Synapses without tension fail to fire in an in vitro network of hippocampal neurons.

Neurons in the brain communicate with each other at their synapses. It has long been understood that this communication occurs through biochemical processes. Here, we reveal that mechanical tension in neurons is essential for communication. Using in vitro rat hippocampal neurons, we find that 1) neurons become tout/tensed after forming synapses resulting in a contractile neural network, and 2) without this contractility, neurons fail to fire. To measure time evolution of network contractility in 3D (not 2D) extracellular matrix, we developed an ultrasensitive force sensor with 1 nN resolution. We employed Multi-Electrode Array and iGluSnFR, a glutamate sensor, to quantify neuronal firing at the network and at the single synapse scale, respectively. When neuron contractility is relaxed, both techniques show significantly reduced firing. Firing resumes when contractility is restored. This finding highlights the essential contribution of neural contractility in fundamental brain functions and has implications for our understanding of neural physiology.

Routine Metagenomics Service for ICU Patients with Respiratory Infection.

Rationale: Respiratory metagenomics (RMg) needs evaluation in a pilot service setting to determine utility and inform implementation into routine clinical practice. Objectives: Feasibility, performance, and clinical impacts on antimicrobial prescribing and infection control were recorded during a pilot RMg service. Methods: RMg was performed on 128 samples from 87 patients with suspected lower respiratory tract infection (LRTI) on two general and one specialist respiratory ICUs at Guy's and St Thomas' NHS Foundation Trust, London. Measurements and Main Results: During the first 15 weeks, RMg provided same-day results for 110 samples (86%), with a median turnaround time of 6.7 hours (interquartile range = 6.1-7.5 h). RMg was 93% sensitive and 81% specific for clinically relevant pathogens compared with routine testing. Forty-eight percent of RMg results informed antimicrobial prescribing changes (22% escalation; 26% deescalation) with escalation based on speciation in 20 out of 24 cases and detection of acquired-resistance genes in 4 out of 24 cases. Fastidious or unexpected organisms were reported in 21 samples, including anaerobes (n = 12), Mycobacterium tuberculosis, Tropheryma whipplei, cytomegalovirus, and Legionella pneumophila ST1326, which was subsequently isolated from the bedside water outlet. Application to consecutive severe community-acquired LRTI cases identified Staphylococcus aureus (two with SCCmec and three with luk F/S virulence determinants), Streptococcus pyogenes (emm1-M1uk clone), S. dysgalactiae subspecies equisimilis (STG62647A), and Aspergillus fumigatus with multiple treatments and public health impacts. Conclusions: This pilot study illustrates the potential of RMg testing to provide benefits for antimicrobial treatment, infection control, and public health when provided in a real-world critical care setting. Multicenter studies are now required to inform future translation into routine service.

Use of Microwave Dielectric Spectroscopy for the In Actu Assessment of Frustrated Lewis Pair Encounter Complexes.

Frustrated Lewis pairs (FLPs) offer an important and promising paradigm for main group catalysis. Reported here is the use of microwave dielectric spectroscopy for the in actu detection of FLP encounter complexes. This technique focuses on the room-temperature measurement of the loss component of microwave permittivity (ε2) over the bandwidth from 0.5 to 6.8 GHz. The microwave loss measured for a Lewis pair in a toluene host solution is compared with the losses of the individual components when measured separately, and the difference in loss Δε2 is used to characterize the electrostatic interaction between the pair. The Δε2 value shows a direct correlation with an ability for the FLP encounter complex to split hydrogen gas and abstract hydrogen from γ-terpinene and has led to the identification of a novel FLP encounter complex, tris-pentafluorophenyl borane-eucalyptol pairing.

A case of cutaneous malignant glomus tumor.

Glomus tumors are well-known but relatively rare vascular neoplasms, with their malignant counterparts still being rarer. There are very few reports of cutaneous malignant glomus tumors, and the current limited evidence suggests that they follow a more indolent course than deep-seated malignant glomus tumors. Herein, we are reporting a case of cutaneous malignant glomus tumor. A 94-year-old male presented with a right-sided ulcerated scalp lesion, which, on biopsy, showed a diffusely infiltrative epithelioid malignancy with considerable pleomorphism and a notable perivascular growth pattern. The tumor cells were positive for smooth muscle actin (SMA) and h-caldesmon, and negative for cytokeratin MNF116, CK5, p40, S100, SOX10, HMB45, Melan-A, ERG, CD31, CD45, CD3, CD20, ALK, desmin, CD68, CD34, and HHV8. A diagnosis of cutaneous malignant glomus tumor was made, and the patient underwent a wider excision. Cutaneous malignant glomus tumors are extremely rare and should be considered when examining unusual cutaneous mesenchymal tumors.

Self-reported chronic conditions and COVID-19 public health measures among Canadian adults: an analysis of the Canadian longitudinal study on aging.

OBJECTIVES: During the COVID-19 pandemic, public health measures were used to reduce the spread of COVID-19; it is unknown whether people with chronic conditions differentially adhered to public health measures. The objectives of this study were to evaluate the association between chronic conditions and adherence and to explore effect modification by sex, age, and income. STUDY DESIGN: An analysis of data from the Canadian Longitudinal Study on Aging COVID-19 Questionnaires (from April to September 2020) was conducted among middle-aged and older adults aged 50-96 years (n = 28,086). METHODS: Self-reported chronic conditions included lung disease, diabetes, heart disease, cancer, obesity, anxiety, and depression. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between chronic conditions and low, medium, and high levels of adherence. Effect modification was evaluated using statistical interaction and stratification. RESULTS: Most people (n = 17,435; 62%) had at least one chronic condition, and 2866 (10%) had three to seven chronic conditions. Among those with high adherence to public health measures, 69% had one or more chronic condition (n = 2266). Having three to seven chronic conditions, compared with none, was associated with higher adherence to public health measures (OR: 2.14; 95% CI: 1.12-1.42). Higher adherence was also noted across chronic conditions, for example, those with diabetes had higher adherence (OR: 1.72; 95% CI: 1.53-1.93). There was limited evidence of effect modification by sex, age, or income. CONCLUSIONS: Canadians with chronic conditions were more likely to adhere to public health measures; however, future research is needed to understand whether adherence helped to prevent adverse COVID-19 outcomes and if adherence had unintended consequences.

Solvent Minimized Synthesis of Amides by Reactive Extrusion.

Herein, we report on the translation of a small scale ball-milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin-screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid-liquid, solid-liquid and solid-solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7-hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).

The shifting shelf task: a new, non-verbal measure for attentional set shifting.

Attentional set shifting is a core ingredient of cognition, allowing for fast adaptation to changes in the environment. How this skill compares between humans and other primates is not well known. We examined performance of 3- to 5-year-old children and chimpanzees on a new attentional set shifting task. We presented participants with two shelves holding the same set of four boxes. To choose the correct box on each shelf, one has to switch attention depending on which shelf one is currently presented with. Experiment 1 (forty-six 3- to 5-year olds, predominantly European White) established content validity, showing that the majority of errors were specific switching mistakes indicating failure to shift attention. Experiment 2 (one hundred and seventy-eight 3- to 6-year olds, predominantly European White) showed that older children made fewer mistakes, but if mistakes were made, a larger proportion were switching mistakes rather than 'random' errors. Experiment 3 (52 chimpanzees) established suitability of the task for non-human great apes and showed that chimpanzees' performance was comparable to the performance of 3- and 4-year olds, but worse than 5-year olds. These results suggest that chimpanzees and young children share attentional set shifting capacities, but that there are unique changes in the human lineage from 5 years of age.

A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α3/α6 signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro.

Identification of immune correlates of fatal outcomes in critically ill COVID-19 patients.

Prior studies have demonstrated that immunologic dysfunction underpins severe illness in COVID-19 patients, but have lacked an in-depth analysis of the immunologic drivers of death in the most critically ill patients. We performed immunophenotyping of viral antigen-specific and unconventional T cell responses, neutralizing antibodies, and serum proteins in critically ill patients with SARS-CoV-2 infection, using influenza infection, SARS-CoV-2-convalescent health care workers, and healthy adults as controls. We identify mucosal-associated invariant T (MAIT) cell activation as an independent and significant predictor of death in COVID-19 (HR = 5.92, 95% CI = 2.49-14.1). MAIT cell activation correlates with several other mortality-associated immunologic measures including broad activation of CD8+ T cells and non-Vδ2 γδT cells, and elevated levels of cytokines and chemokines, including GM-CSF, CXCL10, CCL2, and IL-6. MAIT cell activation is also a predictor of disease severity in influenza (ECMO/death HR = 4.43, 95% CI = 1.08-18.2). Single-cell RNA-sequencing reveals a shift from focused IFNα-driven signals in COVID-19 ICU patients who survive to broad pro-inflammatory responses in fatal COVID-19 -a feature not observed in severe influenza. We conclude that fatal COVID-19 infection is driven by uncoordinated inflammatory responses that drive a hierarchy of T cell activation, elements of which can serve as prognostic indicators and potential targets for immune intervention.

Exploring a peer-based physical activity program in the community for adults with moderate-to-severe traumatic brain injury.

PRIMARY OBJECTIVE: To explore the experiences of program mentors, participants, and employees involved in a peer-based physical activity (PA) program for adults with moderate-to-severe TBI, being piloted by a community fitness center, to develop the program as a measurable intervention. RESEARCH DESIGN: We adopted an exploratory case study approach through an interpretivist paradigm, which focused on discovering realities about the peer-based PA program across the study participants' views, backgrounds, and experiences. METHODS AND PROCEDURES: Semi-structured focus groups and individual interviews were conducted with nine adult program participants (3 peer mentors, 6 participants), and three program employees. Inductive content analysis was used to develop themes about their perceived experiences. MAIN OUTCOMES AND RESULTS: 44 open-codes were grouped into 10 subthemes and three final themes: 1) program impacts identified the importance of the program in daily life and resulting psychological, physical, and social outcomes; 2) program characteristics highlighted program leaders, accessibility, and social inclusion; 3) program sustainability included program adherence, benefits for the center, and the program's future. CONCLUSIONS: Perceptions of program experiences and outcomes identified how peer-based PA for adults with moderate-to-severe TBI can lead to meaningful activities, functioning better, and buy-in from all parties. Implications for research and practice related to supporting health-related behaviors after TBI through group-based, autonomy-supporting approaches are discussed.

Continuous flow mechanochemistry: reactive extrusion as an enabling technology in organic synthesis.

Rapid and wide-ranging developments have established mechanochemistry as a powerful avenue in sustainable organic synthesis. This is primarily due to unique opportunities which have been offered in solvent-free - or highly solvent-minimised - reaction systems. Nevertheless, despite elegant advances in ball-milling technology, limitations in scale-up still remain. This tutorial review covers the first reports into the translation from "batch-mode" ball-milling to "flow-mode" reactive extrusion, using twin-screw extrusion.

Evolution of Solid Processing Methods in Continuous Flow Technology: Reactive Extrusion.

The frustrations of precipitation, fouling and blockages of liquid-based flow reactors is familiar to all researchers that have worked with continuous flow equipment. There have been many innovative solutions to try and circumvent this issue. This short review will highlight the emerging technique of mechanochemistry and reactive extrusion as a continuous process that can directly work on solid (and liquid) materials and elicit chemical transformations.

Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial.

BACKGROUND: Long-term loss of arm function after ischaemic stroke is common and might be improved by vagus nerve stimulation paired with rehabilitation. We aimed to determine whether this strategy is a safe and effective treatment for improving arm function after stroke. METHODS: In this pivotal, randomised, triple-blind, sham-controlled trial, done in 19 stroke rehabilitation services in the UK and the USA, participants with moderate-to-severe arm weakness, at least 9 months after ischaemic stroke, were randomly assigned (1:1) to either rehabilitation paired with active vagus nerve stimulation (VNS group) or rehabilitation paired with sham stimulation (control group). Randomisation was done by ResearchPoint Global (Austin, TX, USA) using SAS PROC PLAN (SAS Institute Software, Cary, NC, USA), with stratification by region (USA vs UK), age (≤30 years vs >30 years), and baseline Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score (20-35 vs 36-50). Participants, outcomes assessors, and treating therapists were masked to group assignment. All participants were implanted with a vagus nerve stimulation device. The VNS group received 0·8 mA, 100 µs, 30 Hz stimulation pulses, lasting 0·5 s. The control group received 0 mA pulses. Participants received 6 weeks of in-clinic therapy (three times per week; total of 18 sessions) followed by a home exercise programme. The primary outcome was the change in impairment measured by the FMA-UE score on the first day after completion of in-clinic therapy. FMA-UE response rates were also assessed at 90 days after in-clinic therapy (secondary endpoint). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, NCT03131960. FINDINGS: Between Oct 2, 2017, and Sept 12, 2019, 108 participants were randomly assigned to treatment (53 to the VNS group and 55 to the control group). 106 completed the study (one patient for each group did not complete the study). On the first day after completion of in-clinic therapy, the mean FMA-UE score increased by 5·0 points (SD 4·4) in the VNS group and by 2·4 points (3·8) in the control group (between group difference 2·6, 95% CI 1·0-4·2, p=0·0014). 90 days after in-clinic therapy, a clinically meaningful response on the FMA-UE score was achieved in 23 (47%) of 53 patients in the VNS group versus 13 (24%) of 55 patients in the control group (between group difference 24%, 6-41; p=0·0098). There was one serious adverse event related to surgery (vocal cord paresis) in the control group. INTERPRETATION: Vagus nerve stimulation paired with rehabilitation is a novel potential treatment option for people with long-term moderate-to-severe arm impairment after ischaemic stroke. FUNDING: MicroTransponder.

Continuous Flow Generation of Acylketene Intermediates via Nitrogen Extrusion.

A flow chemistry process for the generation and use of acylketene precursors through extrusion of nitrogen gas is reported. Key to the development of a suitable continuous protocol is the balance of reaction concentration against pressure in the flow reactor. The resulting process enables access to intercepted acylketene scaffolds using volatile amine nucleophiles and has been demonstrated on the gram scale. Thermal gravimetric analysis was used to guide the temperature set point of the reactor coils for a variety of acyl ketene precursors. The simultaneous generation and reaction of two reactive intermediates (both derived from nitrogen extrusion) is demonstrated.

Silicon photonics 2 × 2 trench coupler design and foundry fabrication.

A 2×2 photonic coupler is realized at the intersection of two 480nm×220nm silicon on insulator waveguides. The designed 2×2 coupler is simulated in both High Frequency Simulator System (HFSS) and Lumerical and shows an equal split of an input signal into transmitted and reflected signals for a 45 deg, ∼100nmSiO2 filled trench. The principle of operation of the coupler is frustrated total internal reflection. Thus, this behavior is reasonably flat across wavelength, which is confirmed by Lumerical simulations and by experiment. Also, it has been shown that this coupler has a flat behavior across trench thickness for the chosen geometry and material system, which makes it insensitive to fabrication variation and resolution. We are interested to make this coupler a part of silicon photonic foundry process development kits. Therefore, fabrication is done at the AIM Photonics Foundry to study the performance in the context of the foundry's design rules and process flow of the foundry. Good agreement between theory and experiment is reported herein. A 2×2 trench coupler is, when operated in the single photon or quantum regime, an integrated photonic realization of a Hadamard gate.

Analgesia for retinopathy of prematurity screening: A systematic review.

BACKGROUND AND AIMS: Premature neonates require regular ophthalmological examination, generally indirect ophthalmoscopy, to screen for retinopathy of prematurity (ROP). Conventional analgesia is provided with topical anesthetic eyedrops and oral sugar solution, but neonates still experience significant pain. Here, the literature base was examined to evaluate the usefulness of other pharmacological analgesics. MATERIALS AND METHODS: A systematic review was undertaken, adhering to a PROSPERO preregistered protocol in accordance with PRISMA guidelines (identifier CRD42022302459). Electronic databases were searched for primary research articles on pharmacological pain interventions used for ROP screening in neonates. The primary outcome measure was pain scores recorded using validated pain scoring tools, with and without pharmacological interventions in neonates during eye examination. For analysis, studies were separated into two categories: topical anesthesia and alternative pharmacological treatments. RESULTS: Eleven studies met the inclusion criteria. Topical analgesia, oral paracetamol, and intranasal fentanyl were found to be effective in reducing the pain of eye examination. Oral morphine and inhaled nitrous oxide had no significant effect on premature infant pain profile (PIPP) scores during indirect ophthalmoscopy. DISCUSSION: In addition to topical anesthesia, premedication with oral paracetamol is recommended during screening examination for ROP. The routine use of fentanyl is not recommended due to the risk of potential side effects. Non-pharmacological measures, such as sweet oral solutions and comfort techniques should also be employed. Further research is required to determine whether the use of nitrous oxide has a role, and to develop a safe and effective analgesic strategy to fully ameliorate the pain of ROP screening.

Challenges Arising from Continuous-Flow Olefin Metathesis.

The versatility of olefin metathesis is evident from its successful applications ranging from natural product synthesis to the valorization of renewable feedstocks. On the other side, flow chemistry has recently gained particular interest among the synthetic community, offering valuable alternatives to classic batch chemistry and paving the way to the development of new transformations. The application of continuous-flow methods to olefin metathesis represents one of the most promising evolutions in the field at the interface of industrially relevant synthesis and reactor engineering, significantly improving some of the typical problems such as undesired self-reactions and ethylene-mediated catalyst deactivation. This Minireview aims to provide a brief survey covering the major aspects of those techniques which we hope may be of interest for the chemical community as well as those interested in catalysis, continuous processing, enabling technologies and reactor design.

Mechanoredox Chemistry as an Emerging Strategy in Synthesis.

Recent research endeavors have established that the mechanochemical activation of piezoelectric materials can open new avenues in redox chemistry. Impact forces, such as those imparted by a ball mill, have been shown to transform piezoelectric materials such as barium titanate (BaTiO3 ) into a highly polarized state, which can then donate an electron to a suitable oxidant and receive an electron from a suitable reductant, mimicking established photoredox catalytic cycles. Proof-of-concept studies have elucidated that mechanoredox chemistry holds great potential in sustainable and efficient radical-based synthesis.

Solvent-Minimized Synthesis of 4CzIPN and Related Organic Fluorophores via Ball Milling.

The mechanochemical synthesis of 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile and related organic fluorophores/photocatalysts via a solvent-minimized four-fold SNAr pathway is herein described. Employing sodium tert-butoxide as base, and negating the need for any air/moisture-sensitive reaction set-ups, a selection of organic dyes was synthesized in just 1 h using this ball-milling technique. Furthermore, the transformation was then showcased on a multigram scale.