Nanoscale ultrastructures increase the visual conspicuousness of signalling traits in obligate cleaner shrimps.

Signal theory predicts organisms should evolve signals that are conspicuous to intended receivers in natural signalling environments. Cleaner shrimps remove ectoparasites from reef fish clients and many signal their intent to clean by whipping long, white antennae. Since white is a reliably conspicuous colour in aquatic environments, we hypothesized that selection has acted to increase broad-spectrum antennal reflectance in cleaners. Using Scanning Electron Microscopy, optical models, and reflectance measurements, we found that the antennae in three obligate cleaner species from two families (Palaemonidae and Lysmatidae) had thick (∼6µm) chitinous layers or densely-packed high refractive index spheres (300-400nm diameter), which models show increase reflectance (400-700nm). Two facultative and non-cleaning species had no visible antennae ultrastructure beyond chitinous exoskeleton. Antennae reflectance was significantly higher in obligate cleaners than facultative and non-cleaning species. Our results suggest that some obligate cleaners may have evolved ultrastructures that increase the conspicuousness of the antennae as signals.

Incidence of Lateral Femoral Cutaneous Nerve Dysfunction After Total Hip Arthroplasty Through the Anterior-Based Muscle-Sparing Surgical Approach.

Background: The anterior-based muscle-sparing (ABMS) approach, using the intramuscular interval between the tensor fascia lata and gluteus medius, is an increasingly popular total hip arthroplasty (THA) approach. Its incidence of lateral femoral cutaneous nerve (LFCN) numbness has not been defined. The incidence of LFCN symptoms in direct anterior THA ranges from 7%-32% at 1-year follow-up. The purpose of this study is to determine the incidence of LFCN symptoms in patients who underwent ABMS THA at 1-year follow-up. Methods: This was a single-center, multisurgeon retrospective study of ABMS THAs with minimum 1-year follow-up data between January 2014 and September 2021. Eight hundred sixty-nine THAs were included. Mean age of the patients was 67.2 years, with 43.4% male and 56.5% female. Mean body mass index was 26.8, and mean American Society of Anesthesiologists was 2.3. Statistical analysis included chi-square tests, 2-sample t-test, and binomial logistic regression. A P-value of .05 was considered statistically significant for all tests. Results: Nine patients (1%) reported LFCN-associated symptoms at 1-year follow-up. The most common complaint was numbness (n = 5, 55.6%), followed by diminished sensation (n = 2, 22.2%), burning (n = 1, 11.1%), and generalized pain (11.1%). There was no difference in age, sex, body mass index, or American Society of Anesthesiologists between the group that experienced symptoms and the group that did not (P = 1.00, P = .34, P = .74, P = .80). Conclusions: The incidence of LFCN dysfunction is 1% at 1 year after surgery with the ABMS approach. Additional studies may elucidate all risks and benefits of the ABMS approach with respect to LFCN injuries.

The harms of promoting the lab leak hypothesis for SARS-CoV-2 origins without evidence.

Science is humanity's best insurance against threats from nature, but it is a fragile enterprise that must be nourished and protected. The preponderance of scientific evidence indicates a natural origin for SARS-CoV-2. Yet, the theory that SARS-CoV-2 was engineered in and escaped from a lab dominates media attention, even in the absence of strong evidence. We discuss how the resulting anti-science movement puts the research community, scientific research, and pandemic preparedness at risk.

Deep Brain Stimulation for Consciousness Disorders; Technical and Ethical Considerations.

Disorders of Consciousness (DoC) result in profound functional impairment, adversely affecting the lives of a predominantly younger patient population. Currently, effective treatment options for those who have reached chronicity (prolonged symptom duration over 4 weeks) are extremely limited, with the majority of such cases facing life-long dependence on carers and a poor quality of life. Here we briefly review the current evidence on caseload, diagnostic and management options in the United Kingdom (UK), United States of America (USA) and the European Union (EU). We identify key differences as well as similarities in these approaches across respective healthcare systems, highlighting unmet needs in this population. We subsequently present past efforts and the most recent advances in the field of surgical modulation of consciousness through implantable neurostimulation systems. We examine the ethical dilemmas that such a treatment approach may pose, proposing mediating solutions and methodological adjustments to address these concerns. Overall, we argue that there is a strong case for the utilisation of deep brain stimulation (DBS) in the DoC patient cohort. This is based on both promising results of recent clinical trials as well as technological developments. We propose a revitalization of surgical neuromodulation for DoC with a multicenter, multidisciplinary approach and strict monitoring guidelines, in order to not only advance treatment options but also ensure the safeguarding of patients' welfare and dignity.

Substantial contribution of transported emissions to organic aerosol in Beijing.

Haze in Beijing is linked to atmospherically formed secondary organic aerosol, which has been shown to be particularly harmful to human health. However, the sources and formation pathways of these secondary aerosols remain largely unknown, hindering effective pollution mitigation. Here we have quantified the sources of organic aerosol via direct near-molecular observations in central Beijing. In winter, organic aerosol pollution arises mainly from fresh solid-fuel emissions and secondary organic aerosols originating from both solid-fuel combustion and aqueous processes, probably involving multiphase chemistry with aromatic compounds. The most severe haze is linked to secondary organic aerosols originating from solid-fuel combustion, transported from the Beijing-Tianjing-Hebei Plain and rural mountainous areas west of Beijing. In summer, the increased fraction of secondary organic aerosol is dominated by aromatic emissions from the Xi'an-Shanghai-Beijing region, while the contribution of biogenic emissions remains relatively small. Overall, we identify the main sources of secondary organic aerosol affecting Beijing, which clearly extend beyond the local emissions in Beijing. Our results suggest that targeting key organic precursor emission sectors regionally may be needed to effectively mitigate organic aerosol pollution.

Enhancing radiotherapy response via intratumoral injection of a TLR9 agonist in autochthonous murine sarcomas.

Radiation therapy (RT) is frequently used to treat cancers, including soft-tissue sarcomas. Prior studies established that the toll-like receptor 9 (TLR9) agonist cytosine-phosphate-guanine oligodeoxynucleotide (CpG) enhances the response to RT in transplanted tumors, but the mechanisms of this enhancement remain unclear. Here, we used CRISPR/Cas9 and the chemical carcinogen 3-methylcholanthrene (MCA) to generate autochthonous soft-tissue sarcomas with high tumor mutation burden. Treatment with a single fraction of 20 Gy RT and 2 doses of CpG significantly enhanced tumor response, which was abrogated by genetic or immunodepletion of CD8+ T cells. To characterize the immune response to CpG+RT, we performed bulk RNA-Seq, single-cell RNA-Seq, and mass cytometry. Sarcomas treated with 20 Gy and CpG demonstrated increased CD8 T cells expressing markers associated with activation and proliferation, such as Granzyme B, Ki-67, and IFN-γ. CpG+RT also upregulated antigen presentation pathways on myeloid cells. Furthermore, in sarcomas treated with CpG+RT, TCR clonality analysis suggests an increase in clonal T cell dominance. Collectively, these findings demonstrate that CpG+RT significantly delays tumor growth in a CD8 T cell-dependent manner. These results provide a strong rationale for clinical trials evaluating CpG or other TLR9 agonists with RT in patients with soft-tissue sarcoma.

Soft tissue laxity is highly variable in patients undergoing total knee arthroplasty.

BACKGROUND: One major goal of total knee arthroplasty (TKA) is to achieve balanced medial and lateral gaps in flexion and extension. While bone resections are planned by the surgeon, soft tissue laxity is largely intrinsic and patient-specific in the absence of additional soft tissue releases. We sought to determine the variability in soft tissue laxity in patients undergoing TKA. METHODS: We retrospectively reviewed 113 patients undergoing TKA. Data on preoperative knee deformity were collected. Data from a dynamic intraoperative stress examination were collected by a robotic tracking system to quantify maximal medial and lateral opening in flexion (85-95 degrees) and extension (-5-20 degrees). T-tests were used to assess the differences between continuous variables. RESULTS: A valgus stress opened the medial compartment a mean of 4.3 ± 2.3 mm (0.0-12.4 mm) in extension and 4.6 ± 2.3 mm (0.0-12.9 mm) in flexion. A varus stress opened the lateral compartment a mean of 5.4 ± 2.4 mm (0.3-12.6 mm) in extension and 6.2 ± 2.5 mm (0.0-13.4 mm) in flexion. The medial compartment of varus knees opened significantly more in response to valgus stress than valgus knees in both extension (5.2 mm vs. 2.6 mm; P < 0.0001) and flexion (5.4 mm vs 3.3 mm; P < 0.0001). The lateral compartment of valgus knees opened significantly more in response to varus stress than varus knees in both extension (6.7 mm vs. 4.8 mm; P < 0.0001) and flexion (7.4 mm vs. 5.8 mm; P = 0.0003). CONCLUSIONS: Soft tissue laxity is highly variable in patients undergoing TKA, contributing anywhere from 0-13 mm to the post-resection gap. Only a small part of this variability is predictable by preoperative deformity. These findings have implications for either measured-resection or gap-balancing techniques. LEVEL OF EVIDENCE: Level III.

A general principle governing neuronal evolution reveals a human-accelerated neuron type potentially underlying the high prevalence of autism in humans.

The remarkable ability of a single genome sequence to encode a diverse collection of distinct cell types, including the thousands of cell types found in the mammalian brain, is a key characteristic of multicellular life. While it has been observed that some cell types are far more evolutionarily conserved than others, the factors driving these differences in evolutionary rate remain unknown. Here, we hypothesized that highly abundant neuronal cell types may be under greater selective constraint than rarer neuronal types, leading to variation in their rates of evolution. To test this, we leveraged recently published cross-species single-nucleus RNA-sequencing datasets from three distinct regions of the mammalian neocortex. We found a strikingly consistent relationship where more abundant neuronal subtypes show greater gene expression conservation between species, which replicated across three independent datasets covering >10 6 neurons from six species. Based on this principle, we discovered that the most abundant type of neocortical neurons-layer 2/3 intratelencephalic excitatory neurons-has evolved exceptionally quickly in the human lineage compared to other apes. Surprisingly, this accelerated evolution was accompanied by the dramatic down-regulation of autism-associated genes, which was likely driven by polygenic positive selection specific to the human lineage. In sum, we introduce a general principle governing neuronal evolution and suggest that the exceptionally high prevalence of autism in humans may be a direct result of natural selection for lower expression of a suite of genes that conferred a fitness benefit to our ancestors while also rendering an abundant class of neurons more sensitive to perturbation.

Bright New Resources for Syphilis Research: Genetically Encoded Fluorescent Tags for Treponema pallidum and Sf1Ep Cells.

The recently discovered methodologies to cultivate and genetically manipulate Treponema pallidum subsp. pallidum (T. pallidum) have significantly helped syphilis research, allowing the in vitro evaluation of antibiotic efficacy, performance of controlled studies to assess differential treponemal gene expression, and generation of loss-of-function mutants to evaluate the contribution of specific genetic loci to T. pallidum virulence. Building on this progress, we engineered the T. pallidum SS14 strain to express a red-shifted green fluorescent protein (GFP) and Sf1Ep cells to express mCherry and blue fluorescent protein (BFP) for enhanced visualization. These new resources improve microscopy- and cell sorting-based applications for T. pallidum, better capturing the physical interaction between the host and pathogen, among other possibilities. Continued efforts to develop and share new tools and resources are required to help our overall knowledge of T. pallidum biology and syphilis pathogenesis reach that of other bacterial pathogens, including spirochetes.

Orexin neurons mediate temptation-resistant voluntary exercise.

Despite the well-known health benefits of physical activity, many people underexercise; what drives the prioritization of exercise over alternative options is unclear. We developed a task that enabled us to study how mice freely and rapidly alternate between wheel running and other voluntary activities, such as eating palatable food. When multiple alternatives were available, mice chose to spend a substantial amount of time wheel running without any extrinsic reward and maintained this behavior even when palatable food was added as an option. Causal manipulations and correlative analyses of appetitive and consummatory processes revealed this preference for wheel running to be instantiated by hypothalamic hypocretin/orexin neurons (HONs). The effect of HON manipulations on wheel running and eating was strongly context-dependent, being the largest in the scenario where both options were available. Overall, these data suggest that HON activity enables an eat-run arbitration that results in choosing exercise over food.

Worry Postponement From the Metacognitive Perspective: A Randomized Waitlist-Controlled Trial.

Background: Pathological worry is associated with appraisals of worrying as uncontrollable. Worry postponement (WP) with a stimulus control rationale appears to be effective in non-clinical samples. However, preliminary research in participants with generalized anxiety disorder (GAD) does not support its efficacy in reducing negative metacognitions or worry. The aim of this study was to investigate the efficacy of WP with a metacognitive rationale. Method: Participants with GAD (n = 47) or hypochondriasis (HYP; n = 35) were randomly assigned to either an intervention group (IG) or waitlist (WL). The IG received a two-session long WP intervention aiming at mainly reducing negative metacognitions concerning uncontrollability of worrying. Participants were instructed to postpone their worry process to a predetermined later time during the six days between the two sessions. Participants completed questionnaires of negative metacognitions and worry at pre-assessment, post-assessment, and follow-up. Results: We observed a significant Time*Group interaction for negative metacognitions and worry. Post-hoc analyses on the total sample and separately for GAD and HYP revealed significantly lower worry scores in the treated GAD sample compared to the WL, representing the only significant effect. In the GAD group, pre-post-effect sizes were small for negative metacognitions and large for worry. Effects persisted to a four-week follow-up. Conclusion: WP with a metacognitive rationale seems to be effective in reducing worry in participants with GAD. The effectiveness for HYP seems limited, possibly due to the small sample size.

A Volume-Adjustable Artificial Womb for Extremely Preterm Infants.

More than 13 million children are born preterm annually. Prematurity-related mortality accounts for 0.9 million deaths worldwide. The majority of those affected are Extremely Preterm Infants (gestational age less than 28 weeks). Immaturity causes organ failure and specific morbidities like germinal matrix hemorrhage, bronchopulmonary dysplasia, and necrotizing enterocolitis. Artificial womb and placenta technologies address these issues. As a bridge-to-life technology, they provide a liquid environment to allow organ maturation under more physiological conditions. The proposed artificial womb can adapt to fetal growth. Volume adjustment is achieved by removing fluid from the interspace between an inner and outer chamber. Results of the in vitro tests showed a temperature constancy of 36.8°C ± 0.3°C without pressure loss over 7 days. The volume of the inner sac was variable between 3.6 and 7.0 L. We designed a filtration and disinfection system for this particular purpose. This system has proven strong disinfection capabilities, effective filtering of metabolic waste, and the ability to avoid phospholipid washout. The presented artificial womb has sufficient volume variability to adapt to the physiologic growth of an extremely preterm neonate over a 4-week period. We regard this as an important step in the development of this bridge-to-life technology.

First-in-Human Percutaneous Use of a Cerebral Flow-Diverting Stent in a Large Coronary Aneurysm.

A 58-year-old man presenting with angina was found to have a large coronary aneurysm on angiography. After coronary bypass and multiple ST-elevation myocardial infarctions over the following months, the decision was made to exclude the aneurysm with a flow-diverting stent, which reduced flow to the aneurysm and left the patient asymptomatic since the procedure. This is the first reported use of a cerebral flow-diverting stent for treatment of a coronary aneurysm.

The impact of diabetes mellitus on foot perfusion measured by ICG NIR fluorescence imaging.

INTRODUCTION: Diabetes Mellitus (DM) is a common chronic disease, affecting 435 million people globally. Impaired vasculature in DM patients leads to complications like lower extremity arterial disease (LEAD) and foot ulcers, often resulting in amputations. DM causes additional peripheral neuropathy leading to multifactorial wound problems. Current diagnostics often deem unreliable, but Near-Infrared Fluorescence with Indocyanine Green (ICG NIR) can be used to assess the foot perfusion. Therefore, this study explores DM's impact on foot perfusion using ICG NIR. METHODS: Baseline ICG NIR fluorescence imaging was performed in LEAD patients with and without DM. Ten perfusion parameters were extracted and analyzed to assess differences in perfusion patterns. RESULTS: Among 109 patients (122 limbs) of the included patients, 32.8 % had DM. Six of ten perfusion parameters, mainly inflow-related, differed significantly between DM and non-DM patients (p-values 0.007-0.039). Fontaine stage 4 DM patients had the highest in- and outflow values, with seven parameters significantly higher (p-values 0.004-0.035). CONCLUSION: DM is associated with increased in- and outflow parameters. Patients with- and without DM should not be compared directly due to different vascular pathophysiology and multifactorial wound problems in DM patients. Quantified ICG NIR fluorescence imaging offers additional insight into the effect of DM on foot perfusion.

Electrochemical classification of benzodiazepines: A comprehensive approach combining insights from voltammetry and liquid chromatography - mass spectrometry.

The growing non-medical use of benzodiazepines (BZs) has led to the emergence of counterfeit BZ pills and new psycho-active substances (NPS) in the BZ class on the illicit market. Comprehensive analytical methods for BZ identification are required to allow law enforcement, first aid responders and drug-checking services to analyze a variety of sample types and contents to make timely decisions on the spot. In this work, the electrochemical behavior of diazepam (DZ), clonazepam (CZ) and alprazolam (AP) is studied on graphite screen-printed electrodes, both with and without dissolved oxygen in the solution, to link their redox signals to their chemical structure. After elucidation of their reduction mechanisms using liquid chromatography coupled to high-resolution mass spectrometry, three structural classes (Class 1, Class 2 and Class 3) were defined, each with different redox centers and electrochemical behavior. Subsequently, 22 confiscated pills containing 14 different BZs were correctly assigned to these three structural classes, with the deoxygenated conditions displaying the highest class selectivity. Finally, the three classes were successfully detected after being spiked into five alcoholic beverages in the context of drug-facilitated sexual assault. For analysis in red wine, which complicated the analysis by interfering with Class 1, a dual test strategy in pH 2 and pH 7 was proposed for accurate detection. Its rapid measurements, broad scope and lack of interference from diluents or colors makes this method a promising approach for aiding various services in combating problematic BZ use.

Neural circuit basis of placebo pain relief.

Placebo effects are striking demonstrations of mind-body interactions 1,2. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain, a phenomenon known as placebo analgesia 3-6. However, despite the strength of placebo effects and their impact on everyday human experience and failure of clinical trials for new therapeutics 7, the neural circuit basis of placebo effects has remained elusive. Here, we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn), a pre-cerebellar nucleus with no established function in pain. We created a behavioral assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain.

Long-term in vitro exposure of Treponema pallidum to sub-bactericidal doxycycline did not induce resistance: Implications for doxy-PEP and syphilis.

Doxycycline post-exposure prophylaxis (doxy-PEP) could significantly reduce syphilis incidence. However, the increase in intermittent doxycycline usage might select resistant Treponema pallidum (T. pallidum) strains. To assess whether resistance to doxycycline could be induced in this pathogen, we exposed the SS14 strain in vitro both intermittently and continuously to a sub-bactericidal doxycycline concentration that still exerts antibiotic pressure. During and after each exposure experiment, we assessed the doxycycline minimal inhibitory concentration in test and control treponemes and performed whole genome sequencing, concluding that no resistance developed. This work suggests that doxycycline-resistant T. pallidum is not an immediate threat for doxy-PEP implementation.

A combined radio-immunotherapy regimen eradicates late-stage tumors in mice.

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors.

Age-dependent heterogeneity in the antigenic effects of mutations to influenza hemagglutinin.

Human influenza virus evolves to escape neutralization by polyclonal antibodies. However, we have a limited understanding of how the antigenic effects of viral mutations vary across the human population and how this heterogeneity affects virus evolution. Here, we use deep mutational scanning to map how mutations to the hemagglutinin (HA) proteins of two H3N2 strains, A/Hong Kong/45/2019 and A/Perth/16/2009, affect neutralization by serum from individuals of a variety of ages. The effects of HA mutations on serum neutralization differ across age groups in ways that can be partially rationalized in terms of exposure histories. Mutations that were fixed in influenza variants after 2020 cause greater escape from sera from younger individuals compared with adults. Overall, these results demonstrate that influenza faces distinct antigenic selection regimes from different age groups and suggest approaches to understand how this heterogeneous selection shapes viral evolution.

Prevalence of non-communicable diseases among household contacts of people with tuberculosis: A systematic review and individual participant data meta-analysis.

OBJECTIVE: To investigate the prevalence of non-communicable diseases among household contacts of people with tuberculosis. METHODS: We conducted a systematic review and individual participant data meta-analysis. We searched Medline, Embase and the Global Index Medicus from inception to 16 May 2023. We included studies that assessed for at least one non-communicable disease among household contacts of people with clinical tuberculosis. We estimated the non-communicable disease prevalence through mixed effects logistic regression for studies providing individual participant data, and compared it with estimates from aggregated data meta-analyses. Furthermore, we compared age and sex-standardised non-communicable disease prevalence with national-level estimates standardised for age and sex. RESULTS: We identified 39 eligible studies, of which 14 provided individual participant data (29,194 contacts). Of the remaining 25 studies, 18 studies reported aggregated data suitable for aggregated data meta-analysis. In individual participant data analysis, the pooled prevalence of diabetes in studies that undertook biochemical testing was 8.8% (95% confidence interval [CI], 5.1%-14.9%, four studies). Age-and sex-standardised prevalence was higher in two studies (10.4% vs. 6.9% and 11.5% vs. 8.4%) than the corresponding national estimates and similar in two studies. Prevalence of diabetes mellitus based on self-report or medical records was 3.4% (95% CI 2.6%-4.6%, 14 studies). Prevalence did not significantly differ compared to estimates from aggregated data meta-analysis. There were limited data for other non-communicable diseases. CONCLUSION: The prevalence of diabetes mellitus among household contacts was high while that of known diabetes was substantially lower, suggesting the underdiagnosis. tuberculosis household contact investigation offers opportunities to deliver multifaceted interventions to identify tuberculosis infection and disease, screen for non-communicable diseases and address shared risk factors.