Reconstructing Prehistoric African Population Structure.

We assembled genome-wide data from 16 prehistoric Africans. We show that the anciently divergent lineage that comprises the primary ancestry of the southern African San had a wider distribution in the past, contributing approximately two-thirds of the ancestry of Malawi hunter-gatherers ∼8,100-2,500 years ago and approximately one-third of the ancestry of Tanzanian hunter-gatherers ∼1,400 years ago. We document how the spread of farmers from western Africa involved complete replacement of local hunter-gatherers in some regions, and we track the spread of herders by showing that the population of a ∼3,100-year-old pastoralist from Tanzania contributed ancestry to people from northeastern to southern Africa, including a ∼1,200-year-old southern African pastoralist. The deepest diversifications of African lineages were complex, involving either repeated gene flow among geographically disparate groups or a lineage more deeply diverging than that of the San contributing more to some western African populations than to others. We finally leverage ancient genomes to document episodes of natural selection in southern African populations. PAPERCLIP.

Modeling recent human evolution in mice by expression of a selected EDAR variant.

An adaptive variant of the human Ectodysplasin receptor, EDARV370A, is one of the strongest candidates of recent positive selection from genome-wide scans. We have modeled EDAR370A in mice and characterized its phenotype and evolutionary origins in humans. Our computational analysis suggests the allele arose in central China approximately 30,000 years ago. Although EDAR370A has been associated with increased scalp hair thickness and changed tooth morphology in humans, its direct biological significance and potential adaptive role remain unclear. We generated a knockin mouse model and find that, as in humans, hair thickness is increased in EDAR370A mice. We identify new biological targets affected by the mutation, including mammary and eccrine glands. Building on these results, we find that EDAR370A is associated with an increased number of active eccrine glands in the Han Chinese. This interdisciplinary approach yields unique insight into the generation of adaptive variation among modern humans.

Ancient West African foragers in the context of African population history.

Our knowledge of ancient human population structure in sub-Saharan Africa, particularly prior to the advent of food production, remains limited. Here we report genome-wide DNA data from four children-two of whom were buried approximately 8,000 years ago and two 3,000 years ago-from Shum Laka (Cameroon), one of the earliest known archaeological sites within the probable homeland of the Bantu language group1-11. One individual carried the deeply divergent Y chromosome haplogroup A00, which today is found almost exclusively in the same region12,13. However, the genome-wide ancestry profiles of all four individuals are most similar to those of present-day hunter-gatherers from western Central Africa, which implies that populations in western Cameroon today-as well as speakers of Bantu languages from across the continent-are not descended substantially from the population represented by these four people. We infer an Africa-wide phylogeny that features widespread admixture and three prominent radiations, including one that gave rise to at least four major lineages deep in the history of modern humans.

Identification of a system for hydroxamate xenosiderophore-mediated iron transport in Burkholderia cenocepacia.

One of the mechanisms employed by the opportunistic pathogen Burkholderia cenocepacia to acquire the essential element iron is the production and release of two ferric iron chelating compounds (siderophores), ornibactin and pyochelin. Here we show that B. cenocepacia is also able to take advantage of a range of siderophores produced by other bacteria and fungi ('xenosiderophores') that chelate iron exclusively by means of hydroxamate groups. These include the tris-hydroxamate siderophores ferrioxamine B, ferrichrome, ferricrocin and triacetylfusarinine C, the bis-hydroxamates alcaligin and rhodotorulic acid, and the monohydroxamate siderophore cepabactin. We also show that of the 24 TonB-dependent transporters encoded by the B. cenocepacia genome, two (FhuA and FeuA) are involved in the uptake of hydroxamate xenosiderophores, with FhuA serving as the exclusive transporter of iron-loaded ferrioxamine B, triacetylfusarinine C, alcaligin and rhodotorulic acid, while both FhuA and FeuA are able to translocate ferrichrome-type siderophores across the outer membrane. Finally, we identified FhuB, a putative cytoplasmic membrane-anchored ferric-siderophore reductase, as being obligatory for utilization of all of the tested bis- and tris-hydroxamate xenosiderophores apart from alcaligin.

S100A8/A9 drives the formation of procoagulant platelets through GPIbα.

S100A8/A9, also known as "calprotectin" or "MRP8/14," is an alarmin primarily secreted by activated myeloid cells with antimicrobial, proinflammatory, and prothrombotic properties. Increased plasma levels of S100A8/A9 in thrombo-inflammatory diseases are associated with thrombotic complications. We assessed the presence of S100A8/A9 in the plasma and lung autopsies from patients with COVID-19 and investigated the molecular mechanism by which S100A8/A9 affects platelet function and thrombosis. S100A8/A9 plasma levels were increased in patients with COVID-19 and sustained high levels during hospitalization correlated with poor outcomes. Heterodimeric S100A8/A9 was mainly detected in neutrophils and deposited on the vessel wall in COVID-19 lung autopsies. Immobilization of S100A8/A9 with collagen accelerated the formation of a fibrin-rich network after perfusion of recalcified blood at venous shear. In vitro, platelets adhered and partially spread on S100A8/A9, leading to the formation of distinct populations of either P-selectin or phosphatidylserine (PS)-positive platelets. By using washed platelets, soluble S100A8/A9 induced PS exposure but failed to induce platelet aggregation, despite GPIIb/IIIa activation and alpha-granule secretion. We identified GPIbα as the receptor for S100A8/A9 on platelets inducing the formation of procoagulant platelets with a supporting role for CD36. The effect of S100A8/A9 on platelets was abolished by recombinant GPIbα ectodomain, platelets from a patient with Bernard-Soulier syndrome with GPIb-IX-V deficiency, and platelets from mice deficient in the extracellular domain of GPIbα. We identified the S100A8/A9-GPIbα axis as a novel targetable prothrombotic pathway inducing procoagulant platelets and fibrin formation, in particular in diseases associated with high levels of S100A8/A9, such as COVID-19.

Bidirectional Associations Between Loneliness, Emotional Support, and Sleep in Daily Life.

OBJECTIVE: Evidence suggests a link between positive social relationship perceptions and improved sleep (e.g., quality, efficiency) across the life span. Less work has probed the directionality of these relationships. Here, we report findings from the first study to examine bidirectional between- and within-person associations between loneliness and emotional support with daily life measures of sleep. METHODS: Participants were 389 healthy adults aged 40 to 64 years (61% female) who completed hourly surveys assessing loneliness and perceptions of emotional support over the course of 4 days. Measures of actigraphy-assessed sleep and nightly sleep quality were also assessed for 7 to 10 days. RESULTS: Individuals with lower average daily loneliness showed higher sleep quality and efficiency than individuals with higher loneliness (r = -0.19, p < .001; r = -0.14, p = .008, respectively), and greater average emotional support was likewise linked with better sleep quality (r = 0.18, p < .001). Controlling for neuroticism attenuated the effects of average loneliness on sleep. Within-person analyses showed unexpected bidirectional effects. Specifically, days in which people felt relatively lonelier were followed by nights with greater sleep efficiency (γ = 1.08, p = .015), and nights when people reported relatively poorer sleep quality were followed by days with greater emotional support (γ = -0.04, p = .013). These unexpected findings are probed in exploratory analyses. CONCLUSIONS: Individuals with higher loneliness and lower emotional support report poorer sleep quality and efficiency, on average. Day-to-day fluctuations in perceptions of social relationships may affect the following night's sleep, and vice versa.

Behavioral-Social Rhythms and Cardiovascular Disease Risk in Retired Night Shift Workers and Retired Day Workers.

OBJECTIVE: Stability in the timing of key daily routine behaviors such as working/doing housework, sleeping, eating, and engaging in social interactions (i.e., behavioral-social rhythms) contributes to health. This study examined whether behavioral-social rhythms were associated with cardiovascular disease (CVD) risk factors in retired night shift workers and retired day workers and explored whether past night shift work exposure moderated this association. METHODS: A total of 154 retired older adults participated in this study. Multiple logistic regression models were used to examine associations between behavioral-social rhythms and CVD risk factors. Independent variables included Social Rhythm Metric (SRM)-5 score and actigraphy rest-activity rhythm intradaily variability (IV) and interdaily stability (IS). Dependent variables were metabolic syndrome prevalence and its five individual components. RESULTS: More regular behavioral-social rhythms were associated with lower odds of prevalent metabolic syndrome (SRM: odds ratio [OR] = 0.57, 95% confidence interval [CI] = 0.35-0.88; IV: OR = 4.00, 95% CI = 1.86-8.58; IS: OR = 0.42, 95% CI = 0.24-0.73) and two of its individual components: body mass index (SRM: OR = 0.56, 95% CI = 0.37-0.85; IV: OR = 2.84, 95% CI = 1.59-5.07; IS: OR = 0.42, 95% CI = 0.26-0.68) and high-density lipoprotein cholesterol (SRM: OR = 0.49, 95% CI = 0.30-0.80; IV: OR = 2.49, 95% CI = 1.25-4.96; IS: OR = 0.35, 95% CI = 0.19-0.66). Past shift work history did not moderate the association between behavioral-social rhythms and metabolic syndrome. CONCLUSIONS: Behavioral-social rhythms were related to CVD risk factors in retired adults regardless of prior night shift work exposure. Older retired workers may benefit from education and interventions aiming to increase behavioral-social rhythm regularity.

Assessing the Sympatholytic Effects of SGLT2 Inhibitors in Anuric Haemodialysis Patients Using Microneurography: Study Protocol for a Mechanistic Proof-of-Concept Trial.

INTRODUCTION: Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have been shown to provide effective cardiorenal protection, reducing mortality in conditions such as heart failure and chronic kidney disease. While several mechanisms have been identified, recent research has shed light on the drug's ability to attenuate sympathetic nervous system (SNS) activity. Controversy exists on whether this is due to the extra-renal effects of the drug, or simply due to its renoprotective effects. However, recent trials have highlighted the persistent efficacy of SGLT2i despite declining renal function. Therefore, investigating the ability of SGLT2i to attenuate the SNS independently of the kidney could lead to more insight into its mechanism of action. So far, there has been limited research done on investigating the extra-renal effects of SGLT2i in human subjects on dialysis where the glycosuric renal effects of SGLT2i are negligible. This current study therefore aims to investigate the effects of SGLT2i on the SNS in anuric haemodialysis patients. METHODS: We developed a protocol for a mechanistic study to investigate the extra-renal effects of SGLT2i on the SNS. The study will be an investigator-led, open-label, prospective study involving 20 adult (aged ≥18 years) haemodialysis patients with a residual urine output of ≤250 mL/day. Participants will be administered empagliflozin 25 mg/day for 6 weeks. Baseline SNS activity will be measured before and after administration by microneurography to assess central SNS outflow. Secondary outcomes such as changes from baseline in SNS stressor response, heart rate variability, and endothelial function will also be examined. We hypothesize that the use of empagliflozin will result in reduced sympathetic drive in anuric haemodialysis patients. DISCUSSION: This will be the first study evaluating the effects of SGLT2i on the SNS in haemodialysis subjects. This study aims to enhance our understanding of the potential role of SGLT2i-induced SNS reduction in the setting of markedly reduced renal function. The study has received ethics approval from the Royal Perth Hospital Human Research Ethics Committee (RGS0000003840) (Australian New Zealand Clinical Trials Registry [ANZCTR] ID: ACTRN12623001237673).

Fabry-specific treatment in Australia: time to align eligibility criteria with international best practices.

BACKGROUND: Disease-specific therapy aims to improve symptoms, stabilise current disease and delay progression in patients with Fabry disease. In Australia, treatment access is subject to eligibility criteria initially established in 2004. Patients and their clinicians question why these criteria have remained unchanged despite significant progress in disease understanding. AIMS: Appraise the clinical quality of the Australian treatment access criteria. METHODS: The Fabry Australia Medical Advisory Committee (N = 6) used the Appraisal of Guidelines for REsearch and Evaluation Global Rating Scale (AGREE II GRS) to assess the clinical quality of the current treatment eligibility criteria. They reviewed the literature, developed 17 clinical statements to help guide reforms of the eligibility criteria and achieved consensus (achievement of ≥75% agreement in the range 5-7 on a 7-point Likert scale) through anonymous voting. The findings were applied to develop proposals for revised classification and treatment initiation criteria. RESULTS: The current treatment eligibility criteria underperformed on the AGREE II GRS. They are pragmatic but out-of-step with contemporary data. Consensus was achieved on all 17 proposed clinical statements. There was strong agreement to differentiate classical male Fabry patients to facilitate timelier access to Fabry-specific treatment. There was also agreement on the value of adopting relevant organ involvement criteria in classical female patients and patients with non-classical disease. CONCLUSIONS: Australian access criteria are misaligned with current clinical evidence. The clinical statements and proposed classification and initiation criteria should prompt discussions to support more equitable access to treatment and better align Australian practice with contemporary evidence and international guidelines.

Same sleep disorder but different sleep patterns: individual differences in sleep health and depressive symptomatology in veterans with obstructive sleep apnea.

PURPOSE: Poor sleep health, a composite measure of key sleep characteristics, may relate to increased depressive symptoms among individuals treated for obstructive sleep apnea. The current investigation examined the association between sleep health and depressive symptomatology. METHODS: In a pilot sample of 13 symptomatic OSA military Veterans with adequate CPAP adherence (mean age = 54.8, 76.9% male, 100% White), empirically validated cutoffs were applied to actigraphy-derived sleep variables: duration, efficiency, timing, and regularity. RESULTS: Participants with zero optimal sleep scores had significantly higher depressive scores (M = 19.0, SD = 3.0) than participants with 1 or 2 (M = 9.8. SD = 4.3, p = .016) and 3 or more optimal sleep scores (M = 11.3, SD = 4.9, p = .038). CONCLUSIONS: These preliminary findings suggest that better sleep health was associated with lower depressive symptomatology. Future work should replicate these preliminary findings in a larger sample.

The Burkholderia cenocepacia iron starvation σ factor, OrbS, possesses an on-board iron sensor.

Burkholderia cenocepacia is an opportunistic pathogen that causes severe infections of the cystic fibrosis (CF) lung. To acquire iron, B. cenocepacia secretes the Fe(III)-binding compound, ornibactin. Genes for synthesis and utilisation of ornibactin are served by the iron starvation (IS) extracytoplasmic function (ECF) σ factor, OrbS. Transcription of orbS is regulated in response to the prevailing iron concentration by the ferric uptake regulator (Fur), such that orbS expression is repressed under iron-sufficient conditions. Here we show that, in addition to Fur-mediated regulation of orbS, the OrbS protein itself responds to intracellular iron availability. Substitution of cysteine residues in the C-terminal region of OrbS diminished the ability to respond to Fe(II) in vivo. Accordingly, whilst Fe(II) impaired transcription from and recognition of OrbS-dependent promoters in vitro by inhibiting the binding of OrbS to core RNA polymerase (RNAP), the cysteine-substituted OrbS variant was less responsive to Fe(II). Thus, the cysteine residues within the C-terminal region of OrbS contribute to an iron-sensing motif that serves as an on-board 'anti-σ factor' in the presence of Fe(II). A model to account for the presence two regulators (Fur and OrbS) that respond to the same intracellular Fe(II) signal to control ornibactin synthesis and utilisation is discussed.

Structural characterization of a novel GPVI-nanobody complex reveals a biologically active domain-swapped GPVI dimer.

Glycoprotein VI (GPVI) is the major signaling receptor for collagen on platelets. We have raised 54 nanobodies (Nb), grouped into 33 structural classes based on their complementary determining region 3 loops, against recombinant GPVI-Fc (dimeric GPVI) and have characterized their ability to bind recombinant GPVI, resting and activated platelets, and to inhibit platelet activation by collagen. Nbs from 6 different binding classes showed the strongest binding to recombinant GPVI-Fc, suggesting that there was not a single dominant class. The most potent 3, Nb2, 21, and 35, inhibited collagen-induced platelet aggregation with nanomolar half maximal inhibitory concentration (IC50) values and inhibited platelet aggregation under flow. The binding KD of the most potent Nb, Nb2, against recombinant monomeric and dimeric GPVI was 0.6 and 0.7 nM, respectively. The crystal structure of monomeric GPVI in complex with Nb2 revealed a binding epitope adjacent to the collagen-related peptide (CRP) binding groove within the D1 domain. In addition, a novel conformation of GPVI involving a domain swap between the D2 domains was observed. The domain swap is facilitated by the outward extension of the C-C' loop, which forms the domain swap hinge. The functional significance of this conformation was tested by truncating the hinge region so that the domain swap cannot occur. Nb2 was still able to displace collagen and CRP binding to the mutant, but signaling was abolished in a cell-based NFAT reporter assay. This demonstrates that the C-C' loop region is important for GPVI signaling but not ligand binding and suggests the domain-swapped structure may represent an active GPVI conformation.

Sex Differences in Cocaine Sensitization Vary by Mouse Strain.

INTRODUCTION: Preclinical literature, frequently utilizing rats, suggests females display a more rapid advancement of substance abuse and a greater risk of relapse following drug abstinence. In clinical populations, it is less clear as to what extent biological sex is a defining variable in the acquisition and maintenance of substance use. Even without considering environmental experiences, genetic factors are presumed to critically influence the vulnerability to addiction. Genetically diverse mouse models provide a robust tool to examine the interactions between genetic background and sex differences in substance abuse. METHODS: We explored mouse strain variability in male versus female behavioral sensitization to cocaine. Locomotor sensitization was observed following 5 consecutive days of subcutaneous cocaine across three genetically different mice strains: C57BL/6J, B6129SF2/J, and Diversity Outbred (DO/J). RESULTS: Sex differences in cocaine locomotor sensitization were dependent on mouse strain. Specifically, we observed opposing sex differences in locomotor sensitization, with male C57BL/6J and female B6129SF2/J mice displaying heightened activity compared to their opposite sex counterparts. Conversely, no sex differences were observed in the DO/J mice. Acute cocaine administration resulted in locomotor differences across strains in male, but not female, mice. The magnitude of sensitization (or lack thereof) also varied by genetic background. CONCLUSIONS: While sex differences in drug addiction may be observed, these effects can be mitigated, or even reversed, depending on genetic background. The clinical implications are that in the absence of understanding the genetic variables underlying vulnerability to addiction, sex provides little information regarding the predisposition of an individual to drug abuse.

Changing Mindsets About Side Effects of the COVID-19 Vaccination: A Randomized Controlled Trial.

BACKGROUND: Side-effect concerns are a major barrier to vaccination against COVID-19 and other diseases. Identifying cost- and time-efficient interventions to improve vaccine experience and reduce vaccine hesitancy-without withholding information about side effects-is critical. PURPOSE: Determine whether a brief symptom as positive signals mindset intervention can improve vaccine experience and reduce vaccine hesitancy after the COVID-19 vaccination. METHODS: English-speaking adults (18+) were recruited during the 15-min wait period after receiving their second dose of the Pfizer COVID-19 vaccination and were randomly allocated to the symptom as positive signals mindset condition or the treatment as usual control. Participants in the mindset intervention viewed a 3:43-min video explaining how the body responds to vaccinations and how common side effects such as fatigue, sore arm, and fever are signs that the vaccination is helping the body boost immunity. The control group received standard vaccination center information. RESULTS: Mindset participants (N = 260) versus controls (N = 268) reported significantly less worry about symptoms at day 3 [t(506)=2.60, p=.01, d=0.23], fewer symptoms immediately following the vaccine [t(484)=2.75, p=.006, d=0.24], and increased intentions to vaccinate against viruses like COVID-19 in the future [t(514)=-2.57, p=.01, d=0.22]. No significant differences for side-effect frequency at day 3, coping, or impact. CONCLUSIONS: This study supports the use of a brief video aimed at reframing symptoms as positive signals to reduce worry and increase future vaccine intentions. CLINICAL TRIAL INFORMATION: Australian New Zealand Clinical Trials Registry: ACTRN12621000722897p.

Side-effect concerns are a major barrier to vaccination against COVID-19 and other diseases. Therefore, the purpose of this study was to determine whether a brief symptom as positive signals mindset intervention could improve vaccine experience and reduce vaccine hesitancy after the COVID-19 vaccination. Participants were recruited during the 15-min wait period after receiving their second dose of the Pfizer COVID-19 vaccination and were randomly allocated to a treatment as usual control condition or to a mindset intervention condition which entailed watching a 3:43-min video explaining how the body responds to vaccinations and how common side effects such as fatigue, sore arm, and fever are signs that the vaccination is helping the body boost immunity. Compared with participants in the control condition, participants in the mindset intervention condition reported significantly less worry about symptoms at day 3, fewer symptoms immediately following the vaccine and increased intentions to vaccinate against viruses like COVID-19 in the future. No significant differences emerged for side-effect frequency at day 3, coping, or impact. These finding provide initial support for cost- and time-efficient interventions to improve vaccine experience and reduce vaccine hesitancy without withholding information about side effects.

Does light physical activity reduce blood pressure responses to laboratory stressors?

Individuals exhibiting exaggerated blood pressure responses to stress are at increased risk for later cardiovascular disease. Engagement in brief bouts of moderate-to-vigorous physical activity may reduce instances of these exaggerated blood pressure responses. While observational work has shown that periods of light physical activity may also be associated with reduced blood pressure responses to stress in daily life, the few experimental studies involving light physical activity have methodological limitations that temper conclusions. The current investigation sought to understand the effects of brief bouts of light physical activity on blood pressure responses to psychological stress. In a between-person, single-session experimental design, 179 healthy, young adults were randomized to 15 min of light physical activity, moderate physical activity, or sitting before engaging in a 10-min computerized Stroop Color-Word Interference Task. Blood pressure readings were collected throughout the study session. Surprisingly, the light physical activity participants showed higher systolic blood pressure responses to stress than control participants by 2.9 mmHg (F (2, 174) = 3.49, ηp 2  = 0.038, p = .03), whereas no significant differences were shown between moderate physical activity and control groups (F (2, 174) = 2.59, ηp 2  = 0.028, p = .078). These findings show that light physical activity may not be related to reduced blood pressure responses to stress in an experimental session involving healthy, college-aged adults and question the extent to which brief bouts of physical activity may reduce acute blood pressure responses to stress.

Outcomes of adults with invasive meningococcal disease with reduced penicillin susceptibility in Auckland 2004-2017.

PURPOSE: The purpose of this study was to assess the clinical outcomes of adults with invasive meningococcal disease (IMD) and to compare the outcomes of patients with IMD caused by a penicillin susceptible isolate (minimum inhibitory concentration (MIC) ≤ 0.06 mg/L) with patients with IMD caused by an isolate with reduced penicillin susceptibility (MIC > 0.06 mg/L). We also assessed the outcomes of patients with IMD caused by an isolate with reduced penicillin susceptibility who were treated exclusively with intravenous (IV) benzylpenicillin. METHODS: Retrospective study of all culture positive IMD in adult patients (age ≥ 15 years) in the Auckland region from 2004 to 2017. RESULTS: One hundred and thirty-nine patients were included; 94 had penicillin susceptible isolates (88 cured, 6 died), and 45 had an isolate with reduced penicillin susceptibility (41 cured, 1 possible relapse, 3 died). The median benzylpenicillin/ceftriaxone treatment duration was 3 days for both groups. There was no difference in the patient outcomes of both groups. Eighteen patients with IMD caused by an isolate with reduced penicillin susceptibility received benzylpenicillin alone and were cured. CONCLUSIONS: This study provides further support to existing data that has shown that short duration IV beta-lactam treatment is effective for IMD in adults. Only a small number of patients with meningitis caused by an isolate with reduced penicillin susceptibility received benzylpenicillin alone, limiting its evaluation. For Neisseria meningitidis meningitis, we recommend ceftriaxone as empiric treatment and as definitive treatment when this is caused by an isolate with reduced penicillin susceptibility.

A Proteomics-Based Assessment of Inflammation Signatures in Endotoxemia.

We have previously shown that multimers of plasma pentraxin-3 (PTX3) were predictive of survival in patients with sepsis. To characterize the release kinetics and cellular source of plasma protein changes in sepsis, serial samples were obtained from healthy volunteers (n = 10; three time points) injected with low-dose endotoxin (lipopolysaccharide [LPS]) and analyzed using data-independent acquisition MS. The human plasma proteome response was compared with an LPS-induced endotoxemia model in mice. Proteomic analysis of human plasma revealed a rapid neutrophil degranulation signature, followed by a rise in acute phase proteins. Changes in circulating PTX3 correlated with increases in neutrophil-derived proteins following LPS injection. Time course analysis of the plasma proteome in mice showed a time-dependent increase in multimeric PTX3, alongside increases in neutrophil-derived myeloperoxidase (MPO) upon LPS treatment. The mechanisms of oxidation-induced multimerization of PTX3 were explored in two genetic mouse models: MPO global knock-out (KO) mice and LysM Cre Nox2 KO mice, in which NADPH oxidase 2 (Nox2) is only deficient in myeloid cells. Nox2 is the enzyme responsible for the oxidative burst in neutrophils. Increases in plasma multimeric PTX3 were not significantly different between wildtype and MPO or LysM Cre Nox2 KO mice. Thus, PTX3 may already be stored and released in a multimeric form. Through in vivo neutrophil depletion and multiplexed vascular proteomics, PTX3 multimer deposition within the aorta was confirmed to be neutrophil dependent. Proteomic analysis of aortas from LPS-injected mice returned PTX3 as the most upregulated protein, where multimeric PTX3 was deposited as early as 2 h post-LPS along with other neutrophil-derived proteins. In conclusion, the rise in multimeric PTX3 upon LPS injection correlates with neutrophil-related protein changes in plasma and aortas. MPO and myeloid Nox2 are not required for the multimerization of PTX3; instead, neutrophil extravasation is responsible for the LPS-induced deposition of multimeric PTX3 in the aorta.

Long-Term Impact of a Smartphone App on Prescriber Adherence to Antibiotic Guidelines for Adult Patients With Community-Acquired Pneumonia: Interrupted Time-Series Study.

BACKGROUND: Mobile health platforms like smartphone apps that provide clinical guidelines are ubiquitous, yet their long-term impact on guideline adherence remains unclear. In 2016, an antibiotic guidelines app, called SCRIPT, was introduced in Auckland City Hospital, New Zealand, to provide local antibiotic guidelines to clinicians on their smartphones. OBJECTIVE: We aimed to assess whether the provision of antibiotic guidelines in a smartphone app resulted in sustained changes in antibiotic guideline adherence by prescribers. METHODS: We analyzed antibiotic guideline adherence rates during the first 24 hours of hospital admission in adults diagnosed with community-acquired pneumonia using an interrupted time-series study with 3 distinct periods post app implementation (ie, 3, 12, and 24 months). RESULTS: Adherence increased from 23% (46/200) at baseline to 31% (73/237) at 3 months and 34% (69/200) at 12 months, reducing to 31% (62/200) at 24 months post app implementation (P=.07 vs baseline). However, increased adherence was sustained in patients with pulmonary consolidation on x-ray (9/63, 14% at baseline; 23/77, 30% after 3 months; 32/92, 35% after 12 month; and 32/102, 31% after 24 months; P=.04 vs baseline). CONCLUSIONS: An antibiotic guidelines app increased overall adherence, but this was not sustained. In patients with pulmonary consolidation, the increased adherence was sustained.

Two-Year Outcomes After Minimally Invasive Surfactant Therapy in Preterm Infants: Follow-Up of the OPTIMIST-A Randomized Clinical Trial.

Importance: The long-term effects of surfactant administration via a thin catheter (minimally invasive surfactant therapy [MIST]) in preterm infants with respiratory distress syndrome remain to be definitively clarified. Objective: To examine the effect of MIST on death or neurodevelopmental disability (NDD) at 2 years' corrected age. Design, Setting, and Participants: Follow-up study of a randomized clinical trial with blinding of clinicians and outcome assessors conducted in 33 tertiary-level neonatal intensive care units in 11 countries. The trial included 486 infants with a gestational age of 25 to 28 weeks supported with continuous positive airway pressure (CPAP). Collection of follow-up data at 2 years' corrected age was completed on December 9, 2022. Interventions: Infants assigned to MIST (n = 242) received exogenous surfactant (200 mg/kg poractant alfa) via a thin catheter; those assigned to the control group (n = 244) received sham treatment. Main Outcomes and Measures: The key secondary outcome of death or moderate to severe NDD was assessed at 2 years' corrected age. Other secondary outcomes included components of this composite outcome, as well as hospitalizations for respiratory illness and parent-reported wheezing or breathing difficulty in the first 2 years. Results: Among the 486 infants randomized, 453 had follow-up data available (median gestation, 27.3 weeks; 228 females [50.3%]); data on the key secondary outcome were available in 434 infants. Death or NDD occurred in 78 infants (36.3%) in the MIST group and 79 (36.1%) in the control group (risk difference, 0% [95% CI, -7.6% to 7.7%]; relative risk [RR], 1.0 [95% CI, 0.81-1.24]); components of this outcome did not differ significantly between groups. Secondary respiratory outcomes favored the MIST group. Hospitalization with respiratory illness occurred in 49 infants (25.1%) in the MIST group vs 78 (38.2%) in the control group (RR, 0.66 [95% CI, 0.54-0.81]) and parent-reported wheezing or breathing difficulty in 73 (40.6%) vs 104 (53.6%), respectively (RR, 0.76 [95% CI, 0.63-0.90]). Conclusions and Relevance: In this follow-up study of a randomized clinical trial of preterm infants with respiratory distress syndrome supported with CPAP, MIST compared with sham treatment did not reduce the incidence of death or NDD by 2 years of age. However, infants who received MIST had lower rates of adverse respiratory outcomes during their first 2 years of life. Trial Registration: anzctr.org.au Identifier: ACTRN12611000916943.

Fetal Loss and Preterm Birth Caused by Intraamniotic Haemophilus influenzae Infection, New Zealand.

Invasive Haemophilus influenzae infection during pregnancy can cause preterm birth and fetal loss, but the mechanism is unclear. We investigated 54 cases of pregnancy-associated invasive H. influenzae disease in 52 unique pregnancies in the Auckland region of New Zealand during October 1, 2008‒September 30, 2018. Intraamniotic infection was identified in 36 (66.7%) of 54 cases. Outcome data were available for 48 pregnancies. Adverse pregnancy outcomes, defined as fetal loss, preterm birth, or the birth of an infant requiring intensive/special care unit admission, occurred in 45 (93.8%) of 48 (pregnancies. Fetal loss occurred in 17 (35.4%) of 48 pregnancies, before 24 weeks' gestation in 13 cases, and at >24 weeks' gestation in 4 cases. The overall incidence of pregnancy-associated invasive H. influenzae disease was 19.9 cases/100,000 births, which exceeded the reported incidence of pregnancy-associated listeriosis in New Zealand. We also observed higher rates in younger women and women of Maori ethnicity.