Human embryonic stem cells (hESCs) have great potentials for future cell-based therapeutics. However, their mechanosensitivity to biophysical signals from the cellular microenvironment is not well ...characterized. Here we introduced an effective microfabrication strategy for accurate control and patterning of nanoroughness on glass surfaces. Our results demonstrated that nanotopography could provide a potent regulatory signal over different hESC behaviors, including cell morphology, adhesion, proliferation, clonal expansion, and self-renewal. Our results indicated that topological sensing of hESCs might include feedback regulation involving mechanosensory integrin-mediated cell–matrix adhesion, myosin II, and E-cadherin. Our results also demonstrated that cellular responses to nanotopography were cell-type specific, and as such, we could generate a spatially segregated coculture system for hESCs and NIH/3T3 fibroblasts using patterned nanorough glass surfaces.
Research on human embryonic stem cells (hESCs) has attracted much attention given their great potential for tissue regenerative therapy and fundamental developmental biology studies. Yet, there is ...still limited understanding of how mechanical signals in the local cellular microenvironment of hESCs regulate their fate decisions. Here, we applied a microfabricated micromechanical platform to investigate the mechanoresponsive behaviors of hESCs. We demonstrated that hESCs are mechanosensitive, and they could increase their cytoskeleton contractility with matrix rigidity. Furthermore, rigid substrates supported maintenance of pluripotency of hESCs. Matrix mechanics-mediated cytoskeleton contractility might be functionally correlated with E-cadherin expressions in cell-cell contacts and thus involved in fate decisions of hESCs. Our results highlighted the important functional link between matrix rigidity, cellular mechanics, and pluripotency of hESCs and provided a novel approach to characterize and understand mechanotransduction and its involvement in hESC function.
Circulating tumor cells (CTCs) detached from both primary and metastatic lesions represent a potential alternative to invasive biopsies as a source of tumor tissue for the detection, characterization ...and monitoring of cancers. Here we report a simple yet effective strategy for capturing CTCs without using capture antibodies. Our method uniquely utilized the differential adhesion preference of cancer cells to nanorough surfaces when compared to normal blood cells and thus did not depend on their physical size or surface protein expression, a significant advantage as compared to other existing CTC capture techniques.
Cognitive impairment is a common, often persistent, symptom of major depressive disorder (MDD) that is disproportionately represented in patients who have not returned to full psychosocial ...functioning. The ultimate goal of treatment in depression is full functional recovery, and assessing patients for cognitive impairment and selecting treatments that address cognitive dysfunction should lead to improved functional outcomes. Unfortunately, many clinicians use screening and assessment tools that are not suited for measuring cognitive impairment in patients with depression. The new THINC-it assessment tool is the first instrument that provides objective and subjective data on dysfunction in all the cognitive domains commonly affected by depression. In regard to treatment, several pharmacologic and nonpharmacologic interventions have been investigated as treatments for cognitive dysfunction in individuals with MDD. However very few studies of treatments for cognitive function in patients with MDD have been adequate, in terms of sample size and study methods, to guide clinical practice. The best evidence supports the moderate efficacy of some antidepressants, cognitive-behavioral therapy, and exercise. .
While there is clearly an association between improvement in depressive symptoms and functioning, symptom improvement can also be dissociated from functional improvement and work loss.3,4 Hence there ...has been increasing recognition that symptomatic remission is an insufficient goal of treatment for MDD and that return to premorbid psychosocial functioning should be targeted.5 Cognitive dysfunction refers to deficits in attention, verbal and nonverbal learning, short-term and working memory, visual and auditory processing, problem solving, processing speed, and motor functioning. Numerous pharmacotherapy augmentation strategies have shown efficacy in MDD, including lithium52 and atypical APs,53 but cognitive dysfunction has not been specifically examined in these studies. ...there is evidence that lithium is associated with adverse cognitive side effects that may negatively impact psychosocial functioning.54 Likewise, there is evidence to suggest that, in BD, atypical APs may worsen cognitive performance.55,56 Psychostimulants may be expected to have positive effects on cognition, but augmentation studies of osmotic-release oral system-methylphenidate57,58 and lisdexamfetamine59,60 in MDD have shown inconsistent results on depressive symptoms and subjective neurocognitive measures, although the latter were not always measured.
•Short-term efficacy of IV and IN ketamine/esketamine is established for TRD.•Interpretation the efficacy of oral ketamine in TRD is limited.•Insufficient data on disparate formulations and routes of ...delivery of ketamine.
Ketamine is established as a rapid and effective treatment in adults with treatment-resistant depression (TRD). The availability of different formulations and routes of delivery invites the need for evaluating relative effect sizes.
Effect size with respect to depression symptom reduction for each formulation and route of delivery was compared at discrete time-points (i.e., 24 h, 2–6 days, 7–20 days, 21–28 days) in adults with TRD. A random-effects meta-analysis was conducted to evaluate the effect size across intravenous, intranasal and oral routes of administration. Analysis was also conducted evaluating the effect size of racemic ketamine to esketamine.
The pooled effect size for intranasal ketamine/esketamine at 24 h was g = 1.247 (n = 5, 95% CI: 0.591–1.903, p < 0.01). At 2–6 days, the pooled effect size for intravenous ketamine/esketamine was g = 0.949 (n = 14, 95% CI: −0.308–2.206, p = 0.139). At 7–20 days, intranasal ketamine had a pooled effect size of g = 1.018 (n = 4, 95% CI: 0.499–1.538, p < 0.01). At 21–28 days, oral ketamine had a pooled effect size of g = 0.633 (n = 2, 95% CI: 0.368–0.898, p < 0.01).
Additional comparative studies are needed with regards to the efficacy of different formulations and routes of delivery.
The short-term efficacy of intravenous and intranasal ketamine/esketamine for adults with TRD was established. Interpreting the efficacy of oral ketamine was limited by the need for studies with larger samples across independent sites. No conclusions regarding comparative efficacy of the disparate formulations and routes of delivery can be derived from this analysis. Direct comparative studies are needed to further inform treatment options for TRD.
Treatment-resistant major depressive disorder is common; repetitive transcranial magnetic stimulation (rTMS) by use of high-frequency (10 Hz) left-side dorsolateral prefrontal cortex stimulation is ...an evidence-based treatment for this disorder. Intermittent theta burst stimulation (iTBS) is a newer form of rTMS that can be delivered in 3 min, versus 37·5 min for a standard 10 Hz treatment session. We aimed to establish the clinical effectiveness, safety, and tolerability of iTBS compared with standard 10 Hz rTMS in adults with treatment-resistant depression.
In this randomised, multicentre, non-inferiority clinical trial, we recruited patients who were referred to specialty neurostimulation centres based at three Canadian university hospitals (Centre for Addiction and Mental Health and Toronto Western Hospital, Toronto, ON, and University of British Columbia Hospital, Vancouver, BC). Participants were aged 18–65 years, were diagnosed with a current treatment-resistant major depressive episode or could not tolerate at least two antidepressants in the current episode, were receiving stable antidepressant medication doses for at least 4 weeks before baseline, and had an HRSD-17 score of at least 18. Participants were randomly allocated (1:1) to treatment groups (10 Hz rTMS or iTBS) by use of a random permuted block method, with stratification by site and number of adequate trials in which the antidepressants were unsuccessful. Treatment was delivered open-label but investigators and outcome assessors were masked to treatment groups. Participants were treated with 10 Hz rTMS or iTBS to the left dorsolateral prefrontal cortex, administered on 5 days a week for 4–6 weeks. The primary outcome measure was change in 17-item Hamilton Rating Scale for Depression (HRSD-17) score, with a non-inferiority margin of 2·25 points. For the primary outcome measure, we did a per-protocol analysis of all participants who were randomly allocated to groups and who attained the primary completion point of 4 weeks. This trial is registered with ClinicalTrials.gov, number NCT01887782.
Between Sept 3, 2013, and Oct 3, 2016, we randomly allocated 205 participants to receive 10 Hz rTMS and 209 participants to receive iTBS. 192 (94%) participants in the 10 Hz rTMS group and 193 (92%) in the iTBS group were assessed for the primary outcome after 4–6 weeks of treatment. HRSD-17 scores improved from 23·5 (SD 4·4) to 13·4 (7·8) in the 10 Hz rTMS group and from 23·6 (4·3) to 13·4 (7·9) in the iTBS group (adjusted difference 0·103, lower 95% CI −1·16; p=0·0011), which indicated non-inferiority of iTBS. Self-rated intensity of pain associated with treatment was greater in the iTBS group than in the 10 Hz rTMS group (mean score on verbal analogue scale 3·8 SD 2·0 vs 3·4 2·0 out of 10; p=0·011). Dropout rates did not differ between groups (10 Hz rTMS: 13 6% of 205 participants; iTBS: 16 8% of 209 participants); p=0·6004). The most common treatment-related adverse event was headache in both groups (10 Hz rTMS: 131 64% of 204; iTBS: 136 65% of 208).
In patients with treatment-resistant depression, iTBS was non-inferior to 10 Hz rTMS for the treatment of depression. Both treatments had low numbers of dropouts and similar side-effects, safety, and tolerability profiles. By use of iTBS, the number of patients treated per day with current rTMS devices can be increased several times without compromising clinical effectiveness.
Canadian Institutes of Health Research.
BackgroundThe goal of this study was to characterize viral loads and factors affecting viral clearance in persons with severe influenza MethodsThis was a 1-year prospective, observational study ...involving consecutive adults hospitalized with influenza. Nasal and throat swabs were collected at presentation, then daily until 1 week after symptom onset. Real-time reverse-transcriptase polymerase chain reaction to determine viral RNA concentration and virus isolation were performed. Viral RNA concentration was analyzed using multiple linear or logistic regressions or mixed-effect models ResultsOne hundred forty-seven inpatients with influenza A (H3N2) infection were studied (mean age ± standard deviation, 72±16 years). Viral RNA concentration at presentation positively correlated with symptom scores and was significantly higher than that among time-matched outpatients (control subjects). Patients with major comorbidities had high viral RNA concentration even when presenting >2 days after symptom onset (mean ± standard deviation, 5.06±1.85 vs 3.62±2.13 log10 copies/mL; P=.005; β, +0.86 95% confidence interval, +0.03 to +1.68). Viral RNA concentration demonstrated a nonlinear decrease with time; 26% of oseltamivir-treated and 57% of untreated patients had RNA detected at 1 week after symptom onset. Oseltamivir started on or before symptom day 4 was independently associated with an accelerated decrease in viral RNA concentration (mean β standard error, −1.19 0.43 and −0.68 0.33 log10 copies/mL for patients treated on day 1 and days 2–3, respectively; P<.05) and viral RNA clearance at 1 week (odds ratio, 0.10 95% confidence interval, 0.03–0.35 and 0.30 0.10–0.90 for patients treated on day 1–2 and day 3–4, respectively). Conversely, major comorbidities and systemic corticosteroid use for asthma or chronic obstructive pulmonary disease exacerbations were associated with slower viral clearance. Viral RNA clearance was associated with a shorter hospital stay (7.0 vs 13.5 days; P=.001) ConclusionPatients hospitalized with severe influenza have more active and prolonged viral replication. Weakened host defenses slow viral clearance, whereas antivirals started within the first 4 days of illness enhance viral clearance
Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of ...this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics.
This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics.
Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory.
Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.
A major technical hurdle in microfluidics is the difficulty in achieving high fidelity lithographic patterning on polydimethylsiloxane (PDMS). Here, we report a simple yet highly precise and ...repeatable PDMS surface micromachining method using direct photolithography followed by reactive ion etching (RIE). Our method to achieve surface patterning of PDMS applied an O(2) plasma treatment to PDMS to activate its surface to overcome the challenge of poor photoresist adhesion on PDMS for photolithography. Our photolithographic PDMS surface micromachining technique is compatible with conventional soft lithography techniques and other silicon-based surface and bulk micromachining methods. To illustrate the general application of our method, we demonstrated fabrication of large microfiltration membranes and free-standing beam structures in PDMS.
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