Search

Abstract With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm.

Abstract Animals sense and respond to nutrient availability in their environments, a task coordinated in part by the mTOR complex 1 (mTORC1) pathway. mTORC1 regulates growth in response to nutrients and, in mammals, senses specific amino acids through specialized sensors that bind the GATOR1/2 signaling hub. Given that animals can occupy diverse niches, we hypothesized that the pathway might evolve distinct sensors in different metazoan phyla. Whether such customization occurs, and how the mTORC1 pathway might capture new inputs, is unknown. Here, we identify the Drosophila melanogaster protein Unmet expectations (CG11596) as a species-restricted methionine sensor that directly binds the fly GATOR2 complex in a fashion antagonized by S-adenosylmethionine (SAM). We find that in Dipterans GATOR2 rapidly evolved the capacity to bind Unmet and to thereby repurpose a previously independent methyltransferase as a SAM sensor. Thus, the modular architecture of the mTORC1 pathway allows it to co-opt preexisting enzymes to expand its nutrient sensing capabilities, revealing a mechanism for conferring evolvability on an otherwise conserved system.

Patients' expectations and beliefs regarding the potential benefits and harms of medical interventions may induce placebo and nocebo effects, and affect the response to pain therapies. In a randomized clinical trial, we examined the effect of placebo and nocebo expectations on pain relief and adverse events (AEs) in association with a topical treatment among 65 cancer survivors experiencing chronic musculoskeletal pain. Participants received either a 1% camphor-based topical pain patch or a placebo treatment for 14 days. We measured pain severity with the worst pain item of the Brief Pain Inventory (BPI) at baseline and 14 days and treatment expectations at baseline with validated expectation questionnaires. We found that high vs. low nocebo expectations decreased pain severity improvements by 2.5 points (95% confidence interval [CI] −3.8 to −1.2; p

Background: Outcome expectancy is an important component of non-specific effect that may play an important role in pain research and clinical care. We sought to evaluate whether pretreatment expectancy predicts pain reduction in cancer survivors receiving electroacupuncture (EA) or battlefield acupuncture (BFA). Methods: We analyzed data from a randomized clinical trial that compared EA and BFA versus wait list control (WLC) for chronic musculoskeletal pain in cancer survivors. Expectancy was measured by the Acupuncture Expectancy Scale (AES) at baseline. Pain severity was assessed using the Brief Pain Inventory (BPI) at baseline and week 12. For each treatment arm, multivariable regression models were used to evaluate the association between pretreatment expectancy and week 12 pain severity, controlling for baseline pain severity, age, sex, race, and education. Results: Among 360 participants enrolled, the mean age was 62.1 years (SD 12.7), with 251 (69.7 %) women and 88 (24.4 %) non-white survivors. Pretreatment expectancy was similar for all groups at baseline (EA: 13.9 ± 3.6; BFA: 13.2 ± 3.7, WLC:12.8 ± 3.3, p = 0.14). Greater pretreatment expectancy was not significantly associated with greater pain reduction in any group, after adjusting for co-variates (EA: Coef. = -0.05, 95 % CI = -0.14 – 0.04, p = 0.28; BFA: Coef. = -0.07, 95 % CI = -0.16 – 0.02, p = 0.15; WLC: Coef. = -0.09, 95 % CI = -0.25 – 0.06, p = 0.23). Conclusions: Pretreatment expectancy did not predict pain reduction for either EA or BFA in cancer survivors. Our study contributes to the interpretation of analgesic effects of EA or BFA, beyond the notion of a mere 'placebo effect'.

Abstract PARP inhibitors (PARPi)‐based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5‐azacytidine (AZA)‐conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self‐assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR‐proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD‐1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC).

Introduction: Use of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) during chemotherapy is associated with decreased hospitalization rates, improved quality of life, and longer survival. Limited data exist on the benefit of this symptom assessment tool for monitoring immune-related adverse events (irAEs). Methods: We incorporated irAE-related items from the National Cancer Institute’s (NCI) PRO-CTCAE in a trial evaluating ipilimumab in combination with androgen deprivation therapy in 16 patients with hormone-sensitive prostate cancer. For comparison, NCI’s CTCAE version 4.0 was used by clinicians. Results: IrAE-related PRO-CTCAE surveys and matched CTCAEs (184 pairs) reporting abdominal pain, diarrhea, fatigue, anorexia, nausea, vomiting, rash, and pruritus were collected at each treatment administration and during follow-up. Fatigue, diarrhea, rash, and pruritus were the symptoms most frequently reported by both patients and clinicians. Agreement was lowest for pruritus (κ = 0.10) and highest for rash (κ = 0.64). IrAEs were more commonly reported and of higher grade with PRO-CTCAE scores compared with CTCAE grades. Conclusion: PRO-CTCAEs focused on irAEs capture the patient’s immunotherapy experience while complementing the clinician’s toxicity assessment measures. Further study is needed to assess PRO-CTCAE’s utility in identifying and managing irAEs.

Post-contact immobility (PCI) is a final attempt to avoid predation. Here, for the first time, we examine the pattern of movement and immobility when antlion larvae resume activity after PCI. To simulate contact with, and escape from, a predator we dropped the larvae onto three different substrates: Paper, Shallow sand (2.3mm-deep) and Deep sand (4.6mm-deep). The Paper lining a Petri dish represented a hard surface that antlion larvae could not penetrate to hide. The Shallow sand permitted the antlions to dig but not to submerge completely whereas the Deep sand allowed them both to dig and to submerge. We tracked their paths automatically and recorded alternating immobility and movement durations over 90min. On the impenetrable substrate, antlion larvae showed super-diffusive dispersal, their movement durations became longer, their immobility durations became shorter and their instantaneous speeds increased. This is consistent with the antlions needing to leave an area of hard substrate and quickly to find somewhere to hide. On Shallow sand, antlion larvae exhibited a modest increase in movement duration, a modest decrease in immobility duration and a concomitant diffusive dispersal. This is consistent with their use of a spiral search, presumably for a suitable depth of sand, to conceal themselves. On Deep sand, the movement and immobility durations of the antlion larvae did not change and their dispersal was sub-diffusive because they were able to bury themselves. On Paper, the distribution of immobility durations had a long tail, consistent with a log-normal distribution. On Shallow and Deep sand, most of the distribution was fitted better by a power law or a log-normal. Our results suggest that PCI in antlion larvae is a disruptive event and that post-PCI movement and immobility gradually return to the pattern typical of intermittent locomotion, depending on the scope for burying and hiding in the substrate.

Governments and society increasingly are demanding that industrial projects result in a net positive impact (NPI) on biodiversity. Impacts are commonly measured in terms of losses and gains of area and quality of vegetation, where quality refers to how closely a site matches the condition of native vegetation in its undisturbed state. Existing vegetation quality frameworks share a number of limitations, including little or no replication, uncertain scope of inference, vulnerability to bias, and inability to measure error. Here we present the Vegetation Quality Assessment (VQA) framework, a sampling-based extension of Quality Hectares that measures vegetation quality in terms of overlap between the probability distributions of ecological indicators at a project site and in undisturbed (benchmark) vegetation of the same kind. Distribution overlap incorporates natural variation at the landscape scale and provides an intuitive measure of quality that varies between 0 and 1. Indicators are measured using a stratified-random sampling design that minimizes bias and supports inference at the scale of the project landscape. Confidence limits of quality and quality hectares are determined by bootstrapping; power and minimum sample sizes are estimated by Monte Carlo simulation. Multiple assessments track losses and gains of quality hectares and enable accurate accounting of progress to NPI. The VQA framework can be implemented using a variety of vegetation sampling methods, allowing existing vegetation databases to be leveraged as sources of data. We conclude by demonstrating the application of VQA at several mining operations in the Elk Valley of southeastern British Columbia, Canada.

Abstract Alzheimer’s Disease (AD) is characterized by the accumulation of extracellular amyloid-β (Aβ) as well as CNS and systemic inflammation. Microglia, the myeloid cells resident in the CNS, use microRNAs to rapidly respond to inflammatory signals. MicroRNAs (miRNAs) modulate inflammatory responses in microglia, and miRNA profiles are altered in Alzheimer’s disease (AD) patients. Expression of the pro-inflammatory miRNA, miR-155, is increased in the AD brain. However, the role of miR-155 in AD pathogenesis is not well-understood. We hypothesized that miR-155 participates in AD pathophysiology by regulating microglia internalization and degradation of Aβ. We used CX3CR1CreER/+ to drive-inducible, microglia-specific deletion of floxed miR-155 alleles in two AD mouse models. Microglia-specific inducible deletion of miR-155 in microglia increased anti-inflammatory gene expression while reducing insoluble Aβ1-42 and plaque area. Yet, microglia-specific miR-155 deletion led to early-onset hyperexcitability, recurring spontaneous seizures, and seizure-related mortality. The mechanism behind hyperexcitability involved microglia-mediated synaptic pruning as miR-155 deletion altered microglia internalization of synaptic material. These data identify miR-155 as a novel modulator of microglia Aβ internalization and synaptic pruning, influencing synaptic homeostasis in the setting of AD pathology.

Traumatic heterotopic ossification (HO) is frequently observed in Service Members following combat-related trauma. Estimates suggest that ~65% of wounded warriors who suffer limb loss or major extremity trauma will experience some type of HO formation. The development of HO delays rehabilitation and can prevent the use of a prosthetic. To date there are limited data to suggest a standard mechanism for preventing HO. This may be due to inadequate animal models not producing a similar bone structure as human HO. We recently showed that traumatic HO growth is possible in an ovine model. Within that study, we demonstrated that 65% of sheep developed a human-relevant hybrid traumatic HO bone structure after being exposed to a combination of seven combat-relevant factors. Although HO formed, we did not determine which traumatic factor contributed most. Therefore, in this study, we performed individual and various combinations of surgical/traumatic factors to determine their individual contribution to HO growth. Outcomes showed that the presence of mature biofilm stimulated a large region of bone growth, while bone trauma resulted in a localized bone response as indicated by jagged bone at the linea aspera. However, it was not until the combinatory factors were included that an HO structure similar to that of humans formed more readily in 60% of the sheep. In conclusion, data suggested that traumatic HO growth can develop following various traumatic factors, but a combination of known instigators yields higher frequency size and consistency of ectopic bone.

ABSTRACT Persistent infection by Staphylococcus aureus has been linked to the bacterial stringent response (SR), a conserved stress response pathway regulated by the Rel protein. Rel synthesizes (p)ppGpp “alarmones” in response to amino acid starvation, which enables adaptation to stress by modulating bacterial growth and virulence. We previously identified five novel protein-altering mutations in rel that arose in patients with persistent methicillin-resistant S. aureus bacteremia. The mutations mapped to both the enzymatic and regulatory protein domains of Rel. Here, we set out to characterize the phenotype of these mutations to understand how they may have been selected in vivo. After introducing each mutation into S. aureus strain JE2, we analyzed growth, fitness, and antibiotic profiles. Despite being located in different protein domains, we found that all of the mutations converged on the same phenotype. Each shortened the time of lag phase growth and imparted a fitness advantage in nutritionally depleted conditions. Through quantification of intracellular (p)ppGpp, we link this phenotype to increased SR activation, specifically during the stationary phase of growth. In contrast to two previously identified clinical rel mutations, we find that our rel mutations do not cause antibiotic tolerance. Instead, our findings suggest that in vivo selection was due to an augmented SR that primes cells for growth in nutrient-poor conditions, which may be a strategy for evading host-imposed nutritional immunity. Importance Host and pathogen compete for available nutrition during infection. For bacteria, the stringent response (SR) regulator Rel responds to amino acid deprivation by signaling the cell to modulate its growth rate, metabolism, and virulence. In this report, we characterize five rel mutations that arose during cases of persistent methicillin-resistant Staphylococcus aureus bacteremia. We find that all of the mutations augmented SR signaling specifically under nutrient-poor conditions, enabling the cell to more readily grow and survive. Our findings reveal a strategy used by bacterial pathogens to evade the nutritional immunity imposed by host tissues during infection.

Abstract Large-scale single-cell ‘omics profiling is being used to define a complete catalogue of brain cell types, something that traditional methods struggle with due to the diversity and complexity of the brain. But this poses a problem: How do we organise such a catalogue - providing a standard way to refer to the cell types discovered, linking their classification and properties to supporting data? Cell ontologies provide a partial solution to these problems, but no existing ontology schemas support the definition of cell types by direct reference to supporting data, classification of cell types using classifications derived directly from data, or links from cell types to marker sets along with confidence scores. Here we describe a generally applicable schema that solves these problems and its application in a semi-automated pipeline to build a data-linked extension to the Cell Ontology representing cell types in the Primary Motor Cortex of humans, mice and marmosets. The methods and resulting ontology are designed to be scalable and applicable to similar whole-brain atlases currently in preparation.

Oxides containing metals or metalloids from the p block of the periodic table (e.g., In, Sn, Sb, Pb, and Bi) are of technological interest as transparent conductors and light absorbers for solar-energy conversion due to the tunability of their electronic conductivity and optical absorption. Comparatively, these oxides have found limited applications in hydrogen photoelectrolysis, primarily due to their high electronegativity, which impedes electron transfer for reducing protons into hydrogen. We have shown recently that inserting s-block cations into p-block metal oxides is effective at lowering electronegativities while affording further control of band gaps. Here, we explain the origins of this dual tunability by demonstrating the mediator role of s-block cations in modulating orbital hybridization while not contributing to frontier electronic states. From this result, we carry out a comprehensive computational study of 109 ternary oxides of s- and p-block metal elements as candidate photocatalysts for solar hydrogen generation. We down-select the most desirable materials using band gaps and band edges obtained from Hubbard-corrected density-functional theory, with Hubbard parameters computed entirely from first principles, evaluate the stability of these oxides in aqueous conditions, and characterize experimentally four of the remaining materials, synthesized with high phase uniformity, to validate and further develop the computational models. We thus propose nine oxide semiconductors, including CsIn_{3}O_{5}, Sr_{2}In_{2}O_{5}, and KSbO_{2}, which, to the extent of our literature review, have not been previously considered as water-splitting photocatalysts.

AimsFractures of the distal radius are common, and form a considerable proportion of the trauma workload. We conducted a study to examine the patterns of injury and treatment for adult patients presenting with distal radius fractures to a major trauma centre serving an urban population.MethodsWe undertook a retrospective cohort study to identify all patients treated at our major trauma centre for a distal radius fracture between 1 June 2018 and 1 May 2021. We reviewed the medical records and imaging for each patient to examine patterns of injury and treatment. We undertook a binomial logistic regression to produce a predictive model for operative fixation or inpatient admission.ResultsOverall, 571 fractures of the distal radius were treated at our centre during the study period. A total of 146 (26%) patients required an inpatient admission, and 385 surgical procedures for fractures of the distal radius were recorded between June 2018 and May 2021. The most common mechanism of injury was a fall from a height of one metre or less. Of the total fractures, 59% (n = 337) were treated nonoperatively, and of those patients treated with surgery, locked anterior-plate fixation was the preferred technique (79%; n = 180).ConclusionThe epidemiology of distal radius fractures treated at our major trauma centre replicated the classical bimodal distribution described in the literature. Patient age, open fractures, and fracture classification were factors correlated with the decision to treat the fracture operatively. While most fractures were treated nonoperatively, locked anterior-plate fixation remains the predominant method of fixation for fractures of the distal radius; this is despite questions and continued debate about the best method of surgical fixation for these injuries.Cite this article: Bone Jt Open 2022;3(8):623–627.

BackgroundCancer survivors represent one of the fastest growing populations in the United States. Unfortunately, nearly 1 in 3 survivors experience anxiety symptoms as a long-term consequence of cancer and its treatment. Characterized by restlessness, muscle tension, and worry, anxiety worsens the quality of life; impairs daily functioning; and is associated with poor sleep, depressed mood, and fatigue. Although pharmacological treatment options are available, polypharmacy has become a growing concern for cancer survivors. Music therapy (MT) and cognitive behavioral therapy (CBT) are evidence-based, nonpharmacological treatments that have demonstrated effectiveness in treating anxiety symptoms in cancer populations and can be adapted for remote delivery to increase access to mental health treatments. However, the comparative effectiveness of these 2 interventions delivered via telehealth is unknown. ObjectiveThe aims of the Music Therapy Versus Cognitive Behavioral Therapy for Cancer-related Anxiety (MELODY) study are to determine the comparative effectiveness of telehealth-based MT versus telehealth-based CBT for anxiety and comorbid symptoms in cancer survivors and to identify patient-level factors associated with greater anxiety symptom reduction for MT and CBT. MethodsThe MELODY study is a 2-arm, parallel-group randomized clinical trial that aims to compare the effectiveness of MT versus CBT for anxiety and comorbid symptoms. The trial will enroll 300 English- or Spanish-speaking survivors of any cancer type or stage who have experienced anxiety symptoms for at least 1 month. Participants will receive 7 weekly sessions of MT or CBT delivered remotely via Zoom (Zoom Video Communications, Inc) over 7 weeks. Validated instruments to assess anxiety (primary outcome), comorbid symptoms (fatigue, depression, insomnia, pain, and cognitive dysfunction), and health-related quality of life will be administered at baseline and at weeks 4, 8 (end of treatment), 16, and 26. Semistructured interviews will be conducted at week 8 with a subsample of 60 participants (30 per treatment arm) to understand individual experiences with the treatment sessions and their impact. ResultsThe first study participant was enrolled in February 2022. As of January 2023, 151 participants have been enrolled. The trial is expected to be completed by September 2024. ConclusionsThis study is the first and largest randomized clinical trial to compare the short- and long-term effectiveness of remotely delivered MT and CBT for anxiety in cancer survivors. Limitations include the lack of usual care or placebo control groups and the lack of formal diagnostic assessments for psychiatric disorders among trial participants. The study findings will help guide treatment decisions for 2 evidence-based, scalable, and accessible interventions to promote mental well-being during cancer survivorship. International Registered Report Identifier (IRRID)DERR1-10.2196/46281

Background:. We undertook this study to investigate the outcomes of surgical treatment for acute carpal tunnel syndrome following our protocol for concurrent nerve decompression and skeletal stabilization for bony wrist trauma to be undertaken within 48 hours. Methods:. We identified all patients treated at our trauma center following this protocol between January 1, 2014 and December 31, 2019. All patients were clinically reviewed at least 12 months after surgery and assessed using the Brief Michigan Hand Outcomes Questionnaire, the Boston Carpal Tunnel Questionnaire, and sensory assessment with Semmes-Weinstein monofilament testing. Results:. The study group was made up of 35 patients. Thirty-three patients were treated within 36 hours. Patients treated with our unit protocol for early surgery comprising nerve decompression and bony stabilization within 36 hours report excellent outcomes at medium term follow-up. Conclusions:. We propose that nerve decompression and bony surgical stabilization should be undertaken as soon as practically possible once the diagnosis is made. This is emergent treatment to protect and preserve nerve function. In our experience, the vast majority of patients were treated within 24 hours; however, where a short period of observation was required, excellent results were generally achieved when treatment was completed within 36 hours.

Metabolic causes such as altered bioenergetics and amino acid metabolism may play a major role in Long COVID. Renal-metabolic regulation is an integral part of these pathways but has not been systematically or routinely investigated in Long COVID. Here we discuss the biochemistry of renal tubular injury as it may contribute to Long COVID symptoms. We propose three potential mechanisms that could be involved in Long COVID namely creatine phosphate metabolism, un-reclaimed glomerular filtrate and COVID specific proximal tubule cells (PTC) injury-a tryptophan paradigm. This approach is intended to allow for improved diagnostics and therapy for the long-haul sufferers.

Additive friction stir deposition (AFSD), a deformation-based, near-net-shaping additive technology, is used to consolidate Al chips from automotive castings to produce fully-dense components, while addressing the energy, environmental, and efficiency challenges associated with recycling these chips via melting. Cold pressing of the chips results in feed-rods with a relative density of 68%. AFSD of these porous feed-rods leads to porosity-free material in the as-printed state. Compared to the base material of bulk cast Al, the as-printed material increases the tensile elongation from less than 1% to 17.8%, while exhibiting significant strain hardening. This upcycling effect is shown to originate from microstructure evolution during deposition, including the second-phase particles and the grain structure. The received Al chips have a hypereutectic composition and thus contain a high proportion of primary Si particles. The minor presence of Fe causes additional intermetallic particles as well. After deposition, these Si and Fe-based particles are refined, spherodized, and uniformly distributed in the Al matrix. Meanwhile, the cast Al microstructure is converted to an equiaxed grain structure with the grain size reduced from ∼ 25 μm to ∼ 2 μm. Finally, the energy consumption of AFSD-enabled upcycling is compared to melt-based recycling; potential pathways are evaluated for energy consumption reduction.

Camel trypanosomiasis (Surra) is endemic in the Horn of Africa. Understanding the spatiotemporal variations in Surra prevalence, vector dynamics, and host-related risk factors is important in developing effective control strategies. A repeated cross-sectional study was conducted to determine the Surra parasitological prevalence, livestock reservoirs, vector density/diversity, and host-related risk factors in Kenya. Random samples of 847, 1079, and 824 camels were screened at the start of the dry season, peak dry season, and during the rainy season, respectively. Blood samples were examined using the dark ground/phase contrast buffy-coat technique, and Trypanosoma species were identified based on their movement and morphology in wet and stained thin smears. Reservoir status for Trypanosoma evansi was assessed in 406 cattle and 372 goats. A rainy and dry seasons entomological surveys were conducted to determine the Surra vector abundance/diversity and spatiotemporal density changes. Surra prevalence was 7.1%, 3.4%, and 4.1% at the start of the dry season, peak dry season, and rainy season, respectively. Camel co-infections by Trypanozoon (T. evansi or Trypanosoma brucei brucei) and Trypanosoma vivax were recorded. Spatial variations in Surra prevalence were recorded at the beginning of dry (X7,N=8462=110.9, p≤0.001), peak dry (X7,N=10792=42.2, p≤0.001), and rainy (X7,N=8242=29.1, p≤0.001) seasons. The screened cattle and goats tested negative for Trypanozoon (T. evansi or T. b. brucei), while two cattle tested positive for Trypanosoma congolense. Biting fly catches were composed of a single species from Tabanus, Atylotus, Philoliche, Chrysops, and Stomoxys genera. The total catches for Philoliche, Chrysops, and Stomoxys were higher in the rainy than dry season consistent with the prevalence results. Surra remains an important camel disease in the region with its prevalence varying in space and time. Camel co-infections by Trypanozoon (T. evansi or T. b. brucei) and T. vivax necessitate proper diagnosis of suspected cases and targeted therapy.

A 79-year-old male presented for removal of what was proven to be a keratoacanthoma. Additional tissue removed deep to the initial lesion revealed intravascular basal cell carcinoma (BCC). Intravascular BCC is exceedingly rare with only 8 cases previously reported in the literature. Intravascular BCC may be associated with more aggressive subtypes. Intravascular infiltration is more common in metastatic BCC, but this finding may not imply causality. More data are required in order to determine prognostic implications of intravascular BCC and to develop a protocol for managing patients with this unique finding.

ABSTRACT Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed over 6 million individuals worldwide and continues to spread in countries where vaccines are not yet widely available or its citizens are hesitant to become vaccinated. Therefore, it is critical to unravel the molecular mechanisms that allow SARS-CoV-2 and other coronaviruses to infect and overtake the host machinery of human cells. Coronavirus replication triggers endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR), a key host cell pathway widely believed to be essential for viral replication. We examined the master UPR sensor IRE1α kinase/RNase and its downstream transcription factor effector XBP1s, which is processed through an IRE1α-mediated mRNA splicing event, in human lung-derived cells infected with betacoronaviruses. We found that human respiratory coronavirus OC43 (HCoV-OC43), Middle East respiratory syndrome coronavirus (MERS-CoV), and murine coronavirus (MHV) all induce ER stress and strongly trigger the kinase and RNase activities of IRE1α as well as XBP1 splicing. In contrast, SARS-CoV-2 only partially activates IRE1α through autophosphorylation, but its RNase activity fails to splice XBP1. Moreover, while IRE1α was dispensable for replication in human cells for all coronaviruses tested, it was required for maximal expression of genes associated with several key cellular functions, including the interferon signaling pathway, during SARS-CoV-2 infection. Our data suggest that SARS-CoV-2 actively inhibits the RNase of autophosphorylated IRE1α, perhaps as a strategy to eliminate detection by the host immune system. IMPORTANCE SARS-CoV-2 is the third lethal respiratory coronavirus, after MERS-CoV and SARS-CoV, to emerge this century, causing millions of deaths worldwide. Other common coronaviruses such as HCoV-OC43 cause less severe respiratory disease. Thus, it is imperative to understand the similarities and differences among these viruses in how each interacts with host cells. We focused here on the inositol-requiring enzyme 1α (IRE1α) pathway, part of the host unfolded protein response to virus-induced stress. We found that while MERS-CoV and HCoV-OC43 fully activate the IRE1α kinase and RNase activities, SARS-CoV-2 only partially activates IRE1α, promoting its kinase activity but not RNase activity. Based on IRE1α-dependent gene expression changes during infection, we propose that SARS-CoV-2 prevents IRE1α RNase activation as a strategy to limit detection by the host immune system.

Introduction Pain, comorbid fatigue and sleep disturbances are common and distressing symptoms for patients with advanced cancer, negatively impacting their quality of life. Clinical guidelines recommend non-pharmacological interventions, including acupuncture and massage, for pain management in adult patients with cancer in adjunct to conventional care. However, high-quality evidence about the comparative effectiveness and long-term durability of these therapies for symptom management is limited.Methods and analysis We describe the design of a two-arm, parallel group, multicentre randomised controlled trial that investigates the use of acupuncture versus massage for musculoskeletal pain among 300 patients with diverse types of advanced cancer. The primary aim is to evaluate the long-term effectiveness (26 weeks from randomisation) of acupuncture vs massage for pain (primary outcome) and comorbid symptoms (fatigue, sleep disturbance and quality of life). The secondary aim is to identify patient-level demographic characteristics (eg, sex, race, age), clinical factors (eg, insomnia, pain severity) and psychological attributes that are associated with a greater reduction in pain for either acupuncture or massage. Patients will receive weekly acupuncture or massage treatments for 10 weeks, followed by monthly booster sessions up to 26 weeks. The primary endpoint will be the change in worst pain intensity score from baseline to 26 weeks. We will collect validated patient-reported outcomes at multiple time points over 26 weeks.Ethics and dissemination The Institutional Review Board at Memorial Sloan Kettering Cancer Center in New York approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. Our findings will help patients and healthcare providers make informed decisions about incorporating non-pharmacological treatments to manage pain for patients with advanced cancer.Trial registration number NCT04095234.

Abstract Background Yoga is a meditative movement therapy focused on mind‐body awareness. The impact of yoga on health‐related quality of life (HRQOL) outcomes in patients with chemotherapy‐induced peripheral neuropathy (CIPN) is unclear. Methods We conducted a pilot randomized wait‐list controlled trial of 8 weeks of yoga (n = 21) versus wait‐list control (n = 20) for CIPN in 41 breast and gynecological cancer survivors with persistent moderate to severe CIPN. HRQOL endpoints were Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI), and Insomnia Severity Index (ISI). The Treatment Expectancy Scale (TES) was administered at baseline. We estimated mean changes and 95% confidence intervals (CIs) from baseline to weeks 8 and 12 and compared arms using constrained linear mixed models. Results At week 8, HADS anxiety scores decreased −1.61 (−2.75, −0.46) in the yoga arm and −0.32 (−1.38, 0.75) points in the wait‐list control arm (p = 0.099). At week 12, HADS anxiety scores decreased −1.42 (−2.57, −0.28) in yoga compared to an increase of 0.46 (−0.60, 1.53) in wait‐list control (p = 0.017). There were no significant differences in HADS depression, BFI, or ISI scores between yoga and wait‐list control. Baseline TES was significantly higher in yoga than in wait‐list control (14.9 vs. 12.7, p = 0.019). TES was not associated with HADS anxiety reduction and HADS anxiety reduction was not associated with CIPN pain reduction. Conclusions Yoga may reduce anxiety in patients with CIPN. Future studies are needed to confirm these findings. Clinical Trial Registration Number: ClinicalTrials.gov Identifier: NCT03292328.

Abstract Importance This study reports the impact of laser surgery on quality of life in patients with oral cavity lesions. Objective To compare postoperative pain and quality of life in patients treated with flexible fiberoptic CO2 laser vs electrocautery in patients with oral cavity precancerous lesions and early stage cancers. Design Randomized controlled trial. Setting Single center. Participants Patients with premalignant oral cavity lesions and early stage oral cancer. Intervention Patients were randomized to have surgical resection using either flexible fiber carbon dioxide laser (Laser) or electrocautery (EC). The patients were then followed over a period of 28 days to assess for outcomes including pain, quality of life, performance status, return to work, and return to diet. Quality of life was measured by the University of Washington Quality of Life (UWQOL) questionnaire and the performance status score (PSS). Main outcome measure The primary endpoint for this study was the numerical pain rating on postoperative day (POD) 7. Results Sixty‐two patients were randomized (32 laser and 30 electrocautery). Lesions excised were carcinoma in 30(48%), dysplasia in 31(50%) and benign in 1(2%). There was no difference in the location of lesion, size of lesion, defect size, type of closure, resection time, and blood loss between Laser and EC arms. Patients who had Laser had less pain compared to EC (mean pain score on POD 7 L = 2.84 vs EC = 3.83, P = 0.11). better UW QOL scores and PSS scores, quicker return to normal diet (median days L = 26.0 vs EC = 28.5, P = 0.17) and faster return to work (median days L = 13.0 vs EC = 16.5, P = 0.14). However, these results were not statistically significant. Conclusion There was a trend for patients treated with laser to have less pain and better quality of life scores but these result were not statistically significant. Based on the actual observed difference, a large multicenter RCT with 90 patients in each arm is required to determine the clinical relevance of our results.

Recent advances in rice breeding in tropical Asia led to the release of high-yielding drought-tolerant cultivars. Together with the use of these cultivars, improved nutrient management under drought should further increase rice productivity in rainfed lowland ecosystems. The objectives of this study were to evaluate cultivar differences in the responses of plant growth and grain yield to fertilizer application regimes. We compared 13 drought-tolerant rice cultivars with two irrigated rice cultivars under three nutrient management conditions in irrigated and rainfed lowlands in the Philippines during the wet seasons of 2014 and 2015. Drought stress was mild in both years, with a yield reduction of 11 to 12%, and there was no significant cultivar × nutrient management interaction in yield. The drought-tolerant cultivar NSIC Rc282 proved fertilizer-responsive, and had similar yield to those of the popular high-yielding cultivar NSIC Rc222 under all conditions. An ancillary experiment in 2016 confirmed that NSIC Rc282 was more drought-adapted than NSIC Rc222, with 11% to 37% higher yield under stress. In order to maximize the yield, NSIC Rc282 required N application only when the drought ended, whereas NSIC Rc222 required additional N during the drought. This shows that the details of drought-adaptive nutrient management differ between irrigated and drought-tolerant rice cultivars. We suggest that the introduction of high-yielding drought-tolerant rice cultivars will both improve productivity and increase the nutrient-use efficiency in rainfed environments.

AngioJet rheolytic thrombectomy, although a successful treatment modality for arterial thrombus removal and recanalization, has been shown to have increased rates of postoperative acute kidney injury (AKI) compared with other methods of treatment for acute limb ischemia. The postinterventional course of AKI can differ markedly from patient to patient, but typically resolves relatively quickly. Herein, we present a case of AKI secondary to AngioJet intervention that demonstrates an exceedingly prolonged but ultimately recoverable course with conservative management and without the need for renal replacement therapy.