To send content items to your account,
please confirm that you agree to abide by our usage policies.
If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account.
Find out more about sending content to .
To send content items to your Kindle, first ensure firstname.lastname@example.org
is added to your Approved Personal Document E-mail List under your Personal Document Settings
on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part
of your Kindle email address below.
Find out more about sending to your Kindle.
Note you can select to send to either the @free.kindle.com or @kindle.com variations.
‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi.
‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.
The brain has the innate ability to undergo neuronal plasticity, which refers to changes in its structure and functions in response to continued changes in the environment. Although these concepts are well established in animal slice preparation models, their application to a large number of human subjects could only be achieved using noninvasive brain stimulation (NIBS) techniques. In this review, we discuss the mechanisms of plasticity induction using NIBS techniques including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), random noise stimulation (RNS), transcranial ultrasound stimulation (TUS), vagus nerve stimulation (VNS), and galvanic vestibular stimulation (GVS). We briefly introduce these techniques, explain the stimulation parameters and potential clinical implications. Although their mechanisms are different, all these NIBS techniques can be used to induce plasticity at the systems level, to examine the neurophysiology of brain circuits and have potential therapeutic use in psychiatric and neurological disorders. TMS is the most established technique for the treatment of brain disorders, and repetitive TMS is an approved treatment for medication-resistant depression. Although the data on the clinical utility of the other modes of stimulation are more limited, the electrical stimulation techniques (tDCS, tACS, RNS, VNS, GVS) have the advantage of lower cost, portability, applicability at home, and can readily be combined with training or rehabilitation. Further research is needed to expand the clinical utility of NIBS and test the combination of different modes of NIBS to optimize neuromodulation induced clinical benefits.
Due to lack of data on the epidemiology, cardiac, and neurological complications among Ontario visible minorities (Chinese and South Asians) affected by coronavirus disease (COVID-19), this population-based retrospective study was undertaken to study them systematically.
From January 1, 2020 to September 30, 2020 using the last name algorithm to identify Ontario Chinese and South Asians who were tested positive by PCR for COVID-19, their demographics, cardiac, and neurological complications including hospitalization and emergency visit rates were analyzed compared to the general population.
Chinese (N = 1,186) with COVID-19 were found to be older (mean age 50.7 years) compared to the general population (N = 42,547) (mean age 47.6 years) (p < 0.001), while South Asians (N = 3,459) were younger (age of 42.1 years) (p < 0.001). The 30-day crude rate for cardiac complications among Chinese was 169/10,000 (p = 0.069), while for South Asians, it was 64/10,000 (p = 0.008) and, for the general population, it was 112/10,000. For neurological complications, the 30-day crude rate for Chinese was 160/10,000 (p < 0.001); South Asians was 40/10,000 (p = 0.526), and general population was 48/10,000. The 30-day all-cause mortality rate was significantly higher for Chinese at 8.1% vs 5.0% for the general population (p < 0.001), while it was lower in South Asians at 2.1% (p < 0.001).
Chinese and South Asians in Ontario affected by COVID-19 during the first wave of the pandemic were found to have a significant difference in their demographics, cardiac, and neurological outcomes.
Approved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.
Patients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.
In this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (least squares mean difference [LSMD]=-4.6; 95% confidence interval [CI]=-6.34, −2.83; effect size vs placebo [ES]=-0.56; P<.0001). Lumateperone treatment was associated with significant MADRS improvement in both patients with bipolar I (LSMD=-4.0; 95% CI=-5.92, −1.99; ES=-0.49; P<.0001) and bipolar II (LSMD=-7.0; 95% CI=-10.92, −3.16; ES=-0.81; P=.0004). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.
Lumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.
Current treatments for schizophrenia are often associated with increased rates of metabolic syndrome (MetSy). MetSy is defined as meeting 3 of the following 5 criteria: waist circumference >40in (men) or >35in (women), triglycerides =150mg/dL, high density lipoprotein cholesterol (HDL) <40mg/dL (men) or <50mg/dL (women), systolic blood pressure (BP) =130mmHg or diastolic BP =85mmHg, fasting glucose =100mg/dL. Patients with MetSy have an elevated risk of developing type II diabetes and increased mortality due to cardiovascular disease. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA approved for the treatment of schizophrenia. This distinct pharmacological profile has been associated with favorable tolerability and a low risk of adverse metabolic effects in clinical trials. This post hoc analysis of 2 randomized, double-blind, placebo-controlled studies of patients with an acute exacerbation of schizophrenia compared rates of MetSy with lumateperone and risperidone. Data from an open-label long-term trial of lumateperone were also evaluated.
The incidence and shift in MetSy were analyzed in data pooled from 2 short-term (4 or 6 week) placebo- and active-controlled (risperidone 4mg) studies of lumateperone 42mg (Studies 005 and 302). The pooled lumateperone data were compared with data for risperidone. Data from an open-label 1-year trial (Study 303) evaluated MetSy in patients with stable schizophrenia switched from prior antipsychotic (PA) treatment to lumateperone 42mg.
In the acute studies (n=256 lumateperone 42mg, n=255 risperidone 4mg), rates of MetSy were similar between groups at baseline (16% lumateperone, 19% risperidone). At the end of treatment (EOT), MetSy was less common with lumateperone than with risperidone (13% vs 25%). More lumateperone patients (46%) compared with risperidone (25%) patients improved from having MetSy at baseline to no longer meeting MetSy criteria at EOT. Conversely, more patients on risperidone than on lumateperone developed MetSy during treatment (13% vs 5%). Differences in MetSy conversion rates were driven by changes in triglycerides and glucose. In the long-term study (n=602 lumateperone 42mg), 33% of patients had MetSy at PA baseline. Thirty-six percent of patients (36%) with MetSy at PA baseline improved to no longer meeting criteria at EOT. Fewer than half that percentage shifted from not meeting MetSy criteria to having MetSy (15%).
In this post hoc analysis, lumateperone 42mg patients had reduced rates of MetSy compared with risperidone patients. In the long-term study, patients with MetSy on PA switched to lumateperone 42mg had a reduction in the risk of MetSy. These results suggest that lumateperone 42mg is a promising new treatment for schizophrenia with a favorable metabolic profile.
It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults.
Lipids were measured at baseline (1985–1986; age: 18–30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes.
There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101–129 mg/dL, 130–159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV.
Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.
Prolonged remission of dystonia occurs rarely; however, well-documented cases are lacking. We report the clinical characteristics and course of four patients with botulinum toxin (BoNT)-associated prolonged remission of idiopathic cervical dystonia. Mean age at onset was 40 years. All had a relatively short duration of symptoms (mean 10.3 months), and with remission occurring after ≤ 3 treatments with BoNT. At last examination, the remission duration was 2–5 years. In the two cases that subsequently relapsed after 4–5 years, there was an altered phenomenology and worsened severity than at the onset. Recognizing this rare phenomenon has valuable clinical implications.
Non-alcoholic fatty liver disease (NAFLD) is an increasing cause of chronic liver disease that accompanies obesity and the metabolic syndrome. Excess fructose consumption can initiate or exacerbate NAFLD in part due to a consequence of impaired hepatic fructose metabolism. Preclinical data emphasized that fructose-induced altered gut microbiome, increased gut permeability, and endotoxemia play an important role in NAFLD, but human studies are sparse. The present study aimed to determine if two weeks of excess fructose consumption significantly alters gut microbiota or permeability in humans.
We performed a pilot double-blind, cross-over, metabolic unit study in 10 subjects with obesity (body mass index [BMI] 30–40 mg/kg/m2). Each arm provided 75 grams of either fructose or glucose added to subjects’ individual diets for 14 days, substituted isocalorically for complex carbohydrates, with a 19-day wash-out period between arms. Total fructose intake provided in the fructose arm of the study totaled a mean of 20.1% of calories. Outcome measures included fecal microbiota distribution, fecal metabolites, intestinal permeability, markers of endotoxemia, and plasma metabolites.
Routine blood, uric acid, liver function, and lipid measurements were unaffected by the fructose intervention. The fecal microbiome (including Akkermansia muciniphilia), fecal metabolites, gut permeability, indices of endotoxemia, gut damage or inflammation, and plasma metabolites were essentially unchanged by either intervention.
In contrast to rodent preclinical findings, excess fructose did not cause changes in the gut microbiome, metabolome, and permeability as well as endotoxemia in humans with obesity fed fructose for 14 days in amounts known to enhance NAFLD.
Major progress has recently been made regarding the biostratigraphy, lithostratigraphy and isotope chemostratigraphy of the lower Cambrian successions in South Australia, in particular of the Arrowie Basin, which has facilitated robust global stratigraphic correlations. However, lack of faunal and sedimentological data from the lower Cambrian Normanville Group in the eastern Stansbury Basin, South Australia – particularly the transition from the Fork Tree Limestone to the Heatherdale Shale – has prevented resolution of the age range, lithofacies, depositional environments and regional correlation of this succession. Here we present detailed sedimentologic, biostratigraphic and chemostratigraphic data through this transition in the eastern Stansbury Basin. Three lithofacies are identified that indicate a deepening depositional environment ranging from inner-mid-shelf (Lithofacies A and B) to outer shelf (Lithofacies C). New δ13C chemostratigraphic data capture global positive excursion III within the lower Heatherdale Shale. Recovered bradoriid Sinskolutella cuspidata supports an upper Stage 2 (Micrina etheridgei Zone). The combined geochemistry and palaeontology data reveal that the lower Heatherdale Shale is older than previously appreciated. This integrated study improves regional chronostratigraphic resolution and interbasinal correlation, and better constrains the depositional setting of this important lower Cambrian package from the eastern Stansbury Basin, South Australia.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
To characterize associations between exposures within and outside the medical workplace with healthcare personnel (HCP) SARS-CoV-2 infection, including the effect of various forms of respiratory protection.
We collected data from international participants via an online survey.
In total, 1,130 HCP (244 cases with laboratory-confirmed COVID-19, and 886 controls healthy throughout the pandemic) from 67 countries not meeting prespecified exclusion (ie, healthy but not working, missing workplace exposure data, COVID symptoms without lab confirmation) were included in this study.
Respondents were queried regarding workplace exposures, respiratory protection, and extra-occupational activities. Odds ratios for HCP infection were calculated using multivariable logistic regression and sensitivity analyses controlling for confounders and known biases.
HCP infection was associated with non–aerosol-generating contact with COVID-19 patients (adjusted OR, 1.4; 95% CI, 1.04–1.9; P = .03) and extra-occupational exposures including gatherings of ≥10 people, patronizing restaurants or bars, and public transportation (adjusted OR range, 3.1–16.2). Respirator use during aerosol-generating procedures (AGPs) was associated with lower odds of HCP infection (adjusted OR, 0.4; 95% CI, 0.2–0.8, P = .005), as was exposure to intensive care and dedicated COVID units, negative pressure rooms, and personal protective equipment (PPE) observers (adjusted OR range, 0.4–0.7).
COVID-19 transmission to HCP was associated with medical exposures currently considered lower-risk and multiple extra-occupational exposures, and exposures associated with proper use of appropriate PPE were protective. Closer scrutiny of infection control measures surrounding healthcare activities and medical settings considered lower risk, and continued awareness of the risks of public congregation, may reduce the incidence of HCP infection.
Little is known about methylphenidate (MPH) use and mortality outcomes.
To investigate the association between MPH use and mortality among children with an attention-deficit hyperactivity disorder (ADHD) diagnosis.
This population-based cohort study analysed data from Taiwan's National Health Insurance Research Database (NHIRD). A total of 68 096 children and adolescents aged 4–17 years with an ADHD diagnosis and prescribed MPH between 2000 and 2010 were compared with 68 096 without an MPH prescription, matched on age, gender and year of first ADHD diagnosis. All participants were followed to death, migration, withdrawal from the National Health Insurance programme or 31 December 2013. MPH prescriptions were measured on a yearly basis during the study period, and the association between MPH use and mortality was analysed using a repeated-measures time-dependent Cox regression model. The outcome measures included all-cause, unnatural-cause (including suicide, accident and homicide) and natural-cause mortality, obtained from linkage to the National Mortality Register in Taiwan.
The MPH group had lower unadjusted all-cause, natural-, unnatural- and accident-cause mortality than the comparison group. After controlling for potential confounders, MPH use was associated with a significantly lower all-cause mortality (adjusted hazard ratio AHR = 0.81, 95% CI 0.67–0.98, P = 0.027), delayed use of MPH was associated with higher mortality (AHR = 1.05, 95% CI 1.01–1.09) and longer MPH use was associated with lower mortality (AHR = 0.83, 95% CI 0.70–0.98).
MPH use is associated with a reduced overall mortality in children with ADHD in this cohort study, but unmeasured confounding cannot be excluded absolutely.
The link between schizophrenia and cigarette smoking has been well established through observational studies. However, the cause–effect relationship remains unclear.
We conducted Mendelian randomisation analyses to assess any causal relationship between genetic variants related to four smoking-related traits and the risk of schizophrenia.
We performed a two-sample Mendelian randomisation using summary statistics from genome-wide association studies (GWAS) of smoking-related traits and schizophrenia (7711 cases, 18 327 controls) in East Asian populations. Single nucleotide polymorphisms (SNPs) correlated with smoking behaviours (smoking initiation, smoking cessation, age at smoking initiation and quantity of smoking) were investigated in relation to schizophrenia using the inverse-variance weighted (IVW) method. Further sensitivity analyses, including Mendelian randomisation-Egger (MR-Egger), weighted median estimates and leave-one-out analysis, were used to test the consistency of the results.
The associated SNPs for the four smoking behaviours were not significantly associated with schizophrenia status. Pleiotropy did not inappropriately affect the results.
Cigarette smoking is a complex behaviour in people with schizophrenia. Understanding factors underlying the observed association remains important; however, our findings do not support a causal role of smoking in influencing risk of schizophrenia.
Glacial retreat in response to warming climates in the arid Xinjiang region of northwestern China directly impacts downstream water resources available for local communities. We used high-resolution satellite imagery from 1969 to 2014 to delineate spatial changes in 54 active glaciers in the upper Kaidu River Basin in the Tian Shan as well as their past expanses during the Little Ice Age (LIA). We manually delineated their boundaries based on the interpretation of glacial, geomorphic and topographic features. From the total glacier surface area, we estimated glacier volume and mass. From 1969 to 2014, glacier area decreased by 10.1 ± 1.0 km2 (relative loss of 34.2 ± 3.5%) and mass by 1.025 ± 0.108 Gt (relative loss of 43 ± 4.6%). From the LIA maximum (est. 1586 CE) to 1969, relative losses were less (25.7 ± 4.3% area loss and 33.1 ± 5.7% mass loss). Our results indicate that glacier recession is accelerating over time and that the glaciers are currently losing over 1.5 times more relative area than elsewhere in the Tian Shan. Using linear and non-linear projections, we estimate that these glaciers may disappear between 2050 and 2150 CE if climatic warming continues at the same pace.
Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.
Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.
When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.
The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.