The Open Pediatric Cancer Project.

Background: In 2019, the Open Pediatric Brain Tumor Atlas (OpenPBTA) was created as a global, collaborative open-science initiative to genomically characterize 1,074 pediatric brain tumors and 22 patient-derived cell lines. Here, we extend the OpenPBTA to create the Open Pediatric Cancer (OpenPedCan) Project, a harmonized open-source multi-omic dataset from 6,112 pediatric cancer patients with 7,096 tumor events across more than 100 histologies. Combined with RNA-Seq from the Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA), OpenPedCan contains nearly 48,000 total biospecimens (24,002 tumor and 23,893 normal specimens). Findings: We utilized Gabriella Miller Kids First (GMKF) workflows to harmonize WGS, WXS, RNA-seq, and Targeted Sequencing datasets to include somatic SNVs, InDels, CNVs, SVs, RNA expression, fusions, and splice variants. We integrated summarized CPTAC whole cell proteomics and phospho-proteomics data, miRNA-Seq data, and have developed a methylation array harmonization workflow to include m-values, beta-vales, and copy number calls. OpenPedCan contains reproducible, dockerized workflows in GitHub, CAVATICA, and Amazon Web Services (AWS) to deliver harmonized and processed data from over 60 scalable modules which can be leveraged both locally and on AWS. The processed data are released in a versioned manner and accessible through CAVATICA or AWS S3 download (from GitHub), and queryable through PedcBioPortal and the NCI's pediatric Molecular Targets Platform. Notably, we have expanded PBTA molecular subtyping to include methylation information to align with the WHO 2021 Central Nervous System Tumor classifications, allowing us to create research- grade integrated diagnoses for these tumors. Conclusions: OpenPedCan data and its reproducible analysis module framework are openly available and can be utilized and/or adapted by researchers to accelerate discovery, validation, and clinical translation.

Yao syndrome: a novel systemic autoinflammatory disease with cutaneous manifestations.

Yao syndrome (YAOS) is a novel systemic autoinflammatory disease linked to the nucleotide-binding oligomerization domain (NOD2) gene. It is characterized by periodic fevers, gastrointestinal (GI) symptoms, arthritis, and dermatitis, among other symptoms. A sparse literature exists on this disease, and little is known about its dermatological manifestations. A review of available literature was performed to characterize the cutaneous manifestations of Yao syndrome. Cutaneous manifestations were documented in 85.7% of patients, with common characteristic descriptions of erythematous patches and plaques involving the face, trunk, abdomen, and extremities. Based on our review of treatment modalities employed for Yao syndrome, prednisone is an appropriate initial approach, with oral sulfasalazine and other disease-modifying antirheumatic drugs serving as appropriate secondary options. YAOS should be considered in the differential diagnosis of patients presenting with a dermatitic rash, especially in the context of concurrent articular symptoms, periodic fever, and GI symptoms.

Recent Trends in Concomitant Distal Clavicle Excision During Rotator Cuff Repair.

The purpose of this study is to evaluate trends in distal clavicle excision (DCE) in association with arthroscopic rotator cuff repair (RCR) from 2010 to 2019. The National Surgical Quality Improvement Program database was queried to identify all patients who underwent arthroscopic RCR from January 1, 2010 to December 31, 2019, and was further subdivided into procedure type: (1) isolated RCR; and (2) RCR with arthroscopic or open DCE. The proportion of each surgery type, by year and within groups, was calculated. The Cochran-Armitage test for trend was used to analyze yearly proportions of RCR with concomitant DCE. In a sample size of 19,163 patients, the proportion of RCR with DCE decreased from 51.2% to 40.8% (r = -0.830; p = 0.003). Although the results of this study suggest that surgeons are performing fewer DCEs in the setting of RCR, many DCEs are still being done. (Journal of Surgical Orthopaedic Advances 33(2):077-079, 2024).

Robotic Arm-assisted Total Hip Arthroplasty Reduces Postoperative Trochanteric Bursitis and Changes in Hip Offset.

We investigated the effect of robotic assistance in a postoperative change in hip offset and the incidence of trochanteric bursitis among total hip arthroplasty (THA) patients. As part of a retrospective study of a consecutive series of patients over a 3-year period, 211 patients (102 traditional; 109 robotic) between 2013 and 2016 who underwent posterior-lateral THA were reviewed. Hip offset was measured on preoperative and postoperative anterior-posterior (AP) pelvis radiographs. The absolute change in total hip offset was higher in patients undergoing non-robotic THA than in patients undergoing robotic THA (5.98 ± 4.47 mm vs 4.33 ± 3.98 mm; p = 0.008). The rate of symptomatic trochanteric bursitis (p = 0.02) and cortisone injection was higher in non-robotic THA patients than in robotic THA patients (p = 0.002). Robotic arm-assisted THA is associated with a decreased postoperative change in hip offset, incidence of symptomatic trochanteric bursitis, and bursal steroid injections. (Journal of Surgical Orthopaedic Advances 32(4):112-116, 2023).

Lack of nuclear localization of the Creb3l1 transcription factor causes defects in caudal fin bifurcation in zebrafish Danio rerio.

The formation of normal bone and bone healing require the cAMP-responsive element binding protein 3-like-1 (Creb3l1) transmembrane transcription factor, as deletion of the murine CREB3L1 results in osteopenic animals with limited capacity to repair bone after fracture. Creb3l1 undergoes regulated intra-membrane proteolysis (RIP) to release the N-terminal transcription activating (TA) fragment that enters the nucleus and regulates the expression of target genes. To expand our understanding of Creb3l1 role in skeletal development and skeletal patterning, we aimed to generate animals expressing only the TA fragment of Creb3l1 lacking the transmembrane domain and thereby not regulated through RIP. However, the CRISPR/Cas9-mediated genome editing in zebrafish D. rerio caused a frame-shift mutation that added 56 random amino acids at the C-terminus of the TA fragment (TA+), making it unable to enter the nucleus. Thus, TA+ doesn't regulate transcription, and the creb3l1TA+/TA+ fish animals are creb3l1 transcriptional nulls. We document that the creb3l1TA+/TA+ fish exhibit defects in the patterning of caudal fin lepidotrichia, with significantly distalized points of proximal bifurcation and decreased secondary bifurcations. Moreover, using the caudal fin amputation model, we show that creb3l1TA+/TA+ fish have decreased capacity for regeneration, and that their regenerates replicate the distalization and bifurcation defects observed in intact fins of creb3l1TA+/TA+ animals. These defects correlate with altered expression of the shha and ptch2 components of the Sonic Hedgehog signaling pathway in creb3l1TA+/TA+ regenerates. Together, our results uncover a previously unknown intersection between Creb3l1 and the Sonic Hedgehog pathway, and document a novel role of Creb3l1 in tissue patterning.

Microbial diversity and gene abundance in denitrifying bioreactors: A comparison of the woodchip surface biofilm versus the interior wood matrix.

Excessive amounts of nitrogen (N) and phosphorus (P) can lead to eutrophication in water sources. Woodchip bioreactors have shown success in removing N from agricultural runoff, but less is known regarding P removal. Woodchip bioreactors are subsurface basins filled with woodchips installed downgradient of agricultural land to collect and treat drainage runoff. Microorganisms use the woodchips as a carbon (C) source to transform N in the runoff, with unresolved biological impacts on P. This study aims to explore microbial communities present in the bioreactor and determine whether milling woodchips to probe the microbial communities within them reveals hidden microbial diversities or potential activities. Metagenomic sequencing and bioinformatic analyses were performed on six woodchip samples (i.e., three unmilled and three milled) collected from a 10-year-old woodchip bioreactor treating agricultural tile drainage. All samples had similar DNA purity, yield, quality, and microbial diversity regardless of milling. However, when sequences were aligned against various protein libraries, our results indicated greater relative abundance of denitrification and P transformation proteins on the outside of the woodchips (unmilled), while the interior of woodchips (milled) exhibited more functional gene abundance for carbohydrate breakdown. Thus, it may be important to characterize microbial communities both within woodchips, and on woodchip surfaces, to gain a more holistic understanding of coupled biogeochemical cycles on N, P, and C in woodchip bioreactors. Based on these findings, we advise that future microbial research on woodchips (and potentially other permeable organic materials) examine both the surface biofilm and the interior organic material during initial studies. Once researchers determine where specific proteins or enzymes of interest are most prevalent, subsequent studies may then focus on either one or both aspects, as needed.

New Lipophilic Hydroxamates as Promising Trypanocidal Agents: Design, Synthesis, SAR, and Conformational Behavior Studies.

A series of novel hydroxamic acid derivatives was designed and synthesized, and their growth inhibitory activity against bloodstream form Trypanosoma brucei was evaluated. These compounds are based on conformationally constrained, lipophilic, spiro carbocyclic 2,6-diketopiperazine (2,6-DKP) scaffolds and bear a side pharmacophoric functionality that contains an acetohydroxamic acid moiety (CH2CONHOH) linked with the imidic nitrogen atom of the 2,6-DKP ring via an acetamido portion [CH2CON(R), R = H, CH3]. Most of these analogues were active in the midnanomolar to low micromolar range against T. brucei. (S)-Isobutyl- or (S)-benzyl-substitution on the methylene carbon located between the amine nitrogen atom and carbonyl of the 2,6-DKP ring was studied. The effect of the methyl-substitution on the nitrogen atom of the acetamido portion in the side pharmacophoric functionality was also examined. Compounds 22 and 23, bearing an isobutyl- or benzyl-substituent, respectively, and concurrently a methyl-substituent, were found to be the most potent hydroxamates of this series (IC50 = 34 and 53 nM, respectively). Both had promising selectivity over the parasite compared to mammalian cells (SI = 940 and 470, respectively). Moreover, an E/Z conformational behavior study on hydroxamic acid 18 and its methyl-substituted counterpart 21 was undertaken using NMR spectroscopy and theoretical calculations.

Calibration using R-programming and parallel processing at the HUC12 subbasin scale in the Mid-Atlantic region: Development of national SWAT hydrologic calibration.

The first phase of a national scale Soil and Water Assessment Tool (SWAT) model calibration effort at the HUC12 (Hydrologic Unit Code 12) watershed scale was demonstrated over the Mid-Atlantic Region (R02), consisting of 3036 HUC12 subbasins. An R-programming based tool was developed for streamflow calibration including parallel processing for SWAT-CUP (SWAT- Calibration and Uncertainty Programs) to streamline the computational burden of calibration. Successful calibration of streamflow for 415 gages (KGE ≥0.5, Kling-Gupta efficiency; PBIAS ≤15%, Percent Bias) out of 553 selected monitoring gages was achieved in this study, yielding calibration parameter values for 2106 HUC12 subbasins. Additionally, 67 more gages were calibrated with relaxed PBIAS criteria of 25%, yielding calibration parameter values for an additional 150 HUC12 subbasins. This first phase of calibration across R02 increases the reliability, uniformity, and replicability of SWAT-related hydrological studies. Moreover, the study presents a comprehensive approach for efficiently optimizing large-scale multi-site calibration.

Effectiveness of BNT162b2 XBB Vaccine Against XBB and JN.1 Sublineages.

We provide updated results (11 October 2023 through 29 February 2024) from our previously conducted test-negative case-control study in Kaiser Permanente Southern California to evaluate sublineage-specific effectiveness of the BNT162b2 XBB1.5-adapted vaccine. Results suggest that XBB1.5-adapted vaccines may have reduced effectiveness against JN.1 versus XBB sublineages.

Odds of Attaining Orthopaedic Leadership Based on Race, Ethnicity, and Sex.

BACKGROUND: Despite widespread acceptance of the importance of diversity in leadership, systemic challenges in leadership attainment in orthopaedic surgery still exist for several groups. We hypothesize that women, underrepresented in medicine groups, and Asians have decreased odds of achieving program director and chairperson positions compared with peers. METHODS: Demographic data were collected from the Association of American Medical Colleges for faculty, program directors, and chairpersons in orthopaedic surgery. Odds ratios were calculated treating race, ethnicity, or sex as the predictor variables and attainment of a leadership position as the outcome, comparing the composition of program directors in 2020 and chairpersons in 2019 with faculty in 2019. RESULTS: Significantly decreased odds were found for women at 0.37 (0.264 to 0.51 [P < 0.0001]) and the Other category at 0.16 (0.065 to 0.3864 [P = 0.0001]) while significantly increased odds were found for White and Black/African American faculty at 1.32 (1.02 to 1.71 [P = 0.0314]) and 1.95 (1.17 to 3.26 [P = 0.011]), respectively, in holding program director positions. Significantly decreased odds of attaining chairpersonship were found for women at 0.17 (0.07 to 0.41 [P = 0.0075]) and Asian faculty at 0.33 (0.14 to 0.75 [P = 0.0062]) while White faculty demonstrated significantly increased odds at 2.43 (1.41 to 4.19 [P = 0.0013]). CONCLUSIONS: Women showed markedly decreased odds of leadership attainment while Black/African American faculty had increased likelihood of becoming program directors but were not markedly more likely to become chairs. Asian faculty were less likely to become program directors and markedly less likely to become chairs. While decreased odds for women were expected based on current literature, decreased odds of Asians becoming chairs and an increased likelihood of Black/African American orthopaedic surgeons becoming program directors but not attaining the role of chairs at the same rate were novel findings, revealing concerning trends for these groups.

Cognitive emotion regulation and learning effectiveness in college students with ADHD symptoms.

BACKGROUND: College students with ADHD have difficulties with emotion regulation and have poorer academic skills than peers without ADHD; however, less is known regarding the relation between ADHD symptoms, maladaptive cognitive emotion regulation strategies (CERS), and learning effectiveness. OBJECTIVES: We examined whether maladaptive CERS predicted learning effectiveness, and whether this relation was moderated by ADHD symptoms. DESIGN: A cross-sectional online survey. METHODS: College students (N = 4,183; Mage = 19.24; 70.1% female) at eight universities completed a battery as part of a larger study. RESULTS: College students in our elevated ADHD group used significantly more maladaptive CERS and performed worse in three domains of learning effectiveness (i.e., Academic Self-Efficacy [ASE], Organization and Attention to Study [OAS], Stress and Time Press [STP]) than college students in our non-ADHD group. Further, ADHD symptoms moderated the relation between maladaptive CERS and OAS, such that individuals with the highest levels of ADHD symptoms were less impacted by maladaptive CERS. CONCLUSION: Increased use of maladaptive CERS is unique to ADHD rather than lack of adaptive CERS. Also, maladaptive CERS and low ADHD symptoms interact to predict poor OAS. Interventions for college students, regardless of ADHD status, should incorporate emotion regulation components to improve learning effectiveness.

Evolving the Role of Black Race in Hypertension Therapeutics.

Black race has been used to guide antihypertensive drug selection for Black patients based on predominant between race (same drug) and intra-race (different drugs) BP response patterns. Accordingly, thiazide diuretics and calcium antagonists have been recommended over renin angiotensin system (RAS) inhibitors (angiotensin receptor blockers, angiotensin converting enzyme inhibitors) and beta blockers for Black patients. Current antihypertensive drug prescribing reflects historical guidance as calcium antagonist and thiazide diuretics are prescribed more and RAS blockers less in Black than White patients. Hypertension control rates in Blacks, lag those for Whites despite their greater use of combination drug therapy and lesser use of monotherapy. This is also true across drug regimens containing any of the four recommended classes for initial therapy as well as for evidence-based combination drug therapy (calcium antagonist or thiazide diuretic + RAS blocker) regimens for which there is no known racial disparity in BP response. Current recommendations acknowledge the need for combination drug therapy in most, especially in Black patients. One exemplar comprehensive hypertension control program achieved > 80% control rates in Black and White patients with minimal racial disparity while utilizing a race-agnostic therapeutic algorithm. Black patients manifest robust, if not outsized, BP responses to diet/lifestyle modifications. Importantly, race neither appears to be a necessary nor sufficient consideration for selection of effective drug therapy. Accordingly, we urge the initiation of adequately intense race-agnostic drug therapy coupled with greater emphasis on diet/lifestyle modifications for Black patients as the cornerstone of a race-informed approach to hypertension therapeutics.

Consensus Statement: Technical Standards for Thoracoabdominal Normothermic Regional Perfusion.

BACKGROUND: Thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a powerful technique for optimizing organ procurement from donation after circulatory death donors. Despite its rapid adoption, standardized guidelines for TA-NRP implementation are lacking, prompting the need for consensus recommendations to ensure safe and effective utilization of this technique. METHODS: A working group composed of members from The American Society of Transplant Surgeons, The International Society of Heart and Lung Transplantation, The Society of Thoracic Surgeons, and The American Association for Thoracic Surgery was convened to develop technical guidelines for TA-NRP. The group systematically reviewed existing literature, consensus statements, and expert opinions to identify key areas requiring standardization, including predonation evaluation, intraoperative management, postdonation procedures, and future research directions. RESULTS: The working group formulated recommendations encompassing donor evaluation and selection criteria, premortem testing and therapeutic interventions, communication protocols, and procedural guidelines for TA-NRP implementation. These recommendations aim to facilitate coordination among transplant teams, minimize variability in practice, and promote transparency and accountability throughout the TA-NRP process. CONCLUSIONS: The consensus guidelines presented herein serve as a comprehensive framework for the successful and ethical implementation of TA-NRP programs in organ procurement from donation after circulatory death donors. By providing standardized recommendations and addressing areas of uncertainty, these guidelines aim to enhance the quality, safety, and efficiency of TA-NRP procedures, ultimately contributing to improved outcomes for transplant recipients.

Surgical Management of Iatrogenic Mercury Poisoning From Subcutaneous Injection Into the Arm.

BACKGROUND: Mercury, an element with threats of severe toxic insult to humans and no biological function, has a surprisingly extensive record of human exposure. Regardless of hesitancies toward its harmfulness, it has been historically identified with an almost supernatural power to provide protection from evil and sickness, give good fortune, lend aid in athletic undertakings, or even allow one to achieve immortality. Mercury poisoning is an iatrogenic disease even today as people attempt to achieve these effects through volitional injections into their body by practitioners. Although an uncommon practice in the United States, awareness of patient presentation after volitional injections of elemental mercury is necessary for appropriate treatment of these patients. We aim to increase awareness of the cultural practice of subcutaneous injections of mercury, as it is uncommonly seen in the United States, to contribute a broader understanding to the patient's medical presentation and describe an approach and the impact of medical and surgical intervention. METHODS: In this report, we describe a rare case of elemental mercury poisoning secondary to volitional subcutaneous injection to the arm. Initial management of care through chelation therapy and monitoring of renal and serum mercury levels in addition to symptoms of systemic spread was overseen by an internal medicine physician and poison control. Surgical intervention via full-thickness excision of the visible mercury to the right arm followed by local flap and skin grafting reconstruction was performed. CONCLUSIONS: Mercury poisoning from intentional subcutaneous administration is an uncommon patient presentation in the United States; however, knowledge of management of this rare condition is important for effective management of iatrogenic mercury toxicity.

Donor-Derived Mycoplasma and Ureaplasma Infections in Lung Transplant Recipients: A Prospective Study of Donor and Recipient Respiratory Tract Screening and Recipient Outcomes.

Mycoplasma hominis and Ureaplasma species are urogenital mollicutes that can cause serious donor-derived infections in lung transplant recipients. Best practices for mollicute screening remain unknown. We conducted a single center prospective study analyzing lung transplants performed from 10/5/20 - 9/5/21 whereby donor and recipient bronchoalveolar lavage (BAL) samples obtained at time of transplant underwent mollicute screening via culture and polymerase chain reaction (PCR). Of 115 total lung transplants performed, 99 (86%) donors underwent combined mollicute BAL culture and PCR testing. The study cohort included these 99 donors and their matched recipients. In total, 18 (18%) of 99 donors screened positive via culture or PCR. Among recipients, 92 (93%) of 99 had perioperative BAL screening performed, and only 3 (3%) had positive results. After transplant, 9 (9%) recipients developed mollicute infection. Sensitivity of donor screening in predicting recipient mollicute infection was 67% (6/9) via culture and 56% (5/9) via PCR. Positive predictive value (PPV) for donor culture was 75% (6/8), compared to 33% (5/15) for PCR. Donor screening via culture predicted all serious recipient mollicute infections and had better PPV than PCR; however, neither screening test predicted all mollicute infections. Independent of screening results, clinicians should remain suspicious for post-transplant mollicute infection.

Progression of Gestational Subclinical Hypothyroidism and Hypothyroxinemia to Overt Hypothyroidism After Pregnancy: Pooled analysis of Data from Two Randomized Controlled Trials.

BACKGROUND: To examine the incidence of overt hypothyroidism 1 and 5 years after pregnancies where screening before 21 weeks identified subclinical hypothyroidism (SH) or hypothyroxinemia (HT). METHODS: Secondary analysis of two multicenter treatment trials for either SH or HT diagnosed between 8-20 weeks gestation. Current analyses focus only on individuals randomized to the placebo groups in the two parallel studies. SH was diagnosed with TSH ≥ 4.0 mU/L and normal free T4 (fT4) (0.86-1.9 ng/dl). HT was diagnosed with normal TSH (0.08-3.99 mU/L) but fT4 <0.86 ng/dl. Serum from initial testing was stored for later thyroid peroxidase (TPO) antibody assay; results were not returned for clinical management. At 1 and 5 years after delivery, participants were asked whether they had either been diagnosed with, or were being treated for, a thyroid condition. Maternal serum was collected at these visits and thyroid function measured. Subsequent overt hypothyroidism was defined as TSH ≥ 4.0 mU/L with fT4 <0.86 ng/dl. RESULTS: Data for 1- and 5-year follow-up were available in 307 of the 338 participants with SH and 229 of the 261 with HT. Subsequent hypothyroidism was more common both at year 1 (13.4% vs 3.1%, p<0.001) and year 5 (15.6% vs 2.6%, p<0.001) for participants with SH compared with those with HT. This progression was more common in individuals with TSH values >10 mIU/mL Baseline TPO level >50 IU/mL in participants with SH was associated with higher rates of hypothyroidism at year 1 [26.7% vs. 6.5% [OR=5.3 (95% CI: 2.6-10.7)] and year 5 [30.5% vs. 7.5%, [OR=5.4 (95% CI: 2.8-10.6)] compared to those with TPO levels ≤50 IU/mL For participants with HT, no differences in overt hypothyroidism were seen at 1 year related to baseline TPO level >50 IU/mL (1/10 (10%) vs. 6/218 (2.8%), [OR=3.9 (95%CI: 0.43-36.1)], but more participants with TPO levels >50 IU/mL developed hypothyroidism by year 5 [(2/10 (20%) vs. 4/218 (1.8%), [OR=13.4 (95% CI: 2.1-84.1)]. CONCLUSION: SH is associated with higher rates of overt hypothyroidism or thyroid replacement therapy within 5 years of delivery than is hypothyroxinemia when these conditions are diagnosed in the first half of pregnancy.

In Vivo Correlation Between Macular Pigment Optical Volume and Retinal Layers Thickness.

Purpose: This study aims to investigate the potential in vivo relationship between macular pigment (MP) and retinal layers thickness in healthy subjects and dry, non-advanced age-related macular degeneration (AMD). Methods: An observational, cross-sectional study was conducted. Healthy subjects >40 years and patients with early or intermediate AMD were recruited. Structural OCT and macular pigment optical volume (MPOV) were collected for each subject. Retinal layers parameters were calculated based on the standard early treatment diabetic retinopathy study (ETDRS) map. Additionally, MPOV within 1°, 2°, and 9° of eccentricity was assessed and associated with retinal layers thickness and volume. Linear mixed-effects models were used to test the relationship between MP and structural OCT parameters, while adjusting for known possible confounding factors. Results: A total of 144 eyes of 91 subjects (60.4% females) were evaluated, comprising 43% normal eyes and 57% with early/intermediate AMD. Among the retinal layers, only the outer nuclear layer (ONL) thickness and volume appeared to be associated to higher MP levels. Specifically, the central ONL thickness was identified as a significant predictor of the MPOV 1°(P = 0.04), while the parafoveal ONL thickness (inner ETDRS subfield) was identified as a significant fixed effect on the MPOV 9° (P = 0.037). Age and the presence of drusen or subretinal drusenoid deposits were also tested without showing significant correlations. Conclusions: Among the retinal layers examined, only the ONL thickness demonstrated a significant association with MPOV. Consequently, ONL thickness might serve as a potential biomarker related to MP levels.

Changes in primary care visits for respiratory illness during the COVID-19 pandemic: a multinational study by the International Consortium of Primary Care Big Data Researchers (INTRePID).

Objectives: The majority of patients with respiratory illness are seen in primary care settings. Given COVID-19 is predominantly a respiratory illness, the INTernational ConsoRtium of Primary Care BIg Data Researchers (INTRePID), assessed the pandemic impact on primary care visits for respiratory illnesses. Design: Definitions for respiratory illness types were agreed on collectively. Monthly visit counts with diagnosis were shared centrally for analysis. Setting: Primary care settings in Argentina, Australia, Canada, China, Norway, Peru, Singapore, Sweden and the United States. Participants: Over 38 million patients seen in primary care settings in INTRePID countries before and during the pandemic, from January 1st, 2018, to December 31st, 2021. Main outcome measures: Relative change in the monthly mean number of visits before and after the onset of the pandemic for acute infectious respiratory disease visits including influenza, upper and lower respiratory tract infections and chronic respiratory disease visits including asthma, chronic obstructive pulmonary disease, respiratory allergies, and other respiratory diseases. Results: INTRePID countries reported a marked decrease in the average monthly visits for respiratory illness. Changes in visits varied from -10.9% [95% confidence interval (CI): -33.1 to +11.3%] in Norway to -79.9% (95% CI: -86.4% to -73.4%) in China for acute infectious respiratory disease visits and - 2.1% (95% CI: -12.1 to +7.8%) in Peru to -59.9% (95% CI: -68.6% to -51.3%) in China for chronic respiratory illness visits. While seasonal variation in allergic respiratory illness continued during the pandemic, there was essentially no spike in influenza illness during the first 2 years of the pandemic. Conclusion: The COVID-19 pandemic had a major impact on primary care visits for respiratory presentations. Primary care continued to provide services for respiratory illness, although there was a decrease in infectious illness during the COVID pandemic. Understanding the role of primary care may provide valuable information for COVID-19 recovery efforts and planning for future global emergencies.

The Public Health Leader Who Brought Antisepsis to William Halsted.

William Halsted wrote to aging surgeon, Stephen Smith, in 1919, that he remembered the lessons Smith had taught him, "when I walked with you through the wards of Bellevue Hospital." Smith was an early advocate of Joseph Lister's antiseptic method, and because of his public health work, he was also an early advocate of environmental hygiene and microbial control based on the unproved germ theory. While Lister's work at the time emphasized germ-killing around the operative site with carbolic acid (antisepsis), Smith adopted and encouraged surgical practices at Bellevue that would be hallmarks of the germ-preventing (asepsis) surgical approach that fully developed after German bacteriologic discoveries in the mid-1880s, and with which Halsted is historically identified. Some physicians and historians have emphasized temporal and conceptual differences between Lister's antisepsis and German asepsis, but Smith and Halsted's experiences argue that surgical asepsis was the evolutionary outcome of germ theory-based surgical changes that began well before scientific proof arrived.

Broadening The Substrate Scope of Aldolases Through Metagenomic Enzyme Discovery.

Bio-processes based on enzymatic catalysis play a major role in the development of green, sustainable processes, and the discovery of new enzymes is key to this approach. In this work, we analysed ten metagenomes and retrieved 48 genes coding for deoxyribose-5-phosphate aldolases (DERAs, EC 4.1.2.4) using a sequence-based approach. These sequences were recombinantly expressed in Escherichia coli and screened for activity towards a range of aldol additions. Among these, one enzyme, DERA-61, proved to be particularly interesting and catalysed the aldol addition of furfural or benzaldehyde with acetone, butanone and cyclobutanone with unprecedented activity. The product of these reactions, aldols, can find applications as building blocks in the synthesis of biologically active compounds. Screening was carried out to identify optimized reaction conditions targeting temperature, pH, and salt concentrations. Lastly, the kinetics and the stereochemistry of the products were investigated, revealing that DERA-61 and other metagenomic DERAs have superior activity and stereoselectivity when they are provided with non-natural substrates, compared to well-known DERAs.