Suppressing Protodeboronation in Cu-Mediated 19F/18F-Fluorination of Arylboronic Acids: A Mechanistically Guided Approach Towards Optimized PET Probe Development.

Fluorinated arenes play a crucial role in drug discovery, specialty materials, and medical imaging. Although several variants for Cu-mediated nucleophilic fluorination of arylboronic acids and derivatives have been developed, these protocols rarely address the occurrence and control of protodeboronation, which greatly complicates product separation and can compromise the effectiveness of a radiotracer for in vivo imaging. Consequently, simpler and more efficient procedures are needed to allow rapid 18F/19F-fluorination of both arylboronic acids and esters while minimizing protodeboronation. Mechanistic controls revealed that in addition to a high temperature, strong donor ligands such as acetonitrile and pyridine accentuate a Cu-mediated protodeboronation. This observation guided the optimization of a ligandless procedure with t-BuOH as solvent to enhance the nucleophilicity of fluoride under milder conditions at lower temperatures minimizing protodeboronation. Additionally, a new copper salt, Cu(ONf)2 was employed to further improve the fluorination efficiency. A large range of functional groups are tolerated under the new procedure, which is complete within 30 minutes at a temperature of 60 °C, and affords fluorinated arenes and heteroarenes in 39% to 84% yield. With minimal modifications, the protocol can also be applied in 18F-radiofluorination, affording radiochemical conversions (RCCs) between 17-54% with minimal protodeboronation compared to previously established protocols.

Removing Neighboring Ring Influence in Monocyclic B-OH Diazaborines: Properties and Reactivity as Phenolic Bioisosteres with Dynamic Hydroxy Exchange.

The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. This challenge is compounded when emphasis is placed on the preparation of new chemotypes that have distinct and practical functions. To expand the structural diversity of boron-containing heterocycles, we report herein the preparation of novel monocyclic hemiboronic acids, diazaborines. These compounds have enabled the study of a pseudoaromatic boranol-containing (B-OH) ring free of influence from an appended aromatic system. Synthetic and spectroscopic studies have provided insight into the aromatic character, Lewis acidic nature, chemical reactivity, and unique ability of the exocyclic B-OH unit to participate in hydroxy exchange, suggesting their use in organocatalysis and as reversible covalent inhibitors. Moreover, density functional theory and nucleus-independent chemical shift calculations reveal that the aromatic character of the boroheterocyclic ring is increased significantly in comparison to known bicyclic benzodiazaborines (naphthoid congeners), consequently leading to attenuated Lewis acidity. Direct structural comparison to a well-established biaryl isostere, 2-phenylphenol, through X-ray crystallographic analysis reveals that N-aryl derivatives are strikingly similar in size and conformation, with attenuated logP values underscoring the value of the polar BNN unit. Their potential application as low-molecular-weight scaffolds in drug discovery is demonstrated through orthogonal diversification and preliminary antifungal evaluation (Candida albicans), which unveiled analogs with low micromolar inhibitory concentration.

Preparing for future pandemics: frailty associates with mortality in hospitalised older people during the entire COVID-19 pandemic, a Dutch multicentre cohort study.

PURPOSE: Viral mutations and improved prevention or treatment options may have changed the association of frailty with mortality throughout the COVID-19 pandemic. We investigated how associations of frailty with in-hospital mortality changed throughout the pandemic in older people hospitalised for COVID-19. METHODS: The COVID-OLD study included COVID-19 patients aged ≥ 70 years hospitalised during the first (early 2020), second (late 2020), third (late 2021) or fourth wave (early 2022). Based on the clinical frailty scale, patients were categorised as fit (1-3), pre-frail (4-5) or frail (6-9). Associations of frailty with in-hospital mortality were assessed with pairwise comparisons with fit as reference category and modelled using binary logistic regression adjusted for age and sex. RESULTS: This study included 2362 patients (mean age 79.7 years, 60% men). In the first wave, in-hospital mortality was 46% in patients with frailty and 27% in fit patients. In-hospital mortality decreased in each subsequent wave to 25% in patients with frailty and 11% in fit patients in the fourth wave. After adjustments, an overall higher risk of in-hospital mortality was found in frail (OR 2.26, 95% CI: 1.66-3.07) and pre-frail (OR 1.73, 95% CI: 1.27-2.35) patients compared to fit patients, which did not change over time (p for interaction = 0.74). CONCLUSIONS: Frailty remained associated with a higher risk of in-hospital mortality throughout the entire COVID-19 pandemic, although overall in-hospital mortality rates decreased. Frailty therefore remains a relevant risk factor in all stages of a pandemic and is important to consider in prevention and treatment guidelines for future pandemics.

In septic shock and CAP, hydrocortisone + fludrocortisone reduced 90-d mortality.

SOURCE CITATION: Heming N, Renault A, Kuperminc E, et al; APROCCHSS investigators and CRICS-TRIGGERSEP network. Hydrocortisone plus fludrocortisone for community acquired pneumonia-related septic shock: a subgroup analysis of the APROCCHSS phase 3 randomised trial. Lancet Respir Med. 2024;12:366-374. 38310918.

Selective Electrochemical Oxygen Reduction to Hydrogen Peroxide by Confinement of Cobalt Porphyrins in a Metal-Organic Framework.

Sustainable alternatives for the energy intensive synthesis of H2O2 are necessary. Molecular cobalt catalysts show potential but are typically restricted by undesired bimolecular pathways leading to the breakdown of both H2O2 and the catalyst. The confinement of cobalt porphyrins in the PCN-224 metal-organic framework leads to an enhanced selectivity towards H2O2 and stability of the catalyst. Consequently, oxygen can now be selectively reduced to hydrogen peroxide with a stable conversion for at least 5 h, illustrating the potential of catalysts confined in MOFs to increase the selectivity and stability of electrocatalytic conversions.

Synergistic Nanomedicine Delivering Topoisomerase I Toxin (SN-38) and Inhibitors of Polynucleotide Kinase 3'-Phosphatase (PNKP) for Enhanced Treatment of Colorectal Cancer.

Inhibitors of a DNA repair enzyme known as polynucleotide kinase 3'-phosphatase (PNKP) are expected to show synergistic cytotoxicity in combination with topoisomerase I (TOP1) inhibitors in cancer. In this study, the synergistic cytotoxicity of a novel inhibitor of PNKP, i.e., A83B4C63, with a potent TOP1 inhibitor, i.e., SN-38, against colorectal cancer cells was investigated. Polymeric micelles (PMs) for preferred tumor delivery of A83B4C63, developed through physical encapsulation of this compound in methoxy poly(ethylene oxide)-poly(α-benzyl carboxylate-ε-caprolactone) (mPEO-b-PBCL) micelles, were combined with SN-38 in free or PM form. The PM form of SN-38 was prepared through chemical conjugation of SN-38 to the functional end group of mPEO-b-PBCL and further assembly of mPEO-b-PBCL-SN-38 in water. Moreover, mixed micelles composed of mPEO-b-PBCL and mPEO-b-PBCL-SN-38 were used to co-load A83B4C63 and SN-38 in the same nanoformulation. The loading content (% w/w) of the SN-38 and A83B4C63 to mPEO-b-PBCL in the co-loaded formulation was 7.91 ± 0.66 and 16.13 ± 0.11% (w/w), respectively, compared to 15.67 ± 0.34 (% w/w) and 23.06 ± 0.63 (% w/w) for mPEO-b-PBCL micelles loading individual drugs. Notably, the average diameter of PMs co-encapsulating both SN-38 and A83B4C63 was larger than that of PMs encapsulating either of these compounds alone but still lower than 60 nm. The release of A83B4C63 from PMs co-encapsulating both drugs was 76.36 ± 1.41% within 24 h, which was significantly higher than that of A83B4C63-encapsulated micelles (42.70 ± 0.72%). In contrast, the release of SN-38 from PMs co-encapsulating both drugs was 44.15 ± 2.61% at 24 h, which was significantly lower than that of SN-38-conjugated PMs (74.16 ± 3.65%). Cytotoxicity evaluations by the MTS assay as analyzed by the Combenefit software suggested a clear synergy between PM/A83B4C63 (at a concentration range of 10-40 µM) and free SN-38 (at a concentration range of 0.001-1 µM). The synergistic cytotoxic concentration range for SN-38 was narrowed down to 0.1-1 or 0.01-1 µM when combined with PM/A83B4C63 at 10 or 20-40 µM, respectively. In general, PMs co-encapsulating A83B4C63 and SN-38 at drug concentrations within the synergistic range (10 µM for A83B4C63 and 0.05-1 µM for SN-38) showed slightly less enhancement of SN-38 anticancer activity than a combination of individual micelles, i.e., A83B4C63 PMs + SN-38 PMs at the same molar concentrations. This was attributed to the slower release of SN-38 from the SN-38 and A83B4C63 co-encapsulated PMs compared to PMs only encapsulating SN-38. Cotreatment of cells with TOP1 inhibitors and A83B4C63 formulation enhanced the expression level of γ-HA2X, cleaved PARP, caspase-3, and caspase-7 in most cases. This trend was more consistent and notable for PMs co-encapsulating both A83B4C63 and SN-38. The overall result from the study shows a synergy between PMs of SN-38 and A83B4C63 as a mixture of two PMs for individual drugs or PMs co-encapsulating both drugs.

Pronounced benefits of JAK inhibition with baricitinib in COVID-19 pneumonia in obese but not lean subjects.

OBJECTIVE: Obesity and age are strongly linked to severe COVID-19 pneumonia where immunomodulatory agents including Janus kinase inhibitors have shown benefits but the efficacy of such therapy in viral pneumonia is not well understood. We evaluated the impact of obesity and age on survival following baricitinib therapy for severe COVID-19. METHODS: A post hoc analysis of the COV-BARRIER multicentre double-blind randomised study of baricitinib versus placebo (PBO) with an assessment of 28-day mortality was performed. All-cause mortality by day 28 was evaluated in a Cox regression analysis (adjusted to age) in three different groups according to body mass index (BMI) (<25 kg/m2, 25-30 kg/m2 and >30 kg/m2) and age <65 years and ≥65 years. RESULTS: In the high BMI group (>25 kg/m2), baricitinib therapy showed a significant survival advantage compared with PBO (incidence rate ratio (IRR) for mortality by day 28 0.53 (95% CI 0.32 to 0.87)) and 0.66 (95% CI 0.46 to 0.94) for the respective <65 years and ≥65 years, respectively. The 28-day all-cause-mortality rates for BMI over 30 were 5.62% for baricitinib and 9.22% for PBO (HR=0.6, p<0.05). For BMI under 25 kg/m2, irrespective of age, baricitinib therapy conferred no survival advantage (IRR of 1.89 (95% CI 0.49 to 7.28) and 0.95 (95% CI 0.46 to 1.99) for <65 years and ≥65 years, respectively) ((mortality 6.6% baricitinib vs 8.1 in PBO), p>0.05). CONCLUSION: The efficacy of baricitinib in COVID-19 pneumonia is linked to obesity suggesting that immunomodulatory therapy benefit is associated with obesity-associated inflammation.

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted. Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies. Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

Complications and outcomes after three-column osteotomy: a 5-year follow-up.

BACKGROUND: Three-column spinal osteotomies (3-CO) are powerful techniques used to correct spinal deformity. These surgeries are associated with an elevated risk of complications. While outcomes have been reported in the literature with 2 years follow-up, longer-term outcomes of three-column osteotomies remain understudied. OBJECTIVES: This study aims to examine patient reported outcomes and complications for three-column osteotomies at 5 years. STUDY DESIGN: Retrospective review of a prospectively collected spinal deformity cases database. PATIENT SAMPLE: All consecutive adult patients at a single spine surgery center treated with either a pedicle subtraction osteotomy (PSO) or vertebral column resection (VCR) for spinal deformity, and with a minimum 5-year follow-up were included. OUTCOME MEASURES: Visual-analog scale (VAS) for back pain score (0 to 10), Oswestry Disability Index (ODI) score (0 to 100), number of complications, revision rate, sagittal balance, lumbar lordosis at preoperative and at 5-year visit. METHODS: Data was extracted from a prospectively collected spinal deformity surgery database continuously updated since 2002 with data from operative reports, patients' medical visit notes and patients' self-reported VAS and ODI questionnaires completed at each office visit. Radiographic measurements were performed on standing full-length spine radiographs taken at pre-op and 5-year visits. Descriptive statistics, comparison of means and proportions among groups, and a logistic regression analysis were conducted using the statistical software package SPSS version 28. Statistical significance was set at p<.05. RESULTS: Of 127 consecutive adult patients with minimum of 5-year follow-up undergoing a 3-CO posterior spinal surgery for spinal deformity were identified and included in the study, 79 (62%) were treated with PSO, and 48 (38%) with VCR. Both PSO and VCR groups demonstrated significant improvements in VAS (PSO pre-op: 6.7, 5-year: 4.6, p<.001; VCR pre-op: 7.1, 5-year: 5.2, p<.001), and ODI (PSO pre-op: 52.9, 5-year: 45.4, p<.001; VCR pre-op: 57.5, 5-year 43.0, p<.001) that were maintained at 5 years. Major and minor complications occurring within 5 years were not statistically different between the PSO and VCR groups (major: 59.5% vs 56.3%, p=.85; minor: 45.6% vs 37.5%, p=.46). The rate of revision surgery within 5 years was 39.4% overall. Of the fifty patients requiring revision, 37.5% were for nonunion, 27.1% instrumentation failure, 14.6% proximal junctional kyphosis (PJK), 12.5% vertebral fracture, 6.3% motor weakness, and 2.1% infection. Improvements in lumbar lordosis were maintained at 5 years in both the PSO (29.9° vs 47.2°, p<.001) and VCR (34.6° vs 48.5°, p<.001) groups while sagittal balance maintained significant improvement in the VCR group (9.5 cm vs 6.3 cm, p=.008) but not the PSO (11.4 cm vs 9.3 cm, p=.065). CONCLUSION: Patients undergoing three-column osteotomies had a major complication rate of 57.5% and a minor complication rate of 42.5% after 5 years. Improvements in lumbar lordosis were maintained at 5-year follow-up, but sagittal balance was only maintained in the VCR group. Despite these radiographic findings, both VCR and PSO groups maintained significant clinical improvements in both VAS and ODI scores at 5-year follow up.

Worldwide Trends in COVID-19-Related Attacks Against Healthcare: A Review of the Safeguarding Health in Conflict Coalition Database.

During the COVID-19 pandemic, violence targeting healthcare reportedly increased. Attacks against healthcare can severely hamper the public health response during a pandemic. Descriptive data analysis of these attacks may be helpful to develop prevention and mitigation strategies. This study aimed to investigate trends regarding COVID-19-related attacks against healthcare from January 2020 until January 2023. COVID-19-related incidents occurring between January 2020 and January 2023 were extracted from the Safeguarding Health in Conflict Coalition database and screened for eligibility. Included incidents were linked to COVID-19 health measures or were attacks directly interfering with COVID-19 healthcare, including conflict-related attacks. Data collected per incident included temporal factors; country; setting; attack and weapon type; perpetrator; motive; number of healthcare workers (HCWs) killed, injured, or kidnapped; and health facility damage. The study identified 255 COVID-19-related attacks against healthcare, with 18 HCWs killed, 147 HCWs injured, and 86 facilities damaged. The highest attack frequency was reported during the beginning of the pandemic and predominantly concerned stigma-related attacks against healthcare. Reported incidents in 2021 included attacks targeting vaccination campaigns, as well as conflict-related attacks interfering with COVID-19 healthcare. COVID-19-related attacks against healthcare occurred in heterogeneous contexts throughout the pandemic. Due to underreporting, the data presented are a minimum estimate of the actual magnitude of violence. The findings of this study emphasize the importance of public education campaigns, improved coordination between healthcare organizations and law enforcement, and the possible need to bolster the security of medical facilities and health workers.

The Incidence of Pulmonary Embolism in Hospitalized Non-ICU Patients with COVID-19 during the First Wave: A Multicenter Retrospective Cohort Study in the Netherlands.

INTRODUCTION: During the first COVID-19 outbreak in 2020 in the Netherlands, the incidence of pulmonary embolism (PE) appeared to be high in COVID-19 patients admitted to the intensive care unit (ICU). This study was performed to evaluate the incidence of PE during hospital stay in COVID-19 patients not admitted to the ICU. METHODS: Data were retrospectively collected from 8 hospitals in the Netherlands. Patients admitted between February 27, 2020, and July 31, 2020, were included. Data extracted comprised clinical characteristics, medication use, first onset of COVID-19-related symptoms, admission date due to COVID-19, and date of PE diagnosis. Only polymerase chain reaction (PCR)-positive patients were included. All PEs were diagnosed with computed tomography pulmonary angiography (CTPA). RESULTS: Data from 1,852 patients who were admitted to the hospital ward were collected. Forty patients (2.2%) were diagnosed with PE within 28 days following hospital admission. The median time to PE since admission was 4.5 days (IQR 0.0-9.0). In all 40 patients, PE was diagnosed within the first 2 weeks after hospital admission and for 22 (55%) patients within 2 weeks after onset of symptoms. Patient characteristics, pre-existing comorbidities, anticoagulant use, and laboratory parameters at admission were not related to the development of PE. CONCLUSION: In this retrospective multicenter cohort study of 1,852 COVID-19 patients only admitted to the non-ICU wards, the incidence of CTPA-confirmed PE was 2.2% during the first 4 weeks after onset of symptoms and occurred exclusively within 2 weeks after hospital admission.

Development and validation of a risk prediction model for hospital admission in COVID-19 patients presenting to primary care.

BACKGROUND: There is a paucity of prognostic models for COVID-19 that are usable for in-office patient assessment in general practice (GP). OBJECTIVES: To develop and validate a risk prediction model for hospital admission with readily available predictors. METHODS: A retrospective cohort study linking GP records from 8 COVID-19 centres and 55 general practices in the Netherlands to hospital admission records. The development cohort spanned March to June 2020, the validation cohort March to June 2021. The primary outcome was hospital admission within 14 days. We used geographic leave-region-out cross-validation in the development cohort and temporal validation in the validation cohort. RESULTS: In the development cohort, 4,806 adult patients with COVID-19 consulted their GP (median age 56, 56% female); in the validation cohort 830 patients did (median age 56, 52% female). In the development and validation cohort respectively, 292 (6.1%) and 126 (15.2%) were admitted to the hospital within 14 days, respectively. A logistic regression model based on sex, smoking, symptoms, vital signs and comorbidities predicted hospital admission with a c-index of 0.84 (95% CI 0.83 to 0.86) at geographic cross-validation and 0.79 (95% CI 0.74 to 0.83) at temporal validation, and was reasonably well calibrated (intercept -0.08, 95% CI -0.98 to 0.52, slope 0.89, 95% CI 0.71 to 1.07 at geographic cross-validation and intercept 0.02, 95% CI -0.21 to 0.24, slope 0.82, 95% CI 0.64 to 1.00 at temporal validation). CONCLUSION: We derived a risk model using readily available variables at GP assessment to predict hospital admission for COVID-19. It performed accurately across regions and waves. Further validation on cohorts with acquired immunity and newer SARS-CoV-2 variants is recommended.

A general practice prediction model based on signs and symptoms of COVID-19 patients reliably predicted hospitalisation.The model performed well in second-wave data with other dominant variants and changed testing and vaccination policies.In an emerging pandemic, GP data can be leveraged to develop prognostic models for decision support and to predict hospitalisation rates.

High prevalence of radiographic erosions in early, untreated PsA: results from the SpARRO cohort.

AIMS: To investigate the prevalence and distribution of bone erosions in an early psoriatic arthritis (PsA) population using conventional radiography (CR) and to explore the agreement between CR and ultrasound (US) detected bone erosions. METHODS: Newly diagnosed, treatment naïve PsA patients fulfilling the ClASsification for Psoriatic Arthritis (CASPAR) classification criteria of ≤5 years symptom duration were recruited as part of the Leeds Spondyloarthropathy Register for Research and Observation and underwent CR and US examination of hands and feet. RESULTS: Overall, 4655 hand and feet joints were assessed in 122 patients. CR erosions were detected in 24.6% (n=30) with lowest prevalence seen below 8 months of symptoms (17.5% vs 24.3%>24 months). The number of erosions was higher on CR (1.55% (63/4,655); US 1.04% (34/3,270)), with 5th metatarsophalangeal (MTP) joint being the most affected site in both CR (5.21% (11/211)) and US (7.14% (15/210)). Erosions in CR were more evenly distributed compared with US where three-quarters of the total number of bone erosions were detected in wrists, second metacarpophalangeal (MCP) and fifth MTP joints. Most joints had almost perfect prevalence-adjusted bias-adjusted kappa values ranging from 0.91 to 1. CONCLUSIONS: Erosions were seen in a quarter of patients with newly diagnosed, untreated PsA with a declining trend around the 8-month symptom duration cut-off. High levels of agreement between CR and US were seen with CR detecting more erosions. A focused US assessment of the wrist, second MCP and fifth MTP joints may be useful to detect bone erosions in early PsA.

Risk of developing psoriatic arthritis in psoriasis cohorts with arthralgia: exploring the subclinical psoriatic arthritis stage.

OBJECTIVE: Subjects with subclinical psoriatic arthritis (PsA), defined as the presence of arthralgia in psoriasis (PsO), are at higher risk of PsA but scant real-world data exist. Our aims were to (1) estimate the probability of PsA development in subclinical PsA, (2) characterise subclinical PsA symptoms and (3) determine the clinical patterns at PsA diagnosis. METHODS: Patients with PsO, mainly subclinical PsA, were evaluated longitudinally in two European cohorts. The key outcome was new-onset PsA. Musculoskeletal symptoms including inflammatory and non-inflammatory symptoms before PsA diagnosis were collected. Occurrence of PsA was analysed with survival analysis and cumulative incidence functions (CIFs). RESULTS: 384 patients with PsO were included with a mean follow-up of 33.0 (±20.9) months. 311 of 384 (80.9%) had subclinical PsA with a PsA incidence rate of 7.7 per 100 patient-years. Subclinical PsA displayed a higher risk of PsA development compared with PsO (HR=11.7 (95% CI 1.57 to 86.7), p=0.016). The probability of new-onset PsA estimated by the CIF was 9.4% (95% CI 4.7% to 10.6%) at month 12 and 22.7% (95% CI 17.2% to 28.6%) at month 36. 58.9% of cases reported inflammatory symptoms in the months immediately prior to PsA diagnosis but prior non-inflammatory symptoms were evident in 83.9% prior to PsA diagnosis. Peripheral joint swelling was the predominant PsA presentation pattern (82.1%). CONCLUSIONS: The probability of PsA development among subclinical PsA was relatively high, emphasising the importance of emergent musculoskeletal symptoms when aiming for PsA prevention. Joint swelling was the dominant feature in new-onset PsA, likely reflecting clinical confidence in recognising joint swelling.

The development of lateral flow devices for urinary biomarkers to assess kidney health.

Serum creatinine levels are insensitive to real-time changes in kidney function or injury. There is a growing interest in assessing kidney injury by measuring biomarkers in body fluid. From our previous studies, we identified and reported three urinary biomarkers namely Uromodulin (UMOD), Osteopontin (OPN), and Interleukin-9 (IL-9) to be associated with kidney health. The availability of a rapid point-of-care test for these urinary biomarkers will potentially accelerate its applicability and accessibility. In this study, we aimed to develop novel lateral flow device (LFD) for UMOD, OPN and IL-9. We tested paired antibodies using Enzyme Linked Immunosorbent Assay wherein we observed functionality only for UMOD and OPN and not for IL-9. A conjugation buffer pH of 7.8 and 8.5 was found suitable at a detection antibody concentration of 15 µg/mL for LFD development. The developed LFDs were found to quantitatively measure UMOD standard (LLOD of 80,000 pg/mL) and OPN standard (LLOD of 8600 pg/mL) respectively. The LFD was also able to measure human urinary UMOD and OPN with a percent CV of 12.12 and 5.23 respectively.

Robust parallel laser driving of quantum dots for multiplexing of quantum light sources.

Deterministic sources of quantum light (i.e. single photons or pairs of entangled photons) are required for a whole host of applications in quantum technology, including quantum imaging, quantum cryptography and the long-distance transfer of quantum information in future quantum networks. Semiconductor quantum dots are ideal candidates for solid-state quantum emitters as these artificial atoms have large dipole moments and a quantum confined energy level structure, enabling the realization of single photon sources with high repetition rates and high single photon purity. Quantum dots may also be triggered using a laser pulse for on-demand operation. The naturally-occurring size variations in ensembles of quantum dots offers the potential to increase the bandwidth of quantum communication systems through wavelength-division multiplexing, but conventional laser triggering schemes based on Rabi rotations are ineffective when applied to inequivalent emitters. Here we report the demonstration of the simultaneous triggering of >10 quantum dots using adiabatic rapid passage. We show that high-fidelity quantum state inversion is possible in a system of quantum dots with a 15 meV range of optical transition energies using a single broadband, chirped laser pulse, laying the foundation for high-bandwidth, multiplexed quantum networks.

Guidance for Healthcare Providers on Newest Guidelines for Over-the-Counter Drug Treatment of Mild Symptoms of COVID-19.

On January 18, 2024, the US Centers for Disease Control and Prevention issued their most recent guidelines for over-the-counter drugs for coronavirus disease 2019 (COVID-19). Specifically, the organization stated that "Most people with COVID-19 have mild illness and can recover at home. You can treat symptoms with over-the-counter medicines, such as acetaminophen (Tylenol) or ibuprofen (Motrin, Advil), to help you feel better." In this review we consider the contributions of different types of evidence and conclude that healthcare providers should make individual clinical judgments for each of their patients in the selection of over-the-counter drugs to treat symptoms of COVID-19. This judgment should be based on the entire benefit to risk profile of the patient. It is our belief that the individual healthcare provider knows far more about each of his or her patients than anyone, including expert members of guideline committees. Their astute and judicious individual clinical decision-making for each individual patient based on all these considerations has the potential to do far more good than harm.