines, costimulatory and counter-regulatory molecules play important roles in the regulation of inflammatory response, and are good candidates involved in the development of ankylosing spondylitis (AS). This study investigated the genotypic distribution of proinflammatory cytokines and T-cell negative regulator cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) in healthy subjects and AS patients. Genomic DNA was extracted from 143 AS patients and 166 ethnic-matched healthy subjects. Nine polymorphisms within the genes of interleukin-4 (IL-4) (-34T>C, -81A>G, -285C>T and -589T>C), interleukin-6 (IL-6) (-174G>C), interleukin-10 (IL-10) (-592A>C and -819T>C) and CTLA-4 (-318C>T and +49A>G) were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. Significantly less AS patients carried the CTLA-4 high-expressing -318 T allele (P = 0.040). The CTLA-4 +49A>G genotypes were associated with circulatory levels of the inflammatory marker C-reactive protein (CRP) (P = 0.022). Our study documented the most complete genetic information of Taiwanese AS patients. The observations that CTLA-4 +49A>G genotypes are associated with circulatory CRP levels and significantly less AS subjects carrying CTLA-4 higher-secretor -318 T allele suggest the level and regulation of inflammation in AS subjects may be pre-determined by and associated with CTLA-4 genotypes.

Topiramate in prevention of cluster headache in the Taiwanese.

Topiramate could potentially effective as prophylaxis for cluster headache, but the experience remains limited in Asians. We performed an open-label clinical study to evaluate the efficacy of topiramate in the tolerable dosage to prevent cluster headache. We studied patients who fulfilled the criteria of episodic or chronic cluster headaches (International Classification of Headache Disorders second edition) prospectively. Headache severity was assessed using a verbal rating scale (excruciating, severe, moderate, mild, and no headache). Treatment was started with a topiramate dose of 50 mg twice daily and was increased by 50-100 mg a day every 3 to 7 days as tolerated to a maximal daily dosage of 400 mg. Of the 12 patients with episodic cluster headache, nine patients had remission of headache at a mean daily dosage of 273 mg (range 100-400 mg), and the patient with chronic cluster headache had remission at a daily dosage of 400 mg. The adverse effects included: paresthesia (84%), slow speech (54%), and dizziness (46%), but were tolerated by most patients. Two patients discontinued topiramate due to adverse events and one due to lack of efficacy. This open-label study suggests that topiramate is effective in the treatment of cluster headache in Taiwanese patients.

Freeze-fracture study of the Drosophila photoreceptor membrane: mutations affecting membrane particle density.

The photoreceptor membrane of Drosophila melanogaster (wild type, vitamin A-deprived wild type, and the mutants ninaAP228, ninaBP315, and oraJK84) was studied by freeze-fracture electron microscopy. The three mutations caused a decrease in the number of particles on the protoplasmic face of the rhabdomeric membrane. The ninaAP228 mutation affected only the peripheral photoreceptors (R1-6), while the ninaBP315 mutation affected both the peripheral (R1-6) and the central photoreceptors (R7). The oraJK84 mutation, which essentially eliminates R1-6 rhabdomeres, was found to drastically deplete the membrane particles in the vestigial R1-6 rhabdomeres but not in the normal rhabdomeres of R7 photoreceptors, suggesting that the failure of the oraJK84 mutant to form normal R1-6 rhabdomeres may be due to a defect in a major R1-6 photoreceptor-specific protein in the mutant. In all cases in which both the rhabdomeric particle density and rhodopsin content were studied, the mutations or vitamin A deprivation was found to reduce both these quantities, supporting the idea that at least the majority of the rhabdomeric membrane particles are closely associated with rhodopsin. Vitamin A deprivation and the mutations also reduced the number of particles in the plasma membrane as in the rhabdomeric membrane, suggesting that both classes of membrane contain rhodopsin.

Refractory thrombotic thrombocytopenic purpura and membranoproliferative glomerulonephritis successfully treated with rituximab: a case associated with hepatitis C virus infection.

Plasmapheresis remains the main treatment modality for patients with thrombotic thrombocytopenic purpura. We report a patient who had simultaneous onset of membranoproliferative glomerulonephritis and thrombotic thrombocytopenic purpura. She did not improve after 48 plasmapheresis sessions. A 6-week course of weekly intravenous doses of rituximab was then given. This achieved complete remission of her nephrotic syndrome and improvement in her renal function, so plasmapheresis was ceased. She had a low ADAMTS13 antigen level and a positive ADAMTS13 antibody, both of which reverted to normal after treatment with rituximab. This coincided with a rise in her hepatitis C virus RNA and liver transaminases. Liver biopsies did not reveal active fibrosis. Her hepatitis C virus RNA titre dropped afterwards, and she had no relapses of her thrombotic thrombocytopenic purpura and nephrotic syndrome, for more than 2 years after remission. The simultaneous onset and successful outcomes of both the membranoproliferative glomerulonephritis and thrombotic thrombocytopenic purpura illustrate the usefulness of rituximab. We discuss its use and risks, in the context of chronic hepatitis C infection.