A dusty compact object bridging galaxies and quasars at cosmic dawn.

Understanding how super-massive black holes form and grow in the early Universe has become a major challenge1,2 since it was discovered that luminous quasars existed only 700 million years after the Big Bang3,4. Simulations indicate an evolutionary sequence of dust-reddened quasars emerging from heavily dust-obscured starbursts that then transition to unobscured luminous quasars by expelling gas and dust5. Although the last phase has been identified out to a redshift of 7.6 (ref. 6), a transitioning quasar has not been found at similar redshifts owing to their faintness at optical and near-infrared wavelengths. Here we report observations of an ultraviolet compact object, GNz7q, associated with a dust-enshrouded starburst at a redshift of 7.1899 ± 0.0005. The host galaxy is more luminous in dust emission than any other known object at this epoch, forming 1,600 solar masses of stars per year within a central radius of 480 parsec. A red point source in the far-ultraviolet is identified in deep, high-resolution imaging and slitless spectroscopy. GNz7q is extremely faint in X-rays, which indicates the emergence of a uniquely ultraviolet compact star-forming region or a Compton-thick super-Eddington black-hole accretion disk at the dusty starburst core. In the latter case, the observed properties are consistent with predictions from cosmological simulations7 and suggest that GNz7q is an antecedent to unobscured luminous quasars at later epochs.

Normal, dust-obscured galaxies in the epoch of reionization.

Over the past decades, rest-frame ultraviolet (UV) observations have provided large samples of UV luminous galaxies at redshift (z) greater than 6 (refs. 1-3), during the so-called epoch of reionization. While a few of these UV-identified galaxies revealed substantial dust reservoirs4-7, very heavily dust-obscured sources at these early times have remained elusive. They are limited to a rare population of extreme starburst galaxies8-12 and companions of rare quasars13,14. These studies conclude that the contribution of dust-obscured galaxies to the cosmic star formation rate density at z > 6 is sub-dominant. Recent ALMA and Spitzer observations have identified a more abundant, less extreme population of obscured galaxies at z = 3-6 (refs. 15,16). However, this population has not been confirmed in the reionization epoch so far. Here, we report the discovery of two dust-obscured star-forming galaxies at z = 6.6813 ± 0.0005 and z = 7.3521 ± 0.0005. These objects are not detected in existing rest-frame UV data and were discovered only through their far-infrared [C II] lines and dust continuum emission as companions to typical UV-luminous galaxies at the same redshift. The two galaxies exhibit lower infrared luminosities and star-formation rates than extreme starbursts, in line with typical star-forming galaxies at z ≈ 7. This population of heavily dust-obscured galaxies appears to contribute 10-25% to the z > 6 cosmic star formation rate density.

Perforated peptic ulcer disease in transferred patients is associated with significant increase in length of stay.

BACKGROUND: Perforated peptic ulcer disease (PPUD) has a prevalence of 0.004-0.014% with mortality of 23.5% (Tarasconi et al. in World J Emerg Surg 15(PG-3):3, 2020). In this single center study, we examined the impact associated with patient transfer from outside facilities to our center for definitive surgical intervention (exploratory laparotomy). METHODS: Using EPIC report workbench, we identified 27 patients between 2018 and 2021 undergoing exploratory laparotomy with a concurrent diagnosis of peptic ulcer disease, nine of which were transferred to our institution for care. We queried this population for markers of disease severity including mortality, length of stay, intensive care unit (ICU) length of stay, and readmission rates. Manual chart reviews were performed to examine these outcomes in more detail and identify patients who had been transferred to our facility for surgery from an outside hospital. RESULTS: A total of 27 patients were identified undergoing exploratory laparotomy for definitive treatment of PPUD. The majority of patients queried underwent level A operations, the most urgent level of activation. In our institution, a Level A operation needs to go to the operating room within one hour of arrival to the hospital. Average mortality for this patient population was 14.8%. The readmission rate was 40.1%, and average length of ICU stay post-operatively was 16 days, with 83% of non-transfer patients requiring ICU admission and 100% of transfer patients requiring ICU admission, although this was not found to be statistically significant. Average length of hospital stay was 27 days overall. For non-transfer patients and transfer patients, LOS was 20 days and 41 days, respectively, which was statistically significant by one-sided t-test (p = 0.05). CONCLUSION: Patients transferred for definitive care of PPUD in a population otherwise notable for high mortality and high readmission rates: their average length of stay compared to non-transfer patients was over twice the length, which was statistically significant. Transferred patients also had higher rates of ICU care requirement although this was not statistically significant. Further inquiry to identify modifiable variables to facilitate the care of transferred patients is warranted, especially in the context of improving quality metrics known to enhance patient outcomes, satisfaction, and value.

GM-CSF is a marker of compartmentalised intrathecal inflammation in multiple sclerosis.

BACKGROUND: Granulocyte-macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine secreted by various immune cells. Several studies have demonstrated an expansion of GM-CSF producing T cells in the blood or CSF of people with MS (pwMS). However, whether this equates to greater concentrations of circulating cytokine remains unknown as quantification is difficult with traditional assays. OBJECTIVE: To determine whether GM-CSF can be quantified and whether GM-CSF levels are elevated in pwMS. METHODS: We employed Single Molecule Array (Simoa) to measure GM-CSF in both CSF and blood. We then investigated relationships between GM-CSF levels and measures of blood-CSF-barrier integrity. RESULTS: GM-CSF was quantifiable in all samples and was significantly higher in the CSF of pwMS compared with controls. No association was found between CSF GM-CSF levels and Q-Albumin - a measure of blood-CSF-barrier integrity. CSF GM-CSF correlated with measures of intrathecal inflammation, and these relationships were greater in primary progressive MS compared with relapsing-remitting MS. CONCLUSION: GM-CSF levels are elevated specifically in the CSF of pwMS. Our results suggest that elevated cytokine levels may reflect (at least partial) intrathecal production, as opposed to simple diffusion across a dysfunctional blood-CSF-barrier.

Two new mouse models of Gjb1-associated Charcot-Marie-Tooth disease type 1X.

BACKGROUND: Charcot-Marie-Tooth disease type 1X is caused by mutations in GJB1, which is the second most common gene associated with inherited peripheral neuropathy. The GJB1 gene encodes connexin 32 (CX32), a gap junction protein expressed in myelinating glial cells. The gene is X-linked, and the mutations cause a loss of function. AIMS: A large number of disease-associated variants have been identified, and many result in mistrafficking and mislocalization of the protein. An existing knockout mouse lacking Gjb1 expression provides a valid animal model of CMT1X, but the complete lack of protein may not fully recapitulate the disease mechanisms caused by aberrant CX32 proteins. To better represent the spectrum of human CMT1X-associated mutations, we have generated a new Gjb1 knockin mouse model. METHODS: CRISPR/Cas9 genome editing was used to produce mice carrying the R15Q mutation in Gjb1. In addition, we identified a second allele with an early frame shift mutation in codon 7 (del2). Mice were analyzed using clinically relevant molecular, histological, neurophysiological, and behavioral assays. RESULTS: Both alleles produce protein detectable by immunofluorescence in Schwann cells, with some protein properly localizing to nodes of Ranvier. However, both alleles also result in peripheral neuropathy with thinly myelinated and demyelinated axons, as well as degenerating and regenerating axons, predominantly in distal motor nerves. Nerve conduction velocities were only mildly reduced at later ages and compound muscle action potential amplitudes were not reduced. Levels of neurofilament light chain in plasma were elevated in both alleles. The del2 mice have an onset at ~3 months of age, whereas the R15Q mice had a later onset at 5-6 months of age, suggesting a milder loss of function. Both alleles performed comparably to wild type littermates in accelerating rotarod and grip strength tests of neuromuscular performance. INTERPRETATION: We have generated and characterized two new mouse models of CMT1X that will be useful for future mechanistic and preclinical studies.

Inflammatory breast cancer defined: proposed common diagnostic criteria to guide treatment and research.

PURPOSE: Inflammatory breast cancer is a deadly and aggressive type of breast cancer. A key challenge relates to the need for a more detailed, formal, objective definition of IBC, the lack of which compromises clinical care, hampers the conduct of clinical trials, and hinders the search for IBC-specific biomarkers and treatments because of the heterogeneity of patients considered to have IBC. METHODS: Susan G. Komen, the Inflammatory Breast Cancer Research Foundation, and the Milburn Foundation convened patient advocates, clinicians, and researchers to review the state of IBC and to propose initiatives to advance the field. After literature review of the defining clinical, pathologic, and imaging characteristics of IBC, the experts developed a novel quantitative scoring system for diagnosis. RESULTS: The experts identified through consensus several "defining characteristics" of IBC, including factors related to timing of onset and specific symptoms. These reflect common pathophysiologic changes, sometimes detectable on biopsy in the form of dermal lymphovascular tumor emboli and often reflected in imaging findings. Based on the importance and extent of these characteristics, the experts developed a scoring scale that yields a continuous score from 0 to 48 and proposed cut-points for categorization that can be tested in subsequent validation studies. CONCLUSION: To move beyond subjective 'clinical diagnosis' of IBC, we propose a quantitative scoring system to define IBC, based on clinical, pathologic, and imaging features. This system is intended to predict outcome and biology, guide treatment decisions and inclusion in clinical trials, and increase diagnostic accuracy to aid basic research; future validation studies are necessary to evaluate its performance.

Moving Forward from the COVID-19 Pandemic: Needed Changes in Movement Disorders Care and Research.

PURPOSE OF REVIEW: The COVID-19 pandemic has dramatically affected the health and well-being of individuals with movement disorders. This manuscript reviews these effects, discusses pandemic-related changes in clinical care and research, and suggests improvements to care and research models. RECENT FINDINGS: During the on-going COVID-19 pandemic, individuals with movement disorders have experienced worsening of symptoms, likely due to decreased access to care, loss of social connection, and decreased physical activity. Through telemedicine, care has moved out of the clinic and into the home. Clinical research has also been significantly disrupted, and there has been a shift to decentralized approaches. The pandemic has highlighted disparities in access to care and representation in research. We must now translate these experiences into better care and research models with a focus on equitable integration of telemedicine, better support of patients and caregivers, the development of meaningful digital endpoints, and optimization of decentralized research designs.

Superiority of continuous over intermittent intraoperative nerve monitoring in preventing vocal cord palsy.

BACKGROUND: Continuous intraoperative nerve stimulation (IONM) with uninterrupted monitoring is likely better than intermittent IONM in preventing vocal cord palsy after thyroid surgery. METHODS: This was a comparative study of intermittent versus continuous IONM in patients with benign and malignant thyroid disease treated at a tertiary centre over 10 years. Early postoperative and permanent vocal cord palsy rates were estimated. Multivariable logistic regression analysis was used to quantify the contributions of clinical and histopathological variables to early postoperative and permanent vocal cord palsy. RESULTS: A total of 6029 patients were included, of whom 3139 underwent continuous and 2890 intermittent IONM. Based on nerves at risk (5208 versus 5024 nerves), continuous IONM had a 1·7-fold lower early postoperative vocal cord palsy rate than intermittent monitoring (1·5 versus 2·5 per cent). This translated into a 30-fold lower permanent vocal cord palsy rate (0·02 versus 0·6 per cent). In multivariable logistic regression analysis, continuous IONM independently reduced early postoperative vocal cord palsy 1·8-fold (odds ratio (OR) 0·56) and permanent vocal cord palsy 29·4-fold (OR 0·034) compared with intermittent IONM. One permanent vocal cord palsy per 75·0 early vocal cord palsies was observed with continuous IONM, compared with one per 4·2 after intermittent IONM. Early postoperative vocal cord palsies were 17·9-fold less likely to become permanent with continuous than intermittent IONM. CONCLUSION: Continuous IONM is superior to intermittent IONM in preventing vocal cord palsy.

Risk of skin cancer in new users of thiazides and thiazide-like diuretics: a cohort study using an active comparator group.

BACKGROUND: Case-control studies report a dose-dependent increased risk of skin cancer in users of hydrochlorothiazide (HCTZ) vs. nonusers. The degree to which other thiazides and thiazide-like diuretics (TZs) are associated with skin cancer is less certain. OBJECTIVES: To assess the risk of skin cancer in new users of different TZs compared with new users of calcium channel blockers (CCBs). METHODS: We conducted a cohort study using a UK primary-care database (1998-2017), including 271 154 new TZ users [87·6% bendroflumethiazide (BFT), 5·8% indapamide and 3·6% HCTZ] and 275 263 CCB users. The outcomes were basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CMM). We estimated incidence rates (IRs) and IR ratios (IRRs) in short-term (< 20 prescriptions) and long-term (≥ 20 prescriptions) users of TZs and CCBs using negative binomial regression, and calculated rate differences (RDs) for selected results. We used fine stratification on the propensity score (PS) to control for 23 baseline covariates. RESULTS: Long-term use of HCTZ increased absolute and relative risks of SCC [PS-weighted IRR 1·95; 95% confidence interval (CI) 1·87-2·02; RD per 100 000 person-years 87.4], but not of BCC or CMM. Long-term use of indapamide was associated with an increased incidence of CMM (IRR 1·43; 95% CI 1·35-1·50). BFT was not meaningfully associated with the risk of any type of skin cancer. CONCLUSIONS: Our results corroborate the previously reported increased risk of SCC (but not of BCC or CMM) for long-term use of HCTZ. BFT may be a safer alternative for patients at increased risk of skin cancer.

Variation in the Internal Transcribed Spacer Region of Phakopsora pachyrhizi and Implications for Molecular Diagnostic Assays.

Phakopsora pachyrhizi, the causal agent of soybean rust (SBR), is a global threat to soybean production. Since the discovery of SBR in the continental United States, quantitative polymerase chain reaction assays based on the internal transcribed spacer (ITS) ribosomal DNA locus were established for its rapid detection. However, insufficient data were initially available to test assays against factors that could give rise to misidentification. This study aimed to reevaluate current assays for (i) the potential for false-positive detection caused by nontarget Phakopsora species and (ii) the potential for false-negative detection caused by intraspecific variation within the ITS locus of P. pachyrhizi. A large amount of intraspecific and intragenomic variation in ITS was detected, including the presence of polymorphic ITS copies within single leaf samples and within single rust sori. The diagnostic assays were not affected by polymorphisms in the ITS region; however, current assays are at risk of false positives when screened against other species of Phakopsora. This study raises caveats to the use of multicopy genes (e.g., ITS) in single-gene detection assays and discusses the pitfalls of inferences concerning the aerobiological pathways of disease spread made in the absence of an evaluation of intragenomic ITS heterogeneity.

Twenty-year experience of paediatric thyroid surgery using intraoperative nerve monitoring.

BACKGROUND: There are few data on intermittent and continuous intraoperative nerve monitoring (IONM) during thyroidectomy in children. METHODS: All children aged 18 years or younger who had standard thyroid operations using intermittent or continuous IONM between January 1998 and December 2016 were included in the study. The impact of age and type of IONM on basal amplitude, latency and complications after thyroidectomy were assessed. RESULTS: A total of 504 children were included in the study. With continuous IONM, median basal amplitude and latency increased significantly with age, more on the left side (from 199 to 870 µV, and from 3·88 to 5·75 ms) than on the right (from 340 to 778 µV, and from 2·63 to 3·50 ms). Compared with intermittent IONM with needle electrode, continuous IONM with tube electrode resulted in an increase in median basal amplitude in children aged 13-18 years on both sides (from 675 to 778 µV on the right and from 450 to 870 µV on the left), and a decrease in median latency in all children older than 3 years: in children aged 4-6 years, from 4·20 to 3·00 ms on the right and from 6·10 to 4·63 ms on the left; in children aged 7-12 years, from 4·60 to 3·50 ms and from 6·00 to 5·25 ms respectively; and in children aged 13-18 years, from 4·60 to 3·50 ms and from 6·40 to 5·75 ms. Overall, wound infection, but not bleeding/haematoma or vocal fold palsy, affected younger children more: 3 per cent of children aged 3 years or less; 2 per cent of children aged 4-6 years; and 0 per cent of children aged over 6 years (P = 0·031). With continuous IONM, no wound infection, bleeding/haematoma or permanent vocal fold palsy was noted in any age group. CONCLUSION: Continuous IONM measures nerve electrophysiology more accurately than intermittent IONM during thyroidectomy in children.

Mitochondrial transfer between cells: Methodological constraints in cell culture and animal models.

Interest in the recently discovered phenomenon of mitochondrial transfer between mammalian cells has gained momentum since it was first described in cell culture systems more than a decade ago. Mitochondria-targeting fluorescent dyes have been repurposed and are now widely used in these studies and in acute disease models, sometimes without due consideration of their limitations, while vectors containing mitochondrially-imported fluorescent proteins have complemented the use of mitochondria-targeting dyes. Genetic approaches that use mitochondrial DNA polymorphisms have also been used in some in vitro studies and in tumor models and are particularly useful where mtDNA is damaged or deleted. These approaches can also be used to study the long-term consequences of mitochondrial transfer such as in bone marrow and organ transplantation and in tumour biology where inherent mitochondrial damage is often a key feature. As research on intercellular mitochondrial transfer moves from cell culture into animal models and human diseases it will be important to understand the limitations of the various techniques in order to apply appropriate methodologies to address physiological and pathophysiological conditions.

Coumestrol Confers Partial Resistance in Soybean Plants Against Cercospora Leaf Blight.

Although previous research showed that the purple symptom of Cercospora leaf blight (CLB) is associated with lower biomass of Cercospora cf. flagellaris and lower concentrations of cercosporin, a reactive oxygen species producer, as compared with blighted leaves, the hypothesis that the purple symptom is a plant reaction to the pathogen has never been tested. In this study, we demonstrated that high levels of coumestrol (COU) were associated with purple symptoms of CLB and that COU has strong antioxidant activity. Additionally, we found that COU is restricted to the pigmented areas of purple leaves, and the pigmentation is restricted to the adaxial surfaces, suggesting that COU may be acting as a sunscreen. Even though COU is associated with the purple leaf symptom, this coumestan is not the direct cause of discoloration in that COU is colorless. Quantification of chlorophyll a and b and total carotenoids suggested that blighted but not purple or asymptomatic leaves were undergoing photooxidative stress. Because the purple symptom is associated with high COU concentrations, lower biomass of C. cf. flagellaris, and lower cercosporin concentrations, we conclude that the purple symptom is a disease resistance reaction, mediated in part by COU, which provides a high level of antioxidant activity and, hence, partial resistance.

The Duffy antigen receptor for chemokines regulates asthma pathophysiology.

BACKGROUND: The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. OBJECTIVE: To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. METHODS: Mice with targeted disruption of the Darc gene (Darc∆E2 ) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics. RESULTS: Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062). CONCLUSIONS AND CLINICAL RELEVANCE: Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.

Decoration of trastuzumab with short oligonucleotides: synthesis and detailed characterization.

Trastuzumab (Herceptin®) is an FDA-approved therapeutic antibody currently employed in the treatment of metastatic stages of breast cancer. Herein, we propose a simple, fast and cost-effective methodology to conjugate trastuzumab with 22-mer 5' thiol-modified oligonucleotides using a bifunctional crosslinker. The conjugates were successfully characterized by MALDI-ToF MS and SDS-PAGE, obviating the need for enzymatic digestion and difficult chromatographic separations. Furthermore, ELISA was performed to ensure that trastuzumab activity is not affected by oligonucleotide conjugation.

Cervical cord and ventricle affection in neuromyelitis optica.

OBJECTIVES: Cervical cord involvement is common in neuromyelitis optica (NMO) and multiple sclerosis (MS), but its impact on disability in NMO has rarely been studied. Recent publications on NMO examined the periventricular system, areas of high aquaporin-4 expression, but not yet by using ventricle volumetry. PURPOSE: To compare cervical cord atrophy, ventricular widening, and supra- and infratentorial brain measures between NMO and MS, and study their impact on clinical disability. METHODS: Magnet resonance imaging-based volumetry of upper cervical cord, third and fourth lateral ventricles, grey matter, white matter, brainstem, cerebellum and clinical status of 18 NMO and 20 MS patients, was compared between the groups and with 26 healthy controls. Patterns of ventricular widening relative to healthy controls were inspected by voxel-based morphometry of the cerebrospinal fluid. RESULTS: Cervical cord atrophy was similar in NMO and MS (75.2 ± 10.0 mm2 , respectively, 76.5 ± 9.5 mm2 vs 84.1 ± 8.6 mm2 in controls).Third ventricle increase in both groups, and specific fourth ventricle widening in MS were detected. Patient groups differed in third to fourth ventricle ratio (P = 0.002). In NMO, white matter correlated inversely with the affected cord segments (P = 0.001) and with cervical cord area (P = 0.043). The disability status was explained by cervical cord area and third ventricle volume (R2 =0.524) in NMO, and by grey matter and fourth ventricle volume (R2 =0.565) in MS. CONCLUSION: Cervical cord atrophy and third ventricular enlargement are both clinically relevant in NMO. Third and fourth ventricle volumetry shows differences between NMO and MS regarding the involvement of periventricular structures.

New implantable cardiac monitor with three-lead ECG and active noise detection.

BACKGROUND: A new implantable cardiac monitor (BioMonitor, Biotronik) with a continuous remote monitoring option was prospectively implanted in patients with suspected arrhythmias or for therapy control after atrial fibrillation (AF) ablation. A three-lead ECG detection was intended to make the implantation more independent of the implantation site and the electrical heart axis. Because noise is a frequent problem in implantable cardiac monitors, an active noise detection algorithm was implemented. The aim of the trial was to evaluate the clinical performance of the device. METHODS: The device performance was evaluated in a prospective nonrandomized multicenter study with a follow-up of 12 months. Study endpoints were device-related serious adverse events at 3 months, appropriate QRS detection in direct comparison with synchronized Holter ECG recordings, sensitivity and positive predictive value of arrhythmia detection in comparison with Holter ECG and independent of it, and noise burden during the entire follow-up period. RESULTS: The implantation was successful in all 152 patients. Two device-related serious adverse events (pocket infections) occurred by 3 months. The mean QRS amplitude of 0.3 ± 0.2 mV at implantation remained stable over 12 months. QRS sensing performance indicated little over- and undersensing in most patients. More than 80 % of the patients had more than 22 h of noise-free monitoring per day. CONCLUSION: BioMonitor effectively detects patients with bradycardia, tachycardia, AF, or asystole. Active noise detection seems to reduce the transmission of meaningless data without diminishing the positive predictive value of the device.

[Key Points of Intraoperative Diagnostic Measures Performed by Anaesthesiologists]. / Relevante Eckpunkte der intraoperativen anästhesiologischen Diagnostik.

The main focus of surgeons and anaesthesiologists during a surgical procedure is on safety and optimal treatment of the patient. Within the scope of interdisciplinary collaboration, the intraoperative communication between surgeons and anaesthesiologists is the basis of case-, findings- and surgery-phases-adapted patient management. The perioperative monitoring of patients and the implementation of diagnostic measures by anaesthesiologists are essential for optimal patient management. The results of the examinations may significantly determine the course of surgery. Therefore, it is important for surgeons to be familiar with the relevant intraoperative diagnostic measures.