A young male with non-resolving consolidation and hepatosplenomegaly.

ABSTRACT: Non-resolving consolidation refers to the persistence of radiographic abnormalities beyond the anticipated timeframe. Conditions such as infection, malignancy, inflammatory disorders, and connective tissue diseases can all manifest as non-resolving consolidation. We share a clinicopathological case study involving a 30-year-old male who exhibits non-resolving consolidation accompanied by hepatosplenomegaly.

Semantic encoding during language comprehension at single-cell resolution.

From sequences of speech sounds1,2 or letters3, humans can extract rich and nuanced meaning through language. This capacity is essential for human communication. Yet, despite a growing understanding of the brain areas that support linguistic and semantic processing4-12, the derivation of linguistic meaning in neural tissue at the cellular level and over the timescale of action potentials remains largely unknown. Here we recorded from single cells in the left language-dominant prefrontal cortex as participants listened to semantically diverse sentences and naturalistic stories. By tracking their activities during natural speech processing, we discover a fine-scale cortical representation of semantic information by individual neurons. These neurons responded selectively to specific word meanings and reliably distinguished words from nonwords. Moreover, rather than responding to the words as fixed memory representations, their activities were highly dynamic, reflecting the words' meanings based on their specific sentence contexts and independent of their phonetic form. Collectively, we show how these cell ensembles accurately predicted the broad semantic categories of the words as they were heard in real time during speech and how they tracked the sentences in which they appeared. We also show how they encoded the hierarchical structure of these meaning representations and how these representations mapped onto the cell population. Together, these findings reveal a finely detailed cortical organization of semantic representations at the neuron scale in humans and begin to illuminate the cellular-level processing of meaning during language comprehension.

Dosimetric Comparison of Dedicated Radiosurgery Platforms for the Treatment of Essential Tremor: Technical Report.

Essential tremor (ET) is one of the most common adult movement disorders. As the worldwide population ages, the incidence and prevalence of ET is increasing. Although most cases can be managed conservatively, there is a subset of ET that is refractory to medical management. By virtue of being "reversible", deep brain stimulation (DBS) of the ventral intermediate nucleus (VIM) of the thalamus is one commonly accepted intervention. As an alternative to invasive and expensive DBS, there has been a renaissance in treating ET with lesion-based approaches, spearheaded most recently by high-intensity focused ultrasound (HIFU), the hallmark of which is that it is non-invasive. Meanwhile, stereotactic radiosurgical (SRS) lesioning of VIM represents another time-honored lesion-based non-invasive treatment of ET, which is especially well suited for those patients that cannot tolerate open neurosurgery and is now also getting a "second look". While multiple SRS platforms have been and continue to be used to treat ET, there is little in the way of dosimetric comparison between different technologies. In this brief technical report we compare the dosimetric profiles of three major radiosurgical platforms (Gamma Knife, CyberKnife Robotic Radiosurgery, and Zap-X Gyroscopic Radiosurgery (GRS)) for the treatment of ET. In general, the GRS and Gamma Knife were shown to have the best theoretical dosimetric profiles for VIM lesioning. Nevertheless the relevance of such superiority to clinical outcomes requires future patient studies.

Swiss Cheese Trachea: An Unwarranted, Unique Form of Post-intubation Tracheal Stenosis.

How to cite this article: Bajad P, Pahuja S, Agarwal S, Khanna A. Swiss Cheese Trachea: An Unwarranted, Unique Form of Post-intubation Tracheal Stenosis. Indian J Crit Care Med 2024;28(1):84-85.

Single-neuronal elements of speech production in humans.

Humans are capable of generating extraordinarily diverse articulatory movement combinations to produce meaningful speech. This ability to orchestrate specific phonetic sequences, and their syllabification and inflection over subsecond timescales allows us to produce thousands of word sounds and is a core component of language1,2. The fundamental cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh-density Neuropixels recordings capable of sampling across the cortical column in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events before utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also accurately predicted the phonetic, syllabic and morphological components of upcoming words and showed a temporally ordered dynamic. Collectively, we show how these mixtures of cells are broadly organized along the cortical column and how their activity patterns transition from articulation planning to production. We also demonstrate how these cells reliably track the detailed composition of consonant and vowel sounds during perception and how they distinguish processes specifically related to speaking from those related to listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and demonstrate a cellular process that can support the production of speech.

Human genetics and molecular genomics of Chiari malformation type 1.

Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.

Modified Neuropixels probes for recording human neurophysiology in the operating room.

Neuropixels are silicon-based electrophysiology-recording probes with high channel count and recording-site density. These probes offer a turnkey platform for measuring neural activity with single-cell resolution and at a scale that is beyond the capabilities of current clinically approved devices. Our team demonstrated the first-in-human use of these probes during resection surgery for epilepsy or tumors and deep brain stimulation electrode placement in patients with Parkinson's disease. Here, we provide a better understanding of the capabilities and challenges of using Neuropixels as a research tool to study human neurophysiology, with the hope that this information may inform future efforts toward regulatory approval of Neuropixels probes as research devices. In perioperative procedures, the major concerns are the initial sterility of the device, maintaining a sterile field during surgery, having multiple referencing and grounding schemes available to de-noise recordings (if necessary), protecting the silicon probe from accidental contact before insertion and obtaining high-quality action potential and local field potential recordings. The research team ensures that the device is fully operational while coordinating with the surgical team to remove sources of electrical noise that could otherwise substantially affect the signals recorded by the sensitive hardware. Prior preparation using the equipment and training in human clinical research and working in operating rooms maximize effective communication within and between the teams, ensuring high recording quality and minimizing the time added to the surgery. The perioperative procedure requires ~4 h, and the entire protocol requires multiple weeks.

Photosealing of dural defects using a biocompatible patch.

PURPOSE: Photosealing of many biological tissues can be achieved using a biocompatible material in combination with a dye that is activated by visible light to chemically bond over the tissue defect via protein cross-linking reactions. The aim of this study was to test the efficacy of photosealing using a commercially available biomembrane (AmnioExcel Plus) to securely close dural defects in comparison to another sutureless method (fibrin glue) in terms of repair strength. METHODS: Two-millimeter diameter holes were created in dura harvested from New Zealand white rabbits and repaired ex vivo using one of two methods: (1) in n = 10 samples, photosealing was used to bond a 6-mm-diameter AmnioExcel Plus patch over the dural defect, and (2) in n = 10 samples, fibrin glue was used to attach the same patch over the dural defect. Repaired dura samples were then subjected to burst pressure testing. Histological analysis was also performed of photosealed dura. RESULTS: The mean burst pressures of rabbit dura repaired with photosealing and fibrin glue were 302 ± 149 mmHg and 26 ± 24 mmHg, respectively. The increased repair strength using photosealing was statistically significant and considerably higher than the normal intracranial pressure of ~ 20 mmHg. Histology demonstrated a tight union at the interface between the dura surface and patch with no disruption of the dura structure. CONCLUSION: The results of this study suggest that photosealing performs better than fibrin glue for the fixation of a patch for ex vivo repair of small dural defects. Photosealing is worthy of testing in pre-clinical models for the repair of dural defects.

INDIan Consensus on the mAnagemenT of cOugh at pRimary care setting (INDICATOR).

BACKGROUND: Cough has a prevalence of 9.6% globally and 5-10% in India. Though it is a reflex action, it affects an individual's quality of life (QoL) when uncontrolled. There was a need to create an integrated guidance document on managing cough focused on primary care physicians in the Indian setting. This consensus intends to bridge this gap by providing clinical recommendations to diagnose and manage cough in primary healthcare in India. MATERIALS AND METHODS: The modified Delphi method was used to arrive at a consensus on clinical statements. The panel comprised 10 experts, including pulmonologists, otolaryngologists, a pediatrician, and a general physician. The statements were discussed under the following domains: definition, etiology, diagnosis, and treatment. RESULTS: A total of 109 clinical statements were framed, with 75 reaching consensus, 13 reaching near consensus, and 21 reaching no consensus. The experts recommended empiric use of nonopioid antitussive agents for symptomatic relief of acute dry cough. The use of oral antihistamines, oral decongestants, or mucoactive agents as a part of fixed-dose combinations (FDCs) in cough associated with rhinitis or upper airway cough syndrome (UACS) can be considered for symptomatic relief. Maintaining good hydration is important to manage a productive cough. Codeine-based preparations are to be considered as a last resort in patients with an unexplained chronic cough when other treatments have failed. Additionally, insights were captured on red flag signs, nonpharmacologic therapy, special populations, and referral to higher centers. Experts have also proposed a management algorithm with an integrated care pathway approach for acute, subacute, and chronic coughs. CONCLUSION: The present consensus fills the existing need and may guide the physician to successfully diagnose and manage cough in the primary healthcare setting in India.

Doxycycline for the prevention of progression of COVID-19 to severe disease requiring intensive care unit (ICU) admission: A randomized, controlled, open-label, parallel group trial (DOXPREVENT.ICU).

BACKGROUND: After admission to hospital, COVID-19 progresses in a substantial proportion of patients to critical disease that requires intensive care unit (ICU) admission. METHODS: In a pragmatic, non-blinded trial, 387 patients aged 40-90 years were randomised to receive treatment with SoC plus doxycycline (n = 192) or SoC only (n = 195). The primary outcome was the need for ICU admission as judged by the attending physicians. Three types of analyses were carried out for the primary outcome: "Intention to treat" (ITT) based on randomisation; "Per protocol" (PP), excluding patients not treated according to randomisation; and "As treated" (AT), based on actual treatment received. The trial was undertaken in six hospitals in India with high-quality ICU facilities. An online application serving as the electronic case report form was developed to enable screening, randomisation and collection of outcomes data. RESULTS: Adherence to treatment per protocol was 95.1%. Among all 387 participants, 77 (19.9%) developed critical disease needing ICU admission. In all three primary outcome analyses, doxycycline was associated with a relative risk reduction (RRR) and absolute risk reduction (ARR): ITT 31.6% RRR, 7.4% ARR (P = 0.063); PP 40.7% RRR, 9.6% ARR (P = 0.017); AT 43.2% RRR, 10.8% ARR (P = 0.007), with numbers needed to treat (NTT) of 13.4 (ITT), 10.4 (PP), and 9.3 (AT), respectively. Doxycycline was well tolerated with not a single patient stopping treatment due to adverse events. CONCLUSIONS: In hospitalized COVID-19 patients, doxycycline, a safe, inexpensive, and widely available antibiotic with anti-inflammatory properties, reduces the need for ICU admission when added to SoC.

Clinical outcomes of bronchiectasis in India: data from the EMBARC/Respiratory Research Network of India registry.

BACKGROUND: Identifying risk factors for poor outcomes can help with risk stratification and targeting of treatment. Risk factors for mortality and exacerbations have been identified in bronchiectasis but have been almost exclusively studied in European and North American populations. This study investigated the risk factors for poor outcome in a large population of bronchiectasis patients enrolled in India. METHODS: The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) and Respiratory Research Network of India (EMBARC-India) registry is a prospective observational study of adults with computed tomography-confirmed bronchiectasis enrolled at 31 sites across India. Baseline characteristics of patients were used to investigate associations with key clinical outcomes: mortality, severe exacerbations requiring hospital admission, overall exacerbation frequency and decline in forced expiratory volume in 1 s. RESULTS: 1018 patients with at least 12-month follow-up data were enrolled in the follow-up study. Frequent exacerbations (≥3 per year) at baseline were associated with an increased risk of mortality (hazard ratio (HR) 3.23, 95% CI 1.39-7.50), severe exacerbations (HR 2.71, 95% CI 1.92-3.83), future exacerbations (incidence rate ratio (IRR) 3.08, 95% CI 2.36-4.01) and lung function decline. Coexisting COPD, dyspnoea and current cigarette smoking were similarly associated with a worse outcome across all end-points studied. Additional predictors of mortality and severe exacerbations were increasing age and cardiovascular comorbidity. Infection with Gram-negative pathogens (predominantly Klebsiella pneumoniae) was independently associated with increased mortality (HR 3.13, 95% CI 1.62-6.06), while Pseudomonas aeruginosa infection was associated with severe exacerbations (HR 1.41, 95% CI 1.01-1.97) and overall exacerbation rate (IRR 1.47, 95% CI 1.13-1.91). CONCLUSIONS: This study identifies risk factors for morbidity and mortality among bronchiectasis patients in India. Identification of these risk factors may support treatment approaches optimised to an Asian setting.

Perceptions and Attitudes of Patients and Their Family Caregivers on Nebulization Therapy for COPD.

Purpose: The aim of the survey was to evaluate attitudes and perceptions toward nebulization therapy for the management of chronic obstructive pulmonary disease (COPD) in Indian population. Patients and methods: A cross-sectional, multicenter, quantitative survey was conducted from July to August 2019 among 103 COPD patients [>40 years, either gender, belonging to socio-economic class (SEC) A or SEC B] and their family caregivers. One-on-one interviews were conducted telephonically via an online survey platform (KoBo data collection tool) using a structured questionnaire. Patients receiving home nebulization were included, and the usage of nebulizers, satisfaction, and benefits and concerns with nebulizers were assessed. Results: Overall, 47% patients were on handheld inhalers + nebulizer, 54% used nebulizer for >8 weeks, and 27% used nebulizers daily for home maintenance. Majority of the patients (77%) were satisfied with nebulization therapy. Around 70% family caregivers opined that the quality of life of COPD patients improved post-nebulization therapy. The benefits of nebulizers perceived by patients were easier breathing (89%), feeling of well-being (86%), and ease of use (86%), while family caregivers reported reduced hospitalization (76%) and easier breathing (75%). Among those with prior experience with inhalers, 72% felt nebulizers gave long-term relief, while 65% perceived having immediate relief compared to inhaler. Overall, 61% opined that benefits with nebulizers outweighed the inconvenience associated with its use. Key concerns regarding nebulizers cited by patients were time-consuming procedure (50%), feeling of dependency (49%), and social embarrassment (48%), while family caregivers highlighted social embarrassment (45%) and multiple daily use (45%) as major concerns. Majority of the patients (73%) were compliant with their recommended frequency of the nebulizer. Conclusion: This first-of-its-kind survey highlights that the majority of patients and family caregivers were satisfied with nebulizers and reported improvements in symptoms and reduced hospitalizations with nebulizer therapy. The patients preferred nebulized therapy to inhalers.

Large-scale neural recordings with single neuron resolution using Neuropixels probes in human cortex.

Recent advances in multi-electrode array technology have made it possible to monitor large neuronal ensembles at cellular resolution in animal models. In humans, however, current approaches restrict recordings to a few neurons per penetrating electrode or combine the signals of thousands of neurons in local field potential (LFP) recordings. Here we describe a new probe variant and set of techniques that enable simultaneous recording from over 200 well-isolated cortical single units in human participants during intraoperative neurosurgical procedures using silicon Neuropixels probes. We characterized a diversity of extracellular waveforms with eight separable single-unit classes, with differing firing rates, locations along the length of the electrode array, waveform spatial spread and modulation by LFP events such as inter-ictal discharges and burst suppression. Although some challenges remain in creating a turnkey recording system, high-density silicon arrays provide a path for studying human-specific cognitive processes and their dysfunction at unprecedented spatiotemporal resolution.

Single inhaler triple therapy in COPD - all that glitters is not gold.

Dear Editor, The recent studies on combination triple therapy of inhaled corticosteroid, long acting beta2 agonist and long-acting muscarinic antagonist (ICS-LABA-LAMA) in COPD have consistently demonstrated an improvement in exacerbation frequency and/or improvement of lung function...

Implications of Managing Chronic Obstructive Pulmonary Disease in Cardiovascular Diseases.

Globally, cardiovascular diseases and chronic obstructive pulmonary disease (COPD) are the leading causes of the noncommunicable disease burden. Overlapping symptoms such as breathing difficulty and fatigue, with a lack of awareness about COPD among physicians, are key reasons for under-diagnosis and resulting sub-optimal care relative to COPD. Much has been published in the past on the pathogenesis and implications of cardiovascular comorbidities in COPD. However, a comprehensive review of the prevalence and impact of COPD management in commonly encountered cardiac diseases is lacking. The purpose of this study was to summarize the current knowledge regarding the prevalence of COPD in heart failure, ischemic heart disease, and atrial fibrillation. We also discuss the real-life clinical presentation and practical implications of managing COPD in cardiac diseases. We searched PubMed, Scopus, EMBASE, and Google Scholar for studies published 1981-May 2020 reporting the prevalence of COPD in the three specified cardiac diseases. COPD has high prevalence in heart failure, atrial fibrillation, and ischemic heart disease. Despite this, COPD remains under-diagnosed and under-managed in the majority of patients with cardiac diseases. The clinical implications of the diagnosis of COPD in cardiac disease includes the recognition of hyperinflation (a treatable trait), implementation of acute exacerbations of COPD (AECOPD) prevention strategies, and reducing the risk of overuse of diuretics. The pharmacological agents for the management of COPD have shown a beneficial effect on cardiac functions and mortality. The appropriate management of COPD improves the cardiovascular outcomes by reducing hyperinflation and preventing AECOPD, thus reducing the risk of mortality, improving exercise tolerance, and quality of life.