Dual Basicity and Nucleophilicity of Organosodium Reagents in Benzylic C-H Additions of Toluenes to Diarylethenes and Ketones.

Profiting from the dual high basicity and nucleophilicity of organosodium complexes, here we report the stepwise lateral metalation of a wide range of alkyl arenes (MeAr), mediated by hydrocarbon-soluble NaCH2SiMe3 ⋅ PMDETA (PMDETA=N,N,N',N'',N''-pentamethyldiethylenetriamine), followed by nucleophilic addition to diarylethenes of the newly generated NaCH2Ar ⋅ PMDETA complexes. This method grants access to a range of functionalised hydrocarbons in excellent yields and can be upgraded to catalytic regimes when using trans-stilbene, a 10 mol% of the alkyl sodium base and toluene as a solvent. Extending this approach to aromatic ketones leads to the formation of stilbenes under mild reaction conditions, resulting from the deprotonative coupling of toluenes with ketones. Combining spectroscopic studies with the trapping and characterisation of key reaction intermediates, mechanistic insights have been gained, advancing the understanding of coordination effects in organosodium chemistry, and shedding light on their special reactivity profiles.

Mild antecedent COVID-19 associated with symptom-specific post-acute sequelae.

BACKGROUND: The impact of COVID-19 severity on development of long-term sequelae remains unclear, and symptom courses are not well defined. METHODS: This ambidirectional cohort study recruited adults with new or worsening symptoms lasting ≥3 weeks from confirmed SARS-CoV-2 infection between August 2020-December 2021. COVID-19 severity was defined as severe for those requiring hospitalization and mild for those not. Symptoms were collected using standardized questionnaires. Multivariable logistical regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between clinical variables and symptoms. RESULTS: Of 332 participants enrolled, median age was 52 years (IQR 42-62), 233 (70%) were female, and 172 (52%) were African American. Antecedent COVID-19 was mild in 171 (52%) and severe in 161 (48%). In adjusted models relative to severe cases, mild COVID-19 was associated with greater odds of fatigue (OR:1.83, CI:1.01-3.31), subjective cognitive impairment (OR:2.76, CI:1.53-5.00), headaches (OR:2.15, CI:1.05-4.44), and dizziness (OR:2.41, CI:1.18-4.92). Remdesivir treatment was associated with less fatigue (OR:0.47, CI:0.26-0.86) and fewer participants scoring >1.5 SD on PROMIS Cognitive scales (OR:0.43, CI:0.20-0.92). Fatigue and subjective cognitive impairment prevalence was higher 3-6 months after COVID-19 and persisted (fatigue OR:3.29, CI:2.08-5.20; cognitive OR:2.62, CI:1.67-4.11). Headache was highest at 9-12 months (OR:5.80, CI:1.94-17.3). CONCLUSIONS: Mild antecedent COVID-19 was associated with highly prevalent symptoms, and those treated with remdesivir developed less fatigue and cognitive impairment. Sequelae had a delayed peak, ranging 3-12 months post infection, and many did not improve over time, underscoring the importance of targeted preventative measures.

Cell lineage analysis with somatic mutations reveals late divergence of neuronal cell types and cortical areas in human cerebral cortex.

The mammalian cerebral cortex shows functional specialization into regions with distinct neuronal compositions, most strikingly in the human brain, but little is known in about how cellular lineages shape cortical regional variation and neuronal cell types during development. Here, we use somatic single nucleotide variants (sSNVs) to map lineages of neuronal sub-types and cortical regions. Early-occurring sSNVs rarely respect Brodmann area (BA) borders, while late-occurring sSNVs mark neuron-generating clones with modest regional restriction, though descendants often dispersed into neighboring BAs. Nevertheless, in visual cortex, BA17 contains 30-70% more sSNVs compared to the neighboring BA18, with clones across the BA17/18 border distributed asymmetrically and thus displaying different cortex-wide dispersion patterns. Moreover, we find that excitatory neuron-generating clones with modest regional restriction consistently share low-mosaic sSNVs with some inhibitory neurons, suggesting significant co-generation of excitatory and some inhibitory neurons in the dorsal cortex. Our analysis reveals human-specific cortical cell lineage patterns, with both regional inhomogeneities in progenitor proliferation and late divergence of excitatory/inhibitory lineages.

Technology to enhance physical rehabilitation of critically ill patients.

BACKGROUND: Neuromuscular complications after critical illness are common and can be severe and persistent. To ameliorate complications, there is growing interest in starting physical medicine and rehabilitation therapy immediately after physiologic stabilization. The introduction of physical medicine and rehabilitation-related technology into the intensive care unit may help facilitate delivery of this therapy. DISCUSSION: Neuromuscular electrical stimulation therapy creates passive contraction of muscles through low-voltage electrical impulses delivered through skin electrodes placed over target muscles. Although neuromuscular electrical stimulation has not been studied in patients with acute critical illness, published guidelines based on available evidence suggest that neuromuscular electrical stimulation may be considered in intensive care unit patients who are at high risk of developing muscle weakness. Bedside cycle ergometry can provide range of motion and muscle strength training for intensive care unit patients who are either sedated or awake, and may help preserve muscle architecture and improve strength and function. Finally, custom-designed technological aids to assist with ambulating mechanically ventilated patients may reduce the human resource requirements and improve the safety and effectiveness of early mobilization in the intensive care unit. CONCLUSION: Physical medicine and rehabilitation-related technologies may play an important role in preventing and treating intensive care unit-acquired neuromuscular complications. Future studies are needed to evaluate their efficacy in intensive care unit patients.

Bench-to-bedside review: mobilizing patients in the intensive care unit--from pathophysiology to clinical trials.

As the mortality from critical illness has improved in recent years, there has been increasing focus on patient outcomes after hospital discharge. Neuromuscular weakness acquired in the intensive care unit (ICU) is common, persistent, and often severe. Immobility due to prolonged bed rest in the ICU may play an important role in the development of ICU-acquired weakness. Studies in other patient populations have demonstrated that moderate exercise is beneficial in altering the inflammatory milieu associated with immobility, and in improving muscle strength and physical function. Recent studies have demonstrated that early mobility in the ICU is safe and feasible, with a potential reduction in short-term physical impairment. However, early mobility requires a significant change in ICU practice, with reductions in heavy sedation and bed rest. Further research is required to determine whether early mobility in the ICU can improve patients' short-term and long-term outcomes.

Method for depth-resolved quantitation of optical properties in layered media using spatially modulated quantitative spectroscopy.

We have demonstrated that spatially modulated quantitative spectroscopy (SMoQS) is capable of extracting absolute optical properties from homogeneous tissue simulating phantoms that span both the visible and near-infrared wavelength regimes. However, biological tissue, such as skin, is highly structured, presenting challenges to quantitative spectroscopic techniques based on homogeneous models. In order to more accurately address the challenges associated with skin, we present a method for depth-resolved optical property quantitation based on a two layer model. Layered Monte Carlo simulations and layered tissue simulating phantoms are used to determine the efficacy and accuracy of SMoQS to quantify layer specific optical properties of layered media. Initial results from both the simulation and experiment show that this empirical method is capable of determining top layer thickness within tens of microns across a physiological range for skin. Layer specific chromophore concentration can be determined to <±10% the actual values, on average, whereas bulk quantitation in either visible or near infrared spectroscopic regimes significantly underestimates the layer specific chromophore concentration and can be confounded by top layer thickness.

Inter-rater reliability of manual muscle strength testing in ICU survivors and simulated patients.

OBJECTIVE: The goal of the paper is to determine inter-rater reliability of trained examiners performing standardized strength assessments using manual muscle testing (MMT). DESIGN, SUBJECTS, AND SETTING: The authors report on 19 trainees undergoing quality assurance within a multi-site prospective cohort study. INTERVENTION: Inter-rater reliability for specially trained evaluators ("trainees") and a reference rater, performing MMT using both simulated and actual patients recovering from critical illness was evaluated. MEASUREMENTS AND RESULTS: Across 26 muscle groups tested by 19 trainee-reference rater pairs, the median (interquartile range) percent agreement and intraclass correlation coefficient (ICC; 95% CI) were: 96% (91, 98%) and 0.98 (0.95, 1.00), respectively. Across all 19 pairs, the ICC (95% CI) for the overall composite MMT score was 0.99 (0.98-1.00). When limited to actual patients, the ICC was 1.00 (95% CI 0.99-1.00). The agreement (kappa; 95% CI) in detecting clinically significant weakness was 0.88 (0.44-1.00). CONCLUSIONS: MMT has excellent inter-rater reliability in trained examiners and is a reliable method of comprehensively assessing muscle strength.