Role of central endpoint adjudication and challenges in trials on neonatal sepsis-a case of ProSPoNS trial.

Despite progress in reducing the infant mortality in India, the neonatal mortality decline has been slower, necessitating concerted efforts to achieve Sustainable Development Goal-3. A promising strategy aiming to prevent neonatal sepsis in high-risk, vulnerable, low birth weight neonates through an innovative intervention includes probiotic supplementation. This article communicates the decision by the ProSPoNS trial investigators to establish a Central Endpoint Adjudication Committee (CEAC) as an addendum to the protocol published in Trials in 2021 for the purpose of clarifying the primary outcome. In the published protocol, the study hypothesis and primary objective are based on "sepsis," the primary outcome has been specified as sepsis/PSBI, whereas the sample size estimation was performed based on the "physician diagnosed sepsis." To align all the three above, the investigators meeting, held on 17th-18th August 2023, at MGIMS Sevagram, Wardha, deliberated and unanimously agreed that "physician diagnosed sepsis" is the primary study outcome which includes sepsis/PSBI. The CEAC, chaired by an external subject expert and members including trial statistician, a microbiologist, and all site principal investigators will employ four criteria to determine "physician diagnosed sepsis": (1) blood culture status, (2) sepsis screen status, (3) PSBI/non-PSBI signs and symptoms, and (4) the clinical course for each sickness event. Importantly, this clarification maintains consistency with the approved study protocol (Protocol No. 5/7/915/2012 version 3.1 dated 14 Feb 2020), emphasizing the commitment to methodological transparency and adherence to predefined standards. The decision to utilize the guidance of a CEAC is recommended as the gold standard in multicentric complex clinical trials to achieve consistency and accuracy in assessment of outcomes.Trial registrationClinical Trial Registry of India (CTRI) CTRI/2019/05/019197. Registered on 16 May 2019.

Solar-Powered Gram-Scale Ammonia Production from Nitrate.

The photoelectrochemical (PEC) method has the potential to be an attractive route for converting and storing solar energy as chemical bonds. In this study, a maximum NH3 production yield of 1.01 g L-1 with a solar-to-ammonia conversion efficiency of 8.17% through the photovoltaic electrocatalytic (PV-EC) nitrate (NO3 -) reduction reaction (NO3 -RR) is achieved, using silicon heterojunction solar cell technology. Additionally, the effect of tuning the operation potential of the PV-EC system and its influence on product selectivity are systematically investigated. By using this unique external resistance tuning approach in the PV-EC system, ammonia production through nitrate reduction performance from 96 to 360 mg L-1 is enhanced, a four-fold increase. Furthermore, the NH3 is extracted as NH4Cl powder using acid stripping, which is essential for storing chemical energy. This work demonstrates the possibility of tuning product selectivity in PV-EC systems, with prospects toward pilot scale on value-added product synthesis.

The functional lumen imaging probe contractile response pattern is the best predictor of botulinum toxin response in esophagogastric junction outflow obstruction.

BACKGROUND: Esophagogastric junction outflow obstruction (EGJOO) is a heterogenous disorder in which the correct management strategy is unclear. We assessed whether functional lumen imaging probe (FLIP) topography data could select EGJOO, which would benefit from lower esophageal sphincter Botulinum toxin (Botox) injection. METHODS: This was a single-center prospective study of adult patients meeting Chicago Classification (CC) v3.0 criteria for EGJOO. We assessed differences in pretreatment physiologic measurements on high-resolution manometry (HRM) and FLIP and other relevant clinical variables in predicting Botox response (>50% in BEDQ at 2 months). KEY RESULTS: Sixty-nine patients were included (ages 33-90, 73.9% female). Of these, 42 (61%) were Botox responders. Majority of physiologic measures on HRM and FLIP and esophageal emptying were not different based on Botox response. However, a spastic-reactive (SR) FLIP contractile response (CR) pattern predicted a Botox response with OR 25.6 (CI 2.9-229.6) when compared to antegrade FLIP CR; and OR for impaired-disordered/absent CR was 22.5 (CI 2.5-206.7). Logistic regression model using backward elimination (p value = 0.0001, AUC 0.79) showed that a SRCR or IDCR/absent response and the upright IRP predicted Botox response. Response rates in tiered diagnostic groups were: (i) CCv3.0 EGJOO (60.9%), (ii) CCv4.0 EGJOO (73.1%), (iii) CCv4.0 + FLIP REO (80%), (iv) CCv4.0, FLIP REO, and abnormal FLIP CR (84.2%), and (v) CCv4.0, FLIP REO, and SR FLIP CR (90%). CONCLUSIONS AND INFERENCES: FLIP helps identify patients with EGJOO who are likely to response to LES Botox therapy. An abnormal FLIP contractile response pattern is the single-most important predictor of a Botox response.

Efficacy of dexamethasone implant in the management of chronic central serous chorioretinopathy without choroidal neovascularization.

PURPOSE: To demonstrate the treatment efficacy of intravitreal dexamethasone (DEX) implant in chronic recurrent/persistent central serous chorioretinopathy (CSC). DESIGN: Prospective, non-randomized, open-label study. METHODS: In this study, subjects with chronic CSC without signs of choroidal neovascularization (CNV) received intravitreal DEX implant therapy. The primary outcome measure was the change in visual acuity. Changes in central macular thickness (CMT) and change in subfoveal choroidal thickness (SFCT) on optical coherence tomography (OCT), incidence of recurrent fluid, and safety of DEX implant were secondary outcome measures. Subjects were followed up for a minimum of 3 months after DEX implantation. RESULTS: In total, 20 eyes of 20 subjects (mean age: 47 ± 9 years) with a median disease duration of 23.5 months were enrolled. With a single injection of DEX implant, a reduction in CMT was noted in 90% of eyes. Complete resolution of subretinal and intraretinal fluid was noted in 55% of eyes within 3 months of injection. A significant improvement in vision (mean Log MAR visual acuity 0.66 ± 0.49 vs. 0.54 ± 0.45; P = 0.020), mean CMT (338 ± 110 microns to 238 ± 73 microns; P < 0.001) and SFCT (514 ± 95 microns to 445 ± 111 microns; P < 0.001) was noted over 3 months. Recurrent fluid was noted in 50% of eyes after a mean follow-up duration of 7 ± 4 months. Elevated intraocular pressure, managed by topical therapy, was noted in six eyes. CONCLUSION: The consistent improvement in visual acuity, fluid resolution, and reduction in choroidal thickness suggests a possible role for DEX implants in managing chronic CSC. A larger randomized trial is warranted.

The Spatial Extracellular Proteomic Tumor Microenvironment Distinguishes Molecular Subtypes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) mortality rates continue to increase faster than those of other cancer types due to high heterogeneity, which limits diagnosis and treatment. Pathological and molecular subtyping have identified that HCC tumors with poor outcomes are characterized by intratumoral collagenous accumulation. However, the translational and post-translational regulation of tumor collagen, which is critical to the outcome, remains largely unknown. Here, we investigate the spatial extracellular proteome to understand the differences associated with HCC tumors defined by Hoshida transcriptomic subtypes of poor outcome (Subtype 1; S1; n = 12) and better outcome (Subtype 3; S3; n = 24) that show differential stroma-regulated pathways. Collagen-targeted mass spectrometry imaging (MSI) with the same-tissue reference libraries, built from untargeted and targeted LC-MS/MS was used to spatially define the extracellular microenvironment from clinically-characterized, formalin-fixed, paraffin-embedded tissue sections. Collagen α-1(I) chain domains for discoidin-domain receptor and integrin binding showed distinctive spatial distribution within the tumor microenvironment. Hydroxylated proline (HYP)-containing peptides from the triple helical regions of fibrillar collagens distinguished S1 from S3 tumors. Exploratory machine learning on multiple peptides extracted from the tumor regions could distinguish S1 and S3 tumors (with an area under the receiver operating curve of ≥0.98; 95% confidence intervals between 0.976 and 1.00; and accuracies above 94%). An overall finding was that the extracellular microenvironment has a high potential to predict clinically relevant outcomes in HCC.

Efficient biodegradation of Polyethylene terephthalate (PET) plastic by Gordonia sp. CN2K isolated from plastic contaminated environment.

Since we rely entirely on plastics or their products in our daily lives, plastics are the invention of the hour. Polyester plastics, such as Polyethylene Terephthalate (PET), are among the most often used types of plastics. PET plastics have a high ratio of aromatic components, which makes them very resistant to microbial attack and highly persistent. As a result, massive amounts of plastic trash accumulate in the environment, where they eventually transform into microplastic (<5 mm). Rather than macroplastics, microplastics are starting to pose a serious hazard to the environment. It is imperative that these polymer microplastics be broken down. Through the use of enrichment culture, the PET microplastic-degrading bacterium was isolated from solid waste management yards. Bacterial strain was identified as Gordonia sp. CN2K by 16 S rDNA sequence analysis and biochemical characterization. It is able to use polyethylene terephthalate as its only energy and carbon source. In 45 days, 40.43 % of the PET microplastic was degraded. By using mass spectral analysis and HPLC to characterize the metabolites produced during PET breakdown, the degradation of PET is verified. The metabolites identified in the spent medium included dimer compound, bis (2-hydroxyethyl) terephthalate (BHET), mono (2-hydroxyethyl) terephthalate (MHET), and terephthalate. Furthermore, the PET sheet exposed to the culture showed considerable surface alterations in the scanning electron microscope images. This illustrates how new the current work is.

Real-world outcomes with durvalumab after chemoradiotherapy in patients with unresectable stage III NSCLC: interim analysis of overall survival from PACIFIC-R.

BACKGROUND: Based on the findings of the PACIFIC trial, consolidation durvalumab following platinum-based chemoradiotherapy (CRT) is a global standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC). An earlier analysis from the ongoing PACIFIC-R study (NCT03798535) demonstrated the effectiveness of this regimen in terms of progression-free survival (PFS). Here, we report the first planned overall survival (OS) analysis. PATIENTS AND METHODS: PACIFIC-R is an observational/non-interventional, retrospective study of patients with unresectable, stage III NSCLC who started durvalumab (10 mg/kg intravenously every 2 weeks) within an AstraZeneca-initiated early access program between September 2017 and December 2018. Primary endpoints are OS and investigator-assessed PFS, estimated using the Kaplan-Meier method. RESULTS: By 30 November 2021, the full analysis set included 1154 participants from 10 countries (median follow-up in censored patients: 38.7 months). Median OS was not reached, and the 3-year OS rate was 63.2% (95% confidence interval 60.3% to 65.9%). Three-year OS rates were numerically higher among patients with programmed death-ligand 1 (PD-L1) expression on ≥1% versus <1% of tumor cells (TCs; 67.0% versus 54.4%) and patients who received concurrent CRT (cCRT) versus sequential CRT (sCRT) (64.8% versus 57.9%). CONCLUSIONS: PACIFIC-R data continue to provide evidence for the effectiveness of consolidation durvalumab after CRT in a large, diverse, real-world population. Better outcomes were observed among patients with PD-L1 TCs ≥1% and patients who received cCRT. Nevertheless, encouraging outcomes were still observed among patients with TCs <1% and patients who received sCRT, supporting use of consolidation durvalumab in a broad population of patients with unresectable, stage III NSCLC.

Spatial N-glycomics of the normal breast microenvironment reveals fucosylated and high-mannose N-glycan signatures related to BI-RADS density and ancestry.

Higher breast cancer mortality rates continue to disproportionally affect black women (BW) compared to white women (WW). This disparity is largely due to differences in tumor aggressiveness that can be related to distinct ancestry-associated breast tumor microenvironments (TMEs). Yet, characterization of the normal microenvironment (NME) in breast tissue and how they associate with breast cancer risk factors remains unknown. N-glycans, a glucose metabolism-linked post-translational modification, has not been characterized in normal breast tissue. We hypothesized that normal female breast tissue with distinct Breast Imaging and Reporting Data Systems (BI-RADS) categories have unique microenvironments based on N-glycan signatures that varies with genetic ancestries. Profiles of N-glycans were characterized in normal breast tissue from BW (n = 20) and WW (n = 20) at risk for breast cancer using matrix assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). A total of 176 N-glycans (32 core-fucosylated and 144 noncore-fucosylated) were identified in the NME. We found that certain core-fucosylated, outer-arm fucosylated and high-mannose N-glycan structures had specific intensity patterns and histological distributions in the breast NME dependent on BI-RADS densities and ancestry. Normal breast tissue from BW, and not WW, with heterogeneously dense breast densities followed high-mannose patterns as seen in invasive ductal and lobular carcinomas. Lastly, lifestyles factors (e.g. age, menopausal status, Gail score, BMI, BI-RADS) differentially associated with fucosylated and high-mannose N-glycans based on ancestry. This study aims to decipher the molecular signatures in the breast NME from distinct ancestries towards improving the overall disparities in breast cancer burden.

Transfer of Guided Emergence Profile Developed Using Customized Provisional Implant Restoration and Cementation Using an Abutment Replica Technique: A Case Report.

The long-term success of dental implants depends not only upon implant osseointegration, but also on the surrounding soft tissue health and profile. An ideal emergence profile contributes to the aesthetics of an implant restoration. It maintains long-term implant health by preventing potential food accumulation and forming a barrier against bacterial ingress. This article describes a method for obtaining an impression of implants that will capture the custom guided peri-implant soft tissue contours accurately, thus contributing to a final restoration with favorable aesthetics. We also describe a technique for reducing excess cement in a cement retained implant crown, thereby contributing to the health of the peri-implant tissues.

Peri-mortem arrhythmias in the non-cardiac intensive care unit.

BACKGROUND: Cardiovascular failure is recognized as a common final pathway at the end of life but there is a paucity of data describing terminal arrhythmias. AIM: We aimed to describe arrhythmias recorded peri-mortem in critically ill patients. STUDY DESIGN: We enrolled intensive care unit patients admitted to two tertiary Canadian medico-surgical centres. Participants wore a continuous electrocardiogram (ECG) monitor for 14 days, until discharge, removal or death. We recorded all significant occurrences of arrhythmias in the final hour of life. RESULTS: Among 39 patients wearing an ECG monitor at the time of death, 22 (56%) developed at least 1 terminal arrhythmia as adjudicated by an arrhythmia physician: 23% (n = 9) had ventricular fibrillation/polymorphic ventricular tachycardia, 18% (n = 7) had sinoatrial pauses, 15% (n = 6) had atrial fibrillation and 13% (n = 5) had high-degree atrioventricular block. Five participants (13%) developed multiple arrythmias. CONCLUSIONS: Arrhythmias are common in dying critically ill patients. There is a roughly even distribution between ventricular arrhythmias, atrial fibrillation, sinus node dysfunction and atrioventricular block. RELEVANCE TO CLINICAL PRACTICE: The results of this study may be most useful for critically ill patients who are organ donation candidates. The appearance of arrhythmias may serve as a marker of change in clinical status for organ donation teams to plan mobilization efforts. In participants who are sedated or intubated, arrhythmias could be a surrogate marker for respiratory or neurologic changes.

Giant Cell Arteritis With Bilateral Central Retinal Artery Occlusion and Tongue Necrosis.

This case report describes a complicated case of giant cell arteritis (GCA) with tongue necrosis and bilateral central retinal artery occlusion (CRAO). An 81-year-old male patient with a history of recent retinal artery occlusion, ischemic stroke, and hypertensive emergency was evaluated. Clinical examination, including a visual acuity assessment, fundus evaluation, and oral examination, was performed. Laboratory investigations, such as erythrocyte sedimentation rate (ESR), were conducted. A temporal artery biopsy was performed to confirm the diagnosis of GCA. The patient presented with sudden vision loss in the left eye following a prior episode of retinal artery occlusion in the right eye. Ophthalmoscopic examination revealed CRAO in the left eye. Additionally, tongue necrosis, a rare manifestation of GCA, was observed. The ESR was significantly elevated. A temporal artery biopsy supported the diagnosis of GCA. The patient was promptly referred for immunologist consultation and initiated on intravenous methylprednisolone therapy. This case highlights the diverse and potentially devastating nature of GCA, involving ocular and systemic manifestations. Bilateral CRAO and tongue necrosis are rare but significant complications of GCA. Prompt diagnosis and early initiation of corticosteroid therapy are crucial to prevent irreversible visual loss and further complications. A multidisciplinary approach involving ophthalmologists and other specialists is essential for the comprehensive management of GCA.

Intra-abdominal Inflammatory Myofibroblastic Tumour (IMFT)-Uncommon Entity.

IMFT (inflammatory myofibroblastic tumour) is an uncommon tumour predominantly affecting the lungs and mediastinum. Most of the published literature supports that it affects children and young individuals. IMFT involving the gastrointestinal tract is rare. We report a case of multifocal IMFT affecting the GI tract which was managed with gross total excision followed by chemotherapy. Surgical resection remains the treatment of choice. The role of chemotherapy and radiation therapy remains limited. The aetiology of these tumours remains unclear and is mostly ALK-positive that could be targeted. Local recurrences are common and hence require close follow-up. The risk of recurrences and metastasis is increased in cases with TP53 positivity, aneuploidy and recurrent lesions.

Neuromodulation and Habituation: A Literature Review and Conceptional Analysis of Sustaining Therapeutic Efficacy and Mitigating Habituation.

Spinal cord stimulation (SCS) is a therapeutic modality for the treatment of various chronic pain conditions that has rapidly evolved over the past 50 years. Unfortunately, over time, patients implanted with SCS undergo a habituation phenomenon leading to decreased pain relief. Consequently, the discovery of new stimulation waveforms and SCS applications has been shown to prolong efficacy and reduce explantation rates. This article explores various SCS waveforms, their applications, and proposes a graded approach to habituation mitigation. We suspect the neural habituation phenomenon parallels that seen in pharmacology. Consequently, we urge further exploration of the early introduction of these stimulation strategies to abate spinal cord stimulation habituation.

Aids to improve understanding of statistical risk in patients consenting for surgery and interventional procedures: A systematic review.

BACKGROUND: Informed consent is an essential process in clinical decision-making, through which healthcare providers educate patients about benefits, risks, and alternatives of a procedure. Statistical risk information is difficult to communicate and the effectiveness of aids aimed at supporting this type of communication is uncertain. This systematic review aims to study the impact of risk communication adjuncts on patients' understanding of statistical risk in surgery and interventional procedures. METHODS: A systematic search was performed across Medline, Embase, PsycINFO, Scopus, and Web of Science until July 2021 with a repeated search in September 2022. RCTs and observational studies examining risk communication tools (e.g., information leaflets and audio-video) in adult (age >16) patients undergoing a surgical or interventional procedure were included. Primary outcomes included the objective assessment of statistical risk recall. Secondary outcomes included patient attitudes with respect to statistical information. Due to the study heterogeneity, a narrative synthesis was performed. RESULTS: A total of 4348 articles were identified, and following abstract and full-text screening 14 articles, including 9 RCTs, were included. The total number of adult patients was 1513. The most common risk communication tool used was written information (n = 7). Most RCTs (7/9, 77.8%) showed statistically significant improvements in patient understanding of statistical risk in the intervention group. Quality assessment found some concerns with all RCTs. CONCLUSION: Risk communication tools appear to improve recall of statistical risk. Additional prospective trials comparing various aids simultaneously are warranted to determine the most effective method of improving understanding.

Improving risk communication: a proof-of-concept randomised control trial assessing the impact of visual aids for neurosurgical consent.

Introduction: Informed consent is a fundamental component in the work-up for surgical procedures. Statistical risk information pertaining to a procedure is by nature probabilistic and challenging to communicate, especially to those with poor numerical literacy. Visual aids and audio/video tools have previously been shown to improve patients' understanding of statistical information. In this study, we aimed to explore the impact of different methods of risk communication in healthy participants randomized to either undergo the consent process with visual aids or the standard consent process for lumbar puncture. Material and methods: Healthy individuals above 18 years old were eligible. The exclusion criteria were prior experience of the procedure or relevant medical knowledge, lack of capacity to consent, underlying cognitive impairment and hospitalised individuals. After randomisation, both groups received identical medical information about the procedure of a lumbar puncture in a hypothetical clinical scenario via different means of consent. The control group underwent the standard consent process in current clinical practice (Consent Form 1 without any illustrative examples), whereas the intervention group received additional anatomy diagrams, the Paling Palette and the Paling perspective scale. Anonymised questionnaires were received to evaluate their perception of the procedure and its associated risks. Results: Fifty-two individuals were eligible without statistically significant differences in age, sex, professional status and the familiarity of the procedure. Visual aids were noted to improve the confidence of participants to describe the risks by themselves (p = 0.009) and participants in the intervention group felt significantly less overwhelmed with medical information (p = 0.028). The enhanced consent process was found to be significantly more acceptable by participants (p = 0.03). There was a trend towards greater appropriateness (p = 0.06) and it appeared to have "good" usability (median SUS = 76.4), although this also did not reach statistical significance (p = 0.06). Conclusion: Visual aids could be an appropriate alternative method for medical consent without being inferior regarding the understanding of the procedure, its risks and its benefits. Future studies could possibly compare or incorporate multiple interventions to determine the most effective tools in a larger scale of population including patients as well as healthy individuals.

Chronic Abdominal Discomfort Syndrome (CADS): Defining and Discussing a Novel Diagnosis.

In this article, we propose a new diagnostic paradigm known as Chronic Abdominal Discomfort Syndrome (CADS). Patient's presentation centers around chronic abdominal pain not explained by acute pathology with or without accompanying dyspepsia, bloating, nausea and vomiting among other symptoms. The pathophysiology is noted to be neurogenic, possibly stemming from visceral sympathetic nerves or abdominal wall afferent nerves. Diagnosis is supported by signs or symptoms traversing clinical, diagnostic and functional criteria. Included is a tool which can assist clinicians in diagnosing patients with CADS per those domains. We hope to facilitate primary care physicians' and gastroenterologists' utilization of our criteria to provide guidance for selecting which patients may benefit from further interventions or evaluation by a pain physician. The pain physician may then offer interventions to provide the patient with relief.

Project EPIC (Empowering People to Independence in COPD): Study protocol for a hybrid effectiveness-implementation pilot randomized controlled trial of telephonic, geriatrics-palliative care nurse-coaching in older adults with COPD and their family caregivers.

BACKGROUND: EPIC (Empowering People to Independence in COPD) is a geriatric-palliative care telephonic, nurse coach intervention informed by Baltes' Theory of Successful Aging and adapted from the ENABLE (Educate, Nurture, Advise, Before Life Ends) intervention. EPIC, focused on improving independence, mobility, well-being, and COPD symptoms, has undergone formative and summative evaluation for adults with COPD. METHODS: The primary study aim is to assess the refined EPIC intervention's feasibility and acceptability via a pilot hybrid effectiveness-implementation randomized control trial in community-dwelling older adults with moderate to severe COPD and their family caregivers. The secondary aim is to explore the impact of EPIC on patient and caregiver outcomes. Older adults with COPD and their family caregivers (target N = 60 dyads) will be randomized to EPIC (intervention) or usual COPD care (control). EPIC includes six patient and four family caregiver weekly, telephone-based nurse coach sessions using a manualized curriculum (Charting Your Course), plus three monthly follow-up calls. Feasibility will be measured as completion of EPIC intervention and trial components (e.g., recruitment, retention, data collection). Acceptability will be evaluated using satisfaction surveys and post-study feedback interviews. A blinded data collector will assess exploratory outcomes (e.g., Life-Space mobility, quality of life, caregiver burden, emotional symptoms, loneliness, cognitive impairment, functional status, healthcare utilization) at baseline, 12, and 24 weeks. DISCUSSION: This intervention fills a gap in addressing the geriatrics and palliative care needs and equity for adults with COPD and their family caregivers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05040386.