Bridging Atom Engineering for Low-Temperature Oxygen Activation in a Robust Metal-Organic Framework.

Achieving active site engineering at the atomic level poses a significant challenge in the design and optimization of catalysts for energy-efficient catalytic processes, especially for a reaction with two reactants competitively absorbed on catalytic active sites. Herein, we show an example that tailoring the local environment of cobalt sites in a robust metal-organic framework through substituting the bridging atom from -Cl to -OH group leads to a highly active catalyst for oxygen activation in an oxidation reaction. Comprehensive characterizations reveal that this variation imparts drastic changes on the electronic structure of metal centers, the competitive reactant adsorption behavior, and the intermediate formation. As a result, exceptional low-temperature CO oxidation performance was achieved with T25(Temperature for 25 % conversion)=35 °C and T100 (Temperature for 100 % conversion)=150 °C, which stands out from existing MOF-based catalysts and even rivals many noble metal catalysts. This work provides a guidance for the rational design of catalysts for efficient oxygen activation for an oxidation reaction.

Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens.

Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution1-11. However, broad clinical application of these methods remains challenging, due to several practical and preanalytical challenges that are incompatible with typical clinical care workflows, namely the need for relatively large, fresh tissue inputs. In the present study, we show that multimodal, single-nucleus (sn)RNA/T cell receptor (TCR) sequencing, spatial transcriptomics and whole-genome sequencing (WGS) are feasible from small, frozen tissues that approximate routinely collected clinical specimens (for example, core needle biopsies). Compared with data from sample-matched fresh tissue, we find a similar quality in the biological outputs of snRNA/TCR-seq data, while reducing artifactual signals and compositional biases introduced by fresh tissue processing. Profiling sequentially collected melanoma samples from a patient treated in the KEYNOTE-001 trial12, we resolved cellular, genomic, spatial and clonotype dynamics that represent molecular patterns of heterogeneous intralesional evolution during anti-programmed cell death protein 1 therapy. To demonstrate applicability to banked biospecimens of rare diseases13, we generated a single-cell atlas of uveal melanoma liver metastasis with matched WGS data. These results show that single-cell genomics from archival, clinical specimens is feasible and provides a framework for translating these methods more broadly to the clinical arena.

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19.

Importance: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration: ClinicalTrials.gov Identifier: NCT04354701.

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Multifunctional Porous Hydrogen-Bonded Organic Frameworks: Current Status and Future Perspectives.

Hydrogen-bonded organic frameworks (HOFs), self-assembled from organic or metalated organic building blocks (also termed as tectons) by hydrogen bonding, π-π stacking, and other intermolecular interactions, have become an emerging class of multifunctional porous materials. So far, a library of HOFs with high porosity has been synthesized based on versatile tectons and supramolecular synthons. Benefiting from the flexibility and reversibility of H-bonds, HOFs feature high structural flexibility, mild synthetic reaction, excellent solution processability, facile healing, easy regeneration, and good recyclability. However, the flexible and reversible nature of H-bonds makes most HOFs suffer from poor structural designability and low framework stability. In this Outlook, we first describe the development and structural features of HOFs and summarize the design principles of HOFs and strategies to enhance their stability. Second, we highlight the state-of-the-art development of HOFs for diverse applications, including gas storage and separation, heterogeneous catalysis, biological applications, sensing, proton conduction, and other applications. Finally, current challenges and future perspectives are discussed.

Maggot Debridement Therapy for Chronic Leg and Foot Ulcers: A Review of Randomized Controlled Trials.

OBJECTIVE: To critically analyze the existing randomized controlled trials (RCTs) on the clinical, economic, and psychological implications of maggot debridement therapy (MDT). DATA SOURCES: An exhaustive literature search for English-language publications was conducted using MEDLINE, EMBASE, and PubMed. STUDY SELECTION: Keywords used for the search were based on the PICO (Population, Intervention, Comparison, Outcome) framework. The titles, abstracts, and relevant full-text articles were screened. Seven RCTs were selected after applying the inclusion and exclusion criteria. DATA EXTRACTION: Data pertaining to the primary and secondary outcomes of each study were extracted. DATA SYNTHESIS: The data extracted were evaluated and categorized into clinical, economic, and psychological outcomes pertaining to MDT. A judicious evaluation of these outcomes was made, and the following conclusions were drawn. CONCLUSIONS: There exists heterogeneity in the extant RCTs, but MDT appears to be effective for a quick early debridement. For diabetic foot ulcers, MDT improves debridement, controls infection, and enhances wound healing. In chronic peripheral vascular disease ulcers, it aids in early debridement, but the final outcome is equivocal. Further robust integrated health economic and parallel qualitative assessment studies are recommended to understand the cost-effectiveness and patient acceptability and experience.

Tuning the type of nitrogen on N-RGO supported on N-TiO2 under ultrasonication/hydrothermal treatment for efficient hydrogen evolution - A mechanistic overview.

Efficient hydrogen production through water splitting has been the challenging task to be achieved in the present context of energy crisis. Among the various catalysts employed, nitrogen doped Titanium dioxide/Reduced graphene oxide (N-TiO2/RGO) nanocomposite has been established to be a promising photocatalytic material for this purpose. However, nuances of doping nitrogen on TiO2 and the type of nitrogen (pyridinic, pyrrolic and graphitic) stabilized on RGO responsible for facilitating the H2 production has not yet been addressed mechanistically. In the present investigation, an attempt has been made to synthesise N-Titanium dioxide/N-Reduced graphene oxide (NTNG) nanocomposite under ultrasonication followed by hydrothermal treatment. A stainlesssteel ultrasonic bath, of 6.5 L tank size (LxBxH) 300 × 150 × 150 mm, was used for ultrasonic treatments. The transducers located at the bottom of the ultrasonic bath generate a frequency of 40 kHz with maximum power of 200 W. A mechanism has been proposed including the nuances of formation and the stabilisation of each type of nitrogen on N-RGO as a function of ultrasonication time. The present work supports the stabilization of a given type of nitrogen on RGO through keto enol tautomerism. XPS and FTIR studies have been undertaken to identify the different types of nitrogen doping and the presence of functional groups respectively. XRD, UV-Vis DRS and PL investigations have been made to establish morphological profile and band gap structure of the nanocomposite. It was observed that pyrrolic type nitrogen stabilized on N-RGO augments the efficiency of photocatalytic activity through hydrogen production by water splitting.

Amine Functionalized Metal-Organic Framework Coordinated with Transition Metal Ions: d-d Transition Enhanced Optical Absorption and Role of Transition Metal Sites on Solar Light Driven H2 Production.

Design and development of efficient photocatalysts for H2 production from water and sunlight have gained significant attention as the solar assisted approach is considered to be a promising approach for the generation of clean fuel. However, the poor charge carrier separation and light harvesting ability of existing photocatalysts limits the efficiency of photoconversion of water. In this work, the synthesis of transition metal ions (M2+ = Co2+ , Cu2+ , and Ni2+ ) coordinated with Ti-metal organic frameworks (Ti-MOFs) through a simple post-synthetic coordination method for efficient solar light-driven H2 production is reported. Notably, coordination of M2+ ions with Ti-MOF significantly improves the optical absorption by d-d transitions and the multimetal sites facilitate the fast charge carrier separation, thereby enhancing the solar light-driven H2 production activity. Very interestingly, the rate of solar light-driven H2 production is varied with respect to different metal ions coordination due to the position of d-d bands absorption in the solar spectrum, and the complexing tendency of M2+ ions with sacrificial electron donors. A maximum solar H2 production rate of 1583.55 µmol h-1 g-1 is achieved with a Cu2+ coordinated Ti-MOF, which is ≈13 fold higher than that of the pristine Ti-MOF.

Reduced graphene oxide (rGO) supported electron deficient B-doped TiO2 (Au/B-TiO2/rGO) nanocomposite: An efficient visible light sonophotocatalyst for the degradation of Tetracycline (TC).

Incorporation of electron deficient boron atoms along with Au doped TiO2 in the presence of rGO support was synthesized by hydrothermal method and demonstrated for the sonophotocatalytic degradation of TC under visible light illumination. The successful incorporation of electron deficient boron atoms and Au on TiO2 was considerably enhanced the optical absorption towards visible region due to the formation acceptor energy levels below to the conduction band of TiO2 by boron doping and surface plasmonic effect of Au. Moreover, formation of acceptor energy levels and introduction of reduced graphene oxide (rGO) support significantly improved the electron-hole pair separation and transportation which were supported by UV-vis-DRS, photo-current and photoluminescence measurements. The individual effect of photocatalysis and ultrasound for the TC degradation was found to be 45% and 12%, respectively. Importantly, a complete degradation (100%) of TC was achieved with 1.3 folds synergistic effect when ultrasound coupled with photocatalysis in 1 h. The enhanced degradation activity was mainly attributed to combined effect of rapid electron-hole pair separation facilitated by electron deficient B-atoms and rGO support and physical forces of ultrasound as well. In addition, ∼74% of Total Organic Carbon (TOC) removal was achieved within 1 h which further confirmed the effective demineralization of TC by the Au/B-TiO2/rGO composite.

Effectiveness of education and antibiotic control programme at All India Institute of Medical Sciences, New Delhi.

Background: We aimed to assess the impact of antibiotic optimization education along with understanding the antibiogram on antibiotic-prescribing practices, antibiotic consumption, antimicrobial resistance and cost of antibiotics in a tertiary care hospital in New Delhi. Methods: We divided the study into 3 phases-before and after intervention and a phase of education in between. We collected data on demographics, indication for antibiotic prescription, appropriateness or reasons for inappropriate antibiotic uses, antibiotic consumption (i.e. the rate and duration of antibiotic use), bacterial resistance and antibiotic cost. Interventions included education, introduction of an antibiogram and use of antibiotic prescription forms. Similar data were collected for the post-interventional phase. The study was conducted at the Department of Medicine, All India Institute of Medical Sciences, New Delhi, India. Results: There was an improvement in the number of patients who underwent de-escalation of antibiotics, 21/100 v. 36/100 (p = 0.019); appropriate antibiotic usage, 25/ 100 v. 46/100 (p = 0.002); switching from intravenous to oral promptly, 16/52 v. 1 9/36 (p = 0.003) and decrease in expenditure, ₹24 207.5 v. ₹16 51 7.5 per patient (p = 0.001 ); in the post-interventional phase. Significant reductions in the incidence of infections due to Acinetobacter (60% v. 31%; p<0.001) and improvement in sensitivity pattern with cephalosporin sulbactam (80% v. 100%; p<0.001) were seen. Multivariate analysis revealed that Acute Physiology and Chronic Health Evaluation (APACHE) score, hospital stay <10 days, ventilator-associated pneumonia and methicillin-resistant Staphylococcus aureus coverage were independent predictors of mortality with odds ratio of 1.14, 0.1, 9.7 and 1.14, respectively. Conclusion: Education and an antibiotic control programme constituted an effective and cost-saving strategy to optimise antibiotic use at a tertiary care centre.

Concurrent radiotherapy and ipilimumab immunotherapy for patients with melanoma.

Ipilimumab and radiotherapy are commonly used to treat unresectable and metastatic melanoma. Results from preclinical studies and case reports suggest a biologic interaction between these two treatments. To understand the clinical implications of the interaction, we carried out a retrospective study reviewing records of patients treated with ipilimumab and radiotherapy for melanoma at our institution between 2005 and 2011. The review included details of treatment, response, adverse events (AE), and overall survival (OS). Twenty-nine patients underwent 33 courses of non-brain radiotherapy between their first and last dose of ipilimumab. Immune-related AEs (ir-AEs) were observed in 43% of patients receiving ipilimumab at 10 mg/kg and in 22% of patients receiving 3 mg/kg; the frequency of ir-AEs was not significantly different compared with previous studies of ipilimumab alone. Radiotherapy-related AEs were significantly more common in patients receiving higher doses of radiation. Palliation of symptoms was reported by 77% of patients after radiotherapy. Median OS was 9 and 39 months in patients receiving radiotherapy during induction and maintenance with ipilimumab, respectively. In this retrospective study, concurrent ipilimumab and radiotherapy was neither associated with higher than expected rates of AEs nor did it abrogate palliative effects of radiotherapy or survival benefits of ipilimumab. Further studies to prospectively explore the efficacy of this therapeutic combination are warranted.

Role of dexamethasone in acute bacterial meningitis in adults.

OBJECTIVE: To evaluate the role of dexamethasone as adjunctive therapy in adult acute bacterial meningitis (ABM) in two groups of patients treated with antibiotics alone or a combination of antibiotics and dexamethasone. DESIGN: Systematic sampling interventional open cohort study. SETTING: Department of Medicine (Medical Unit II), Jinnah Postgraduate Medical Centre, Karachi. PATIENTS: Sixty eight patients aged 12-85 years admitted in Medical Unit II and diagnosed to have ABM. Patients were divided into two groups. Group A received anti-microbial therapy for 14 days (a combination of benzyl penicillin 6 million units I/V 6 hourly and chloramphenicol 1 gm I/V 6 hourly) and group B received the same antimicrobial therapy with dexamethasone 0.6 mg/kg/day in 3 divided doses for 4 days. MAIN OUTCOME MEASURES: Differences in mortality and morbidity in the two groups and differences in the CSF inflammatory parameters between the two groups of patients. RESULTS: There was early resolution of fever, headache and altered consciousness in group B as compared to group A. Cranial nerves involvement was lower in group B. There was no difference in the occurrence of other focal neurological deficits between the two groups. CSF inflammatory parameters (glucose, protein and WBC count) were significantly better in group B by day 5. No complications attributable to dexamethasone were seen in group B. CONCLUSION: There was early resolution of symptoms and CSF inflammatory parameters in the group that received dexamethasone as adjuvant therapy. Mortality was lower in the group treated with dexamethasone but the difference was not statistically significant. Dexamethasone should be administered to all adults patients with ABM.

Amoebic versus pyogenic liver abscess.

OBJECTIVES: To study the differences between the clinical presentation and complications of amoebic and pyogenic liver abscess. To correlate the diagnostic significance of Entamoeba Indirect Haemagglutination test (E.IHA) in establishing the diagnosis of amoebic liver abscess. DESIGN: Open cohort observational study. SETTING: Department of Medicine (Medical Unit II) Jinnah Postgraduate Medical Centre, Karachi. PARTICIPANTS: Fifty two patients aged 13-70 years admitted in Medical Unit II and diagnosed to have liver abscess. INTERVENTIONS: Group A comprised of patients clinically diagnosed to have amoebic liver abscess and received Metronidazole 500mg iv x 8 hourly for atleast 10 days or more if patient developed complications. Group B comprised of patients diagnosed to have pyogenic abscess and received Cefotaxime 1g iv x 8 hourly for the same duration or more if complicated (antibiotic reviewed in accordance with culture and sensitivity report). MAIN OUTCOME MEASURES: Differences in the clinical presentation, complications and diagnostic parameters between the two groups of patients. RESULTS: It was not possible to differentiate between amoebic and pyogenic liver abscess on clinical grounds, routine investigations and imaging techniques. Aspiration of pus, especially if the abscess was multiple, was most helpful in differentiating the two types of abscesses. Serological test of E.IHA was highly specific and sensitive for amoebic liver abscess. CONCLUSION: Majority of liver abscesses in Karachi are due to Entamoeba Histolytica. Pyogenic abscess though less frequent, must be excluded by pus aspiration and culture and sensitivity. E.IHA is a good rapid method of discriminating between the two types of abscesses.