SER-109, an Oral Microbiome Therapy for Recurrent Clostridioides difficile Infection.

BACKGROUND: Current therapies for recurrent Clostridioides difficile infection do not address the disrupted microbiome, which supports C. difficile spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent C. difficile infection. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of C. difficile infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment. The primary efficacy objective was to show superiority of SER-109 as compared with placebo in reducing the risk of C. difficile infection recurrence up to 8 weeks after treatment. Diagnosis by toxin testing was performed at trial entry, and randomization was stratified according to age and antibiotic agent received. Analyses of safety, microbiome engraftment, and metabolites were also performed. RESULTS: Among the 281 patients screened, 182 were enrolled. The percentage of patients with recurrence of C. difficile infection was 12% in the SER-109 group and 40% in the placebo group (relative risk, 0.32; 95% confidence interval [CI], 0.18 to 0.58; P<0.001 for a relative risk of <1.0; P<0.001 for a relative risk of <0.833). SER-109 led to less frequent recurrence than placebo in analyses stratified according to age stratum (relative risk, 0.24 [95% CI, 0.07 to 0.78] for patients <65 years of age and 0.36 [95% CI, 0.18 to 0.72] for those ≥65 years) and antibiotic received (relative risk, 0.41 [95% CI, 0.22 to 0.79] with vancomycin and 0.09 [95% CI, 0.01 to 0.63] with fidaxomicin). Most adverse events were mild to moderate and were gastrointestinal in nature, with similar numbers in the two groups. SER-109 dose species were detected as early as week 1 and were associated with bile-acid profiles that are known to inhibit C. difficile spore germination. CONCLUSIONS: In patients with symptom resolution of C. difficile infection after treatment with standard-of-care antibiotics, oral administration of SER-109 was superior to placebo in reducing the risk of recurrent infection. The observed safety profile of SER-109 was similar to that of placebo. (Funded by Seres Therapeutics; ECOSPOR III ClinicalTrials.gov number, NCT03183128.).

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19.

BACKGROUND: Severe coronavirus disease 2019 (Covid-19) is associated with dysregulated inflammation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known. METHODS: We conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15. RESULTS: A total of 1033 patients underwent randomization (with 515 assigned to combination treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treatment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, -5.0 percentage points; 95% CI, -9.8 to -0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, -5.3 percentage points; 95% CI, -8.7 to -1.9; P = 0.003). CONCLUSIONS: Baricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.).

Electrostatically Mediated In Situ Polymerization for Enzyme Immobilization and Activation.

Enzyme immobilization in nanoparticles is of interest for boosting their catalytic applications, yet rational approaches to designs achieving both high enzyme loading and activation remain a challenge. Herein, we report an electrostatically mediated in situ polymerization strategy that simultaneously realizes enzyme immobilization and activation. This was achieved by copolymerizing cationic monomers with a cross-linker in the presence of the enzyme lipase (anionic) as the template, which produces enzyme-loaded nanogels. The effects of different control factors such as pH, lipase dosage, and cross-linker fraction on nanogel formation are investigated systematically, and optimal conditions for enzyme loading and activation have been determined. A central finding is that the cationic polymer network of the nanogel creates a favorable environment that not only protects the enzyme but also boosts enzymatic activity nearly 2-fold as compared to free lipase. The nanogels improve the stability of the lipase to tolerate a broader working range of pH (5.5-8.5) and temperature (25-70 °C) and allow recycling such that after six cycles of reaction, 70% of the initial activity is conserved. The established fabrication strategy can be applied generally to different cationic monomers, and most of these nanogels exhibit adequate immobilization and activation of lipase. Our study confirms that in situ polymerization based on electrostatic interaction provides a facile and robust strategy for enzyme immobilization and activation. The wide variety of ionic monomers, therefore, features great potential for developing functional platforms toward satisfying enzyme immobilization and demanding applications.

Comparison of coccidioidal complement fixation and quantitative immunodiffusion serology at a reference laboratory.

The incidence of coccidioidomycosis continues to increase. The diagnosis frequently relies on non-invasive diagnostic testing with immunodiffusion and complement fixation (CF) testing the current gold standard. A direct comparison of quantitative immunodiffusion and CF for IgG antibodies has not been previously reported. In a comparison of 368 samples, there was close concordance observed (360/368 = 97.8%) (P-value < .001). These tests can be considerably interchangeable in the reference laboratory setting.

There are several diagnostic methodologies available in coccidioidomycosis. Direct comparisons of these methods are limited. Prior studies have not compared quantitative immunodiffusion to complement fixation testing. Our results show these tests are highly concordant.

Safety of fluconazole in kidney transplant recipients for prevention of coccidioidomycosis.

Coccidioides is an endemic fungus that causes infections ranging from mild respiratory illness to life-threatening disease, and immunocompromised hosts such as solid organ transplant recipients are at higher risk for disseminated infection and mortality. Our center administers fluconazole prophylaxis to kidney transplant recipients residing in geographic areas with higher incidences of coccidioidomycosis. However, because drug-drug interactions occur between triazoles and immunosuppressants used in transplant medicine, we undertook a study to ascertain whether fluconazole prophylaxis was associated with any important safety outcomes in kidney transplant recipients. This retrospective study evaluated patients who had undergone kidney transplantation between 2016 and 2019. Data on patient demographics, transplant-related clinical information, use of fluconazole prophylaxis (200 mg daily for 6-12 months post-transplant), and patient outcomes were obtained. The primary outcome was mean estimated glomerular filtration rate (eGFR) at 12 months, comparing those who received fluconazole prophylaxis to those who did not. Secondary outcomes included mean eGFR at 3 months, 6 months, and 9 months post-transplant, patient survival, biopsy-proven graft rejection, graft loss, or a new requirement for post-transplant dialysis, all within 12 months post-transplant. The mean eGFR at 12 months was similar between both groups, with 66.4 ml/min/1.73 m² in the fluconazole prophylaxis group vs. 64.3 ml/min/1.73 m² in the non-fluconazole prophylaxis group (P = 0.55). Secondary outcomes were similar across both groups. Multivariable linear regression found no significant association between fluconazole use and graft function. Fluconazole prophylaxis for prevention of coccidioidomycosis was not associated with adverse graft outcomes in kidney transplant recipients.

Solid organ transplant recipients can be highly immune suppressed, and infection with Coccidioides (valley fever) after transplant can lead to severe infections in these patients. Our study showed that fluconazole was safe and effective for preventing Coccidioides in kidney transplant recipients.

Maternal and Fetal Radiation-Induced Cancer Risk From Computed Tomography Pulmonary Angiography During Pregnancy: A Retrospective Cohort Study Across a Multihospital Integrated Health Care Network.

OBJECTIVE: Computed tomography pulmonary angiogram (CTPA) is important to evaluate suspected pulmonary embolism in pregnancy but has maternal/fetal radiation risks. The objective of this study was to estimate maternal and fetal radiation-induced cancer risk from CTPA during pregnancy. METHODS: Simulation modeling via the National Cancer Institute's Radiation Risk Assessment Tool was used to estimate excess cancer risks from 17 organ doses from CTPA during pregnancy, with doses determined by a radiation dose indexing monitoring system. Organ doses were obtained from a radiation dose indexing monitoring system. Maternal and fetal cancer risks per 100,000 were calculated for male and female fetuses and several maternal ages. RESULTS: The 534 CTPA examinations had top 3 maternal organ doses to the breast, lung, and stomach of 17.34, 15.53, and 9.43 mSv, respectively, with a mean uterine dose of 0.21 mSv. The total maternal excess risks of developing cancer per 100,000 were 181, 151, 121, 107, 94.5, 84, and 74.4, respectively, for a 20-, 25-, 30-, 35-, 40-, 45-, and 50-year-old woman undergoing CTPA, compared with baseline cancer risks of 41,408 for 20-year-old patients. The total fetal excess risks of developing cancer per 100,000 were 12.3 and 7.3 for female and male fetuses, respectively, when compared with baseline cancer risks of 41,227 and 48,291. DISCUSSION: Excess risk of developing cancer from CTPA was small relative to baseline cancer risk for pregnant patients and fetuses, decreased for pregnant patients with increasing maternal age, and was greater for female fetuses than male fetuses.

Ultralow-Dose Dynamic Expiratory CT and Repeated Imaging Enhance Evaluation for Tracheomalacia.

OBJECTIVE: This study aims to determine if a novel imaging protocol (ultralow-dose dynamic expiratory computed tomography [CT] with repeated imaging) identifies tracheomalacia (TM) more reliably than traditional dynamic tracheal CT. METHODS: We performed a retrospective evaluation of 184 consecutive ultralow-dose dynamic CTs for TM during 2017. The protocol obtains images during 1 inspiration and 2 forced expirations. Tracheal narrowing during both expirations (airway narrowing [percentage] during first dynamic expiration CT [DE1], airway narrowing [percentage] during second dynamic expiration CT [DE2]) was reported as a percentage of inspiratory area. We identified maximum narrowing of each patient's sequence (maximum narrowing [percentage] on either dynamic expiration CT [DEmax] = greatest narrowing of DE1 or DE2) and compared DE1, DE2, and DEmax in individual studies and between patients. Outcomes included frequency of TM, tracheal narrowing, and severity. Reliability was assessed by comparing tracheal area narrowing and TM grade. RESULTS: There was significantly more airway narrowing using 2 expiratory image acquisitions. Average DEmax tracheal area was 12% narrower than DE1 alone and 21% worse than DE2 alone (both P < 0.001). Using DEmax, TM was diagnosed 35% more often than DE1 alone and 31% more often than DE2 alone ( P < 0.001). DEmax identified more severe distribution of TM compared with DE1 or DE2 alone ( P < 0.001). Reliability between DE1 and DE2 was good for tracheal narrowing and moderate for TM grade. The mean effective radiation dose was 2.41 millisievert (mSv) for routine inspiration CT and 0.07 mSv for each dynamic expiration CT (total effective radiation, 2.55 mSv). CONCLUSIONS: Dynamic expiration CT with 2 expiratory image acquisitions enhanced evaluation of TM, minimally increased radiation dose, and should be considered as a noninvasive screening option.

Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

BACKGROUND: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. METHODS: Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. RESULTS: Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. CONCLUSIONS: In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.

Compassionate Use of Remdesivir for Patients with Severe Covid-19.

BACKGROUND: Remdesivir, a nucleotide analogue prodrug that inhibits viral RNA polymerases, has shown in vitro activity against SARS-CoV-2. METHODS: We provided remdesivir on a compassionate-use basis to patients hospitalized with Covid-19, the illness caused by infection with SARS-CoV-2. Patients were those with confirmed SARS-CoV-2 infection who had an oxygen saturation of 94% or less while they were breathing ambient air or who were receiving oxygen support. Patients received a 10-day course of remdesivir, consisting of 200 mg administered intravenously on day 1, followed by 100 mg daily for the remaining 9 days of treatment. This report is based on data from patients who received remdesivir during the period from January 25, 2020, through March 7, 2020, and have clinical data for at least 1 subsequent day. RESULTS: Of the 61 patients who received at least one dose of remdesivir, data from 8 could not be analyzed (including 7 patients with no post-treatment data and 1 with a dosing error). Of the 53 patients whose data were analyzed, 22 were in the United States, 22 in Europe or Canada, and 9 in Japan. At baseline, 30 patients (57%) were receiving mechanical ventilation and 4 (8%) were receiving extracorporeal membrane oxygenation. During a median follow-up of 18 days, 36 patients (68%) had an improvement in oxygen-support class, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation. CONCLUSIONS: In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo-controlled trials of remdesivir therapy. (Funded by Gilead Sciences.).

Effects of Control Factors on Protein-Polyelectrolyte Complex Coacervation.

Protein-polyelectrolyte complex coacervation is of particular interest for mimicking intracellular phase separation and organization. Yet, the challenge arises from regulating the coacervation due to the globular structure and anisotropic distributed charges of protein. Herein, we fully investigate the different control factors and reveal their effects on protein-polyelectrolyte coacervation. We prepared mixtures of BSA (bovine serum albumin) with different cationic polymers, which include linear and branched polyelectrolytes covering different spacer and charge groups, chain lengths, and polymer structures. With BSA-PDMAEMA [poly(N,N-dimethylaminomethyl methacrylate)] as the main investigated pair, we find that the moderate pH and ionic strength are essential for the adequate electrostatic interaction and formation of coacervate droplets. For most BSA-polymer mixtures, excess polyelectrolytes are required to achieve the full complexation, as evidenced by the deviated optimal charge mixing ratios from the charge stoichiometry. Polymers with longer chains or primary amine groups and a branched structure endow a strong electrostatic interaction with BSA and cause a bigger charge ratio deviation associated with the formation of solid-like coacervate complexes. Nevertheless, both the liquid- and solid-like coacervates hardly interrupt the BSA structure and activity, indicating the safe encapsulation of proteins by the coacervation with polyelectrolytes. Our study validates the crucial control of the diverse factors in regulating protein-polyelectrolyte coacervation, and the revealed principles shall be instructive for establishing other protein-based coacervations and boosting their potential applications.

Ion-Induced Reassembly between Protein Nanotubes and Nanospheres.

Proteins used as building blocks to template nanostructures with manifold morphologies have been widely reported. Understanding their self-assembly and reassembly mechanism is important for designing functional biomaterials. Herein, we show that enzyme-hydrolyzed α-lactalbumin (α-lac) can self-assemble into either nanotubes in the presence of Ca2+ ions or nanospheres in the absence of Ca2+ in solution. Remarkably, such assembled α-lac nanotubes can be elongated by adding preassembled α-lac nanospheres and Ca2+ solution, which suggests that the self-assembled α-lac nanospheres undergo disassembly and reassembly processes into existing nanotube nuclei. By performing atomic force microscopy (AFM), transmission electron microscopy (TEM), and confocal laser scanning microscopy (CLSM), it indicates that there is an equilibrium among nanotubes, nanospheres, hydrolyzed α-lac, and Ca2+ in solution. The structural transition between nanotubes and nanospheres is driven from a less stable structure into a more stable structure determined by the conditions. During the transition from nanospheres into nanotubes, the hydrolyzed α-lac in nanospheres transfers into helical ribbon form at both nanotube extremities. Then helical ribbons close into mature nanotubes, extending the length of the initial nuclei. Besides, by dilution or adding ethylene glycol bis(2-aminoethyl ether) tetraacetic acid (EGTA), the decreased Ca2+ concentration in solution drives the Ca2+ dissociating from nanotubes into solution, leading to the transitions from nanotubes into nanospheres. The reversible transformation between nanotubes and nanospheres is achieved by adjusting the pH value from 7.5 to 5.0 and back to 7.5. This is because the stability of nanotubes decreases from pH 7.5 to 5 but increases from 5 to 7.5. Significantly, this approach can be used for the fabrication of various responsive nanomaterials from the same starting material.

Hierarchical self-assembly of metal-organic supramolecular fibers with lanthanide-derived functionalities.

Achieving organized assembly structures with high complexity and adjustable functionalities is a central quest in supramolecular chemistry. In this report, we study what happens when a discotic benzene-1,3,5-tricarboxamide (BTA) ligand containing three dipicolinic acid (DPA) groups is allowed to coordinate with lanthanide (Ln) ions. A multi-BTA coordination cluster forms, which behaves as a type of "supramolecular monomer", stacking into fibers via hydrogen bonds enabled by multiple BTA cores. The fibrous morphology and size, as well as the packing unit and the process by which it grows, were investigated by light scattering measurements, luminescence spectra, TEM images and molecular simulation data. More notably, by selecting the kind of lanthanide or mixture of lanthanides that is incorporated, tunable luminescence and magnetic relaxation properties without compromising the fibrous structure can be realized. This case of hierarchical self-assembly is made possible by the special structure of our BTA-like building block, which makes non-covalent bond types that are different along the radial (coordination bonds) and axial (H-bonds) directions, respectively, each with just the right strength. Moreover, the use of lanthanide coordination leads to materials with metal-derived optical and magnetic properties. Therefore, the established approach demonstrates a novel strategy for designing and fabrication of multi-functional supramolecular materials.

Synthesis of zwitterionic polyelectrolyte nanogels via electrostatic-templated polymerization.

Zwitterionic polyelectrolyte nanogels are prospective nanocarriers due to their soft loading pocket and regulated charges. We here report a facile strategy, namely, electrostatic-templated polymerization (ETP) for synthesizing zwitterionic nanogels with controlled size and properties. Specifically, with anionic-neutral diblock polymers as the template, zwitterionic monomers such as carboxybetaine methacrylate (CBMA) or carboxybetaine acrylamide (CBAA) are polymerized together with a cross-linker at pH 2 where the monomers exhibit only positive charge due to the protonation of the carboxyl group. The obtained polyelectrolyte complex micelles dissociate upon introducing a concentrated salt. The subsequent separation yields the released template and zwitterionic nanogels with regulated size and swelling ability, achieved by tuning the salt concentration and cross-linker fraction during polymerization. The obtained PCBMA nanogels exhibit charges depending on the pH, which enables not only the selective loading of different dye molecules, but also encapsulation and intracellular delivery of cytochrome c protein. Our study develops a facile and robust way for fabricating zwitterionic nanogels and validates their potential applications as promising nanocarriers for load and delivery of functional charged cargos.

Temporal Improvements in COVID-19 Outcomes for Hospitalized Adults: A Post Hoc Observational Study of Remdesivir Group Participants in the Adaptive COVID-19 Treatment Trial.

BACKGROUND: The COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear. OBJECTIVE: To evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial). DESIGN: ACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]). SETTING: 94 hospitals in 10 countries (86% U.S. participants). PARTICIPANTS: Adults hospitalized with COVID-19. INTERVENTION: SOC. MEASUREMENTS: 28-day mortality and recovery. RESULTS: Although outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages. LIMITATION: Unmeasured confounding. CONCLUSION: Changes in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas. PRIMARY FUNDING SOURCE: National Institute of Allergy and Infectious Diseases.

Patient and Fetal Radiation-Induced Malignancy Risk From Imaging For Evaluation of Pulmonary Embolism in Pregnancy.

BACKGROUND: Imaging for diagnosis of suspected pulmonary embolism in pregnancy presents radiation concerns for patient and fetus. OBJECTIVES: Estimate the risks of radiation-induced breast cancer and childhood leukemia from common imaging techniques for the evaluation of suspected pulmonary embolism in pregnancy. METHODS: Breast and uterine absorbed doses for various imaging techniques were input into the National Cancer Institute Radiation Risk Assessment Tool to calculate risk of breast cancer for the patient and childhood leukemia for the fetus. Absorbed doses were obtained by synthesizing data from a recent systematic review and the International Commission on Radiological Protection. Primary outcomes were the estimated excess incidences of breast cancer and childhood leukemia per 100,000 exposures. RESULTS: Baseline incidences of breast cancer for a 30-year-old woman and childhood leukemia for a male fetus were 13,341 and 939, respectively. Excess incidences of breast cancer were 0.003 and 0.275 for a single and two-view chest radiograph, respectively, 9.53 and 20.6 for low- and full-dose computed tomography pulmonary angiography (CTPA), respectively, 0.616 and 2.54 for low- and full-dose perfusion scan, respectively, and 0.732 and 2.66 for low- and full-dose ventilation perfusion scan, respectively. Excess incidences of childhood leukemia were 0.004 and 0.007 for a single and two-view chest radiograph, respectively, 0.069 and 0.490 for low- and full-dose CTPA, respectively, 0.359 and 1.47 for low- and full-dose perfusion scan, respectively, and 0.856 and 1.97 for low- and full-dose ventilation perfusion scan, respectively. CONCLUSION: Excess cancer risks for all techniques were small relative to baseline cancer risks, with CTPA techniques carrying slightly higher risk of breast cancer for the patient and ventilation perfusion techniques a higher risk of childhood leukemia.

Fluorescent Probes Based on AIEgen-Mediated Polyelectrolyte Assemblies for Manipulating Intramolecular Motion and Magnetic Relaxivity.

Uniting photothermal therapy (PTT) with magnetic resonance imaging (MRI) holds great potential in nanotheranostics. However, the extensively utilized hydrophobicity-driven assembling strategy not only restricts the intramolecular motion-induced PTT, but also blocks the interactions between MR agents and water. Herein, we report an aggregation-induced emission luminogen (AIEgen)-mediated polyelectrolyte nanoassemblies (APN) strategy, which bestows a unique "soft" inner microenvironment with good water permeability. Femtosecond transient spectra verify that APN well activates intramolecular motion from the twisted intramolecular charge transfer process. This de novo APN strategy uniting synergistically three factors (rotational motion, local motion, and hydration number) brings out high MR relaxivity. For the first time, APN strategy has successfully modulated both intramolecular motion and magnetic relaxivity, achieving fluorescence lifetime imaging of tumor spheroids and spatio-temporal MRI-guided high-efficient PTT.

Secondary Cases of Delta Variant Coronavirus Disease 2019 Among Vaccinated Healthcare Workers With Breakthrough Infections is Rare.

In a retrospective, cohort study at 4 medical centers with high coronavirus disease 2019 vaccination rates, we evaluated breakthrough severe acute respiratory syndrome coronavirus 2 Delta variant infections in vaccinated healthcare workers. Few work-related secondary cases were identified. Breakthrough cases were largely due to unmasked social activities outside of work.

Clinical Metagenomic Sequencing for Diagnosis of Meningitis and Encephalitis.

BACKGROUND: Metagenomic next-generation sequencing (NGS) of cerebrospinal fluid (CSF) has the potential to identify a broad range of pathogens in a single test. METHODS: In a 1-year, multicenter, prospective study, we investigated the usefulness of metagenomic NGS of CSF for the diagnosis of infectious meningitis and encephalitis in hospitalized patients. All positive tests for pathogens on metagenomic NGS were confirmed by orthogonal laboratory testing. Physician feedback was elicited by teleconferences with a clinical microbial sequencing board and by surveys. Clinical effect was evaluated by retrospective chart review. RESULTS: We enrolled 204 pediatric and adult patients at eight hospitals. Patients were severely ill: 48.5% had been admitted to the intensive care unit, and the 30-day mortality among all study patients was 11.3%. A total of 58 infections of the nervous system were diagnosed in 57 patients (27.9%). Among these 58 infections, metagenomic NGS identified 13 (22%) that were not identified by clinical testing at the source hospital. Among the remaining 45 infections (78%), metagenomic NGS made concurrent diagnoses in 19. Of the 26 infections not identified by metagenomic NGS, 11 were diagnosed by serologic testing only, 7 were diagnosed from tissue samples other than CSF, and 8 were negative on metagenomic NGS owing to low titers of pathogens in CSF. A total of 8 of 13 diagnoses made solely by metagenomic NGS had a likely clinical effect, with 7 of 13 guiding treatment. CONCLUSIONS: Routine microbiologic testing is often insufficient to detect all neuroinvasive pathogens. In this study, metagenomic NGS of CSF obtained from patients with meningitis or encephalitis improved diagnosis of neurologic infections and provided actionable information in some cases. (Funded by the National Institutes of Health and others; PDAID ClinicalTrials.gov number, NCT02910037.).

Synthesis of Anionic Nanogels for Selective and Efficient Enzyme Encapsulation.

Polyelectrolyte nanogels containing cross-linked ionic polymer networks feature both soft environment and intrinsic charges which are of great potential for enzyme encapsulation. In this work, well-defined poly(acrylic acid) (PAA) nanogels have been synthesized based on a facile strategy, namely, electrostatic assembly directed polymerization (EADP). Specifically, AA monomers are polymerized together with a cross-linker in the presence of a cationic-neutral diblock copolymer as the template. Effects of control factors including pH, salt concentration, and cross-linking degree have been investigated systematically, based on which the optimal preparation of PAA nanogels has been established. The obtained nanogel features not only compatible pocket for safely loading enzymes without disturbing their structures, but also abundant negative charges which enable selective and efficient encapsulation of cationic enzymes. The loading capacities of PAA nanogels for cytochrome (cyt c) and lysozyme are 100 and 125 µg/mg (enzyme/nanogel), respectively. More notably, the PAA network seems to modulate a favorable microenvironment for cyt c and induces 2-fold enhanced activity for the encapsulated enzymes, as indicated by the steady-state kinetic assay. Our study reveals the control factors of EADP for optimal synthesis of anionic nanogels and validates their distinctive advances with respect to efficient loading and activation of cationic enzymes.

Dendrimer-Based Polyion Complex Vesicles: Loops Make Loose.

Associations of amphiphiles assume their various morphologies according to the so-called packing parameter under thermodynamic control. However, one may raise the question of whether polymers can always relax fast enough to obey thermodynamic control, and how this may be checked. Here, a case of polyion complex (PIC) assemblies where the morphology appears to be subject to kinetic control is discussed. Poly (ethylene oxide)-b-(styrene sulfonate) block copolymers are combined with cationic PAMAM dendrimers of various generations (2-7). The PEO-PSS diblocks, and the corresponding PSS-PEO-PSS triblocks should have nearly identical packing parameters, but surprisingly creat different assemblies, namely core-shell micelles and vesicles, respectively. Moreover, the micelles are very stable against added salt, whereas the vesicles are not only much more sensitive to added salt, but also appear to exchange matter on relevant time scales. The small and largely quenched early-stage precursor complexes are responsible for the morphological and dynamic differences, implying that kinetic control may also be a way to obtain particles with well-defined and useful properties. The exciting new finding that triblocks produce more "active" vesicles will hopefully trigger the exploration of more pathways, and so learn how to tune PICsomes toward specific applications.