TGF-ß is responsible for NK cell immaturity during ontogeny and increased susceptibility to infection during mouse infancy.

A large gap in our understanding of infant immunity is why natural killer (NK) cell responses are deficient, which makes infants more prone to viral infection. Here we demonstrate that transforming growth factor-ß (TGF-ß) was responsible for NK cell immaturity during infancy. We found more fully mature NK cells in CD11c(dnR) mice, whose NK cells lack TGF-ß receptor (TGF-ßR) signaling. Ontogenic maturation of NK cells progressed faster in the absence of TGF-ß signaling, which results in the formation of a mature NK cell pool early in life. As a consequence, infant CD11c(dnR) mice efficiently controlled viral infections. These data thus demonstrate an unprecedented role for TGF-ß in ontogeny that can explain why NK cell responses are deficient early in life.

Systematic Coarse Graining of Environments for the Nonperturbative Simulation of Open Quantum Systems.

Conducting precise electronic-vibrational dynamics simulations of molecular systems poses significant challenges when dealing with realistic environments composed of numerous vibrational modes. Here, we introduce a technique for the construction of effective phonon spectral densities that capture accurately open-system dynamics over a finite time interval of interest. When combined with existing nonperturbative simulation tools, our approach can reduce significantly the computational costs associated with many-body open-system dynamics.

Fingerprint and Universal Markovian Closure of Structured Bosonic Environments.

We exploit the properties of chain mapping transformations of bosonic environments to identify a finite collection of modes able to capture the characteristic features, or fingerprint, of the environment. Moreover we show that the countable infinity of residual bath modes can be replaced by a universal Markovian closure, namely, a small collection of damped modes undergoing a Lindblad-type dynamics whose parametrization is independent of the spectral density under consideration. We show that the Markovian closure provides a quadratic speedup with respect to standard chain mapping techniques and makes the memory requirement independent of the simulation time, while preserving all the information on the fingerprint modes. We illustrate the application of the Markovian closure to the computation of linear spectra but also to nonlinear spectral response, a relevant experimentally accessible many body coherence witness for which efficient numerically exact calculations in realistic environments are currently lacking.

Ileocolic anastomosis after right hemicolectomy: stapled end-to-side, stapled side-to-side, or handsewn?

PURPOSE: Anastomotic leak (AL) following ileocolic anastomosis is a cause of significant morbidity and mortality. Stapled end-to-side (ESA), stapled side-to-side (SSA), and handsewn anastomoses (HSA) are commonly performed techniques. There is however conflicting data on the superiority of one technique over the other. The aim of this study was to compare the outcomes of ESA against SSA and HSA. METHODS: This retrospective cohort study was conducted at a tertiary colorectal unit. All patients who underwent an ileocolic anastomosis from October 2008 to May 2020 were included. Exclusion criteria were missing data on anastomotic technique or clinicopathological variables. Primary outcomes were AL and anastomotic bleeding (AB). Secondary outcomes were length of stay (LoS) and return of gut function. RESULTS: A total of 1390 patients met the inclusion criteria. A total of 976 (70%) ESA, 308 (22%) SSA, and 108 (8%) HSA were performed. AL occurred in 17/1390 (1.2%) patients, and 54/1390 (3.9%) had AB. On adjusted analysis, ESA experienced a lower AL when compared with SSA (OR 4.93, p = 0.005), with a trend towards a lower AL when compared to HSA (OR 2.6, p = 0.27). There was no difference in AB between all techniques: ESA vs. SSA (OR 1.07 p = 0.84), and ESA vs. HSA (OR 0.24 p = 0.76). Both stapled techniques were associated with a shorter return to gut function compared to HSA; 3.3 vs. 4.2 days (p < 0.001). There was no difference in LoS. CONCLUSION: ESA has the lowest leak rate when compared to other anastomotic techniques without any increased risk of anastomotic bleeding.

Smart-Home Concept for Remote Monitoring of Instrumental Activities of Daily Living (IADL) in Older Adults with Cognitive Impairment: A Proof of Concept and Feasibility Study.

Assessment of instrumental activities of daily living (IADL) is essential for the diagnosis and staging of dementia. However, current IADL assessments are subjective and cannot be administered remotely. We proposed a smart-home design, called IADLSys, for remote monitoring of IADL. IADLSys consists of three major components: (1) wireless physical tags (pTAG) attached to objects of interest, (2) a pendant-sensor to monitor physical activities and detect interaction with pTAGs, and (3) an interactive tablet as a gateway to transfer data to a secured cloud. Four studies, including an exploratory clinical study with five older adults with clinically confirmed cognitive impairment, who used IADLSys for 24 h/7 days, were performed to confirm IADLSys feasibility, acceptability, adherence, and validity of detecting IADLs of interest and physical activity. Exploratory tests in two cases with severe and mild cognitive impairment, respectively, revealed that a case with severe cognitive impairment either overestimated or underestimated the frequency of performed IADLs, whereas self-reporting and objective IADL were comparable for the case with mild cognitive impairment. This feasibility and acceptability study may pave the way to implement the smart-home concept to remotely monitor IADL, which in turn may assist in providing personalized support to people with cognitive impairment, while tracking the decline in both physical and cognitive function.

Limited Aggregation and E-Cigarettes.

INTRODUCTION: Nonconsequentialist ethicists have noted that small harms, goods, or claims should not count against large claims. For example, given a choice between saving one life and a large group of people with minor headaches, we ought to save the one life, no matter how large the group is. This principle has been called limited aggregation. The principle of limited aggregation might have implications on public health policy, given that public health policy involves weighing the claims of individuals against one another. AIMS AND METHODS: I aim to show that limited aggregation has implications for policies on e-cigarettes and alternative nicotine delivery systems. The methodology used in this study involves critical analysis of existing literature and pre-theoretical moral views. RESULTS: This study does not use empirical research. CONCLUSIONS: In deciding to allow or encourage the use of e-cigarettes or alternative nicotine delivery systems, we sometimes must weigh benefits to each existing smoker affected by the policy against risks to each nonsmoker affected. I argue in this paper that when these risks, to each individual nonsmoker, are sufficiently small, we ought not to count them against more significant benefits to smokers. This applies even when the number of nonsmokers affected by a policy exceeds the number of smokers. IMPLICATIONS: This paper implies that policymakers ought to be sensitive to the scale of benefits or risks introduced by a policy on individuals. If the negative side effects, on each affected individual, of a proposed policy are sufficiently small, they do not count against the beneficial goals of that policy. Depending on the expected effects of each given e-cigarette policy, this may give policymakers defeasible reasons to prioritize the needs of current smokers, who may each gain a lot from various means of smoking cessation, over nonsmokers, who each may only have a small chance of picking up smoking.

Transcriptome analysis reveals intermittent fasting-induced genetic changes in ischemic stroke.

Genetic changes due to dietary intervention in the form of either calorie restriction (CR) or intermittent fasting (IF) are not reported in detail until now. However, it is well established that both CR and IF extend the lifespan and protect against neurodegenerative diseases and stroke. The current research aims were first to describe the transcriptomic changes in brains of IF mice and, second, to determine whether IF induces extensive transcriptomic changes following ischemic stroke to protect the brain from injury. Mice were randomly assigned to ad libitum feeding (AL), 12 (IF12) or 16 (IF16) h daily fasting. Each diet group was then subjected to sham surgery or middle cerebral artery occlusion and consecutive reperfusion. Mid-coronal sections of ipsilateral cerebral tissue were harvested at the end of the 1 h ischemic period or at 3, 12, 24 or 72 h of reperfusion, and genome-wide mRNA expression was quantified by RNA sequencing. The cerebral transcriptome of mice in AL group exhibited robust, sustained up-regulation of detrimental genetic pathways under ischemic stroke, but activation of these pathways was suppressed in IF16 group. Interestingly, the cerebral transcriptome of AL mice was largely unchanged during the 1 h of ischemia, whereas mice in IF16 group exhibited extensive up-regulation of genetic pathways involved in neuroplasticity and down-regulation of protein synthesis. Our data provide a genetic molecular framework for understanding how IF protects brain cells against damage caused by ischemic stroke, and reveal cellular signaling and bioenergetic pathways to target in the development of clinical interventions.

Dissipation-Assisted Matrix Product Factorization.

Charge and energy transfer in biological and synthetic organic materials are strongly influenced by the coupling of electronic states to a highly structured dissipative environment. Nonperturbative simulations of these systems require a substantial computational effort, and current methods can only be applied to large systems if environmental structures are severely coarse grained. Time evolution methods based on tensor networks are fundamentally limited by the times that can be reached due to the buildup of entanglement in time, which quickly increases the size of the tensor representation, i.e., the bond dimension. In this Letter, we introduce a dissipation-assisted matrix product factorization (DAMPF) method that combines a tensor network representation of the vibronic state within a pseudomode description of the environment where a continuous bosonic environment is mapped into a few harmonic oscillators under Lindblad damping. This framework is particularly suitable for a tensor network representation, since damping suppresses the entanglement growth among oscillators and significantly reduces the bond dimension required to achieve a desired accuracy. We show that dissipation removes the "time-wall" limitation of existing methods, enabling the long-time simulation of large vibronic systems consisting of 10-50 sites coupled to 100-1000 underdamped modes in total and for a wide range of parameter regimes. For these reasons, we believe that our formalism will facilitate the investigation of spatially extended systems with applications to quantum biology, organic photovoltaics, and quantum thermodynamics.

Resection of Pheochromocytoma Improves Diabetes Mellitus in the Majority of Patients.

BACKGROUND: Catecholamine excess in patients with pheochromocytoma often results in impaired glucose tolerance, leading to diabetes mellitus. Little data are available on the long-term effect of surgery on diabetes. OBJECTIVE: The primary aim of this study was to determine the likelihood of diabetes cure after surgery, while secondary objectives were to determine risk factors for development of diabetes preoperatively and persistence of diabetes postoperatively. METHODS: All patients undergoing surgery for pheochromocytoma from 1996 to 2015 were retrospectively reviewed to identify those with a preoperative diagnosis of diabetes. Demographic and diabetes-specific data were collected. Median follow-up was 52.1 months. RESULTS: Overall, 153 patients underwent surgery. Diabetes was seen in 36 (23.4%) patients. Eight patients met the exclusion criteria and were removed from the final analysis, while 22 (78.6%) patients had complete resolution of diabetes. Four patients remained on medication with improved control. Overall, 93.0% of patients had improvement of their diabetes; two patients did not improve. Patients with large, symptomatic tumors were more likely to develop preoperative diabetes, and diabetes was more likely to persist in patients who had an elevated body mass index (BMI). CONCLUSIONS: Diabetes was found concurrently with pheochromocytoma in 23% of patients, more often in those with large, symptomatic tumors. The majority of patients had long-term resolution of diabetes after successful resection; however, some patients may continue to require treatment of diabetes after operation, especially those with a higher BMI.

Signatures of spatially correlated noise and non-secular effects in two-dimensional electronic spectroscopy.

We investigate how correlated fluctuations affect oscillatory features in rephasing and non-rephasing two-dimensional (2D) electronic spectra of a model dimer system. Based on a beating map analysis, we show that non-secular environmental couplings induced by uncorrelated fluctuations lead to oscillations centered at both cross- and diagonal-peaks in rephasing spectra as well as in non-rephasing spectra. Using an analytical approach, we provide a quantitative description of the non-secular effects in terms of the Feynman diagrams and show that the environment-induced mixing of different inter-excitonic coherences leads to oscillations in the rephasing diagonal-peaks and non-rephasing cross-peaks. We demonstrate that as correlations in the noise increase, the lifetime of oscillatory 2D signals is enhanced at rephasing cross-peaks and non-rephasing diagonal-peaks, while the other non-secular oscillatory signals are suppressed. We discuss that the asymmetry of 2D lineshapes in the beating map provides information on the degree of correlations in environmental fluctuations. Finally we investigate how the oscillatory features in 2D spectra are affected by inhomogeneous broadening.

Cost Analysis of Endoscopic Mucosal Resection vs Surgery for Large Laterally Spreading Colorectal Lesions.

BACKGROUND & AIMS: Large laterally spreading lesions (LSL) in the colon and rectum can be safely and effectively removed by endoscopic mucosal resection (EMR). However, many patients still undergo surgery. Endoscopic treatment may be more cost effective. We compared the costs of endoscopic versus surgical management of large LSL. METHODS: We performed a prospective, observational, multicenter study of consecutive patients referred to 1 of 7 academic hospitals in Australia for the management of large LSL (≥ 20 mm) from January 2010 to December 2013. We collected data on numbers of patients undergoing EMR, actual endoscopic management costs (index colonoscopy, hospital stay, adverse events, and first surveillance colonoscopy), characteristics of patients and lesions, outcomes, and adverse events, and findings from follow-up examinations 14 days, 4-6 months, and 16-18 months after treatment. We compared data from patients who underwent EMR with those from a model in which all patients underwent surgery without any complications. Event-specific costs, based on Australian refined diagnosis-related group codes, were used to estimate average cost per patient. RESULTS: EMR was performed on 1489 lesions (mean size, 36 mm) in 1353 patients (mean age, 67 years; 52.1% male). Total costs involved in the endoscopic management of large LSL were US $6,316,593 and total inpatient hospitalization length of stay was 1180 days. The total cost predicted for the surgical management group was US $16,601,502, with a total inpatient hospitalization length of stay of 4986 days. Endoscopic management produced a potential total cost saving of US $10,284,909; the mean cost difference per patient was US $7602 (95% confidence interval, $8458-$9220; P < .001). Inpatient hospitalization length of stay was reduced by 2.81 nights per patient (95% confidence interval, 2.69-2.94; P < .001). CONCLUSIONS: In a large multicenter study, endoscopic management of large LSL by EMR was significantly more cost-effective than surgery. Endoscopic management by EMR at an appropriately experienced and resourced tertiary center should be considered the first line of therapy for most patients with this disorder. This approach is likely to deliver substantial overall health expenditure savings. ClinicalTrials.gov, Number: NCT01368289.

Microscopic Positive Tumor Margin Does Not Increase the Risk of Recurrence in Patients with T1-T2 Well-Differentiated Thyroid Cancer.

BACKGROUND: Incomplete surgical resection with gross positive tumor margin increases the risk of recurrence in patients with well-differentiated thyroid cancer (WDTC); however, it is not clear whether a microscopic positive margin found only on final pathology has similar implications on patient outcomes. METHODS: We conducted a single-institution retrospective review of all patients undergoing total thyroidectomy for T1-T2 WDTC (January 2000-January 2010). Factors that may influence the risk of locoregional recurrence or distant metastasis were evaluated by univariate and multivariate analysis. RESULTS: Of 1000 consecutive patients undergoing surgical resection for WDTC, 684 T1-T2 cancers were included. Mean age was 46 years and 81 % were women. Of this total cohort, 78 (11 %) patients had microscopic positive margins. Radioactive iodine (RAI) was administered in 47/78 (60 %) patients with positive margins versus 312/606 (51 %) patients without positive margins. After a mean follow-up of 46 months, 53 (8 %) patients developed recurrent disease (1 local and 52 nodal). On multivariate analysis, nodal metastases (N1, odds ratio [OR] 7.7) and contralateral multifocality (OR 3.7) were independent risk factors for recurrent disease. A microscopic positive margin was not a risk factor for recurrence. CONCLUSIONS: A microscopic positive margin found only on final pathological analysis does not increase the risk of recurrence in T1-T2 WDTC. Clinicians should interpret such pathology findings accordingly when considering further surveillance and treatment decisions such as the use of RAI ablation.

Effects of acute stress on cardiac endocannabinoids, lipogenesis, and inflammation in rats.

OBJECTIVE: Trauma exposure can precipitate acute stress (AS) and cardiovascular disorders (CVD). Identifying AS-related physiologic changes that affect CVD risk could inform development of early CVD prevention strategies. The endocannabinoid system (ECS) regulates hypothalamic-pituitary-adrenal axis and stress-related cardiovascular function. We examine stress-related ECS activity and its association with cardiovascular biochemistry/function after AS. METHODS: Rodents (n = 8-16/group) were exposed to predator odor or saline; elevated plus maze, blood pressure, serum and cardiac ECS markers, and lipid metabolism were assessed 24 hours and 2 weeks postexposure. RESULTS: At 24 hours, the predator odor group demonstrated anxiety-like behavior and had a) elevated serum markers of cardiac failure/damage (brain natriuretic peptide: 275.1 versus 234.6, p = .007; troponin I: 1.50 versus 0.78, p = .076), lipogenesis (triacylglycerols: 123.5 versus 85.93, p = .018), and inflammation (stearoyl delta-9 desaturase activity: 0.21 versus 0.07, p < .001); b) decreased cardiac 2-arachidonoyl-sn-glycerol (29.90 versus 65.95, p < .001), oleoylethanolamide (114.3 versus 125.4, p = .047), and palmitoylethanolamide (72.96 versus 82.87, p = .008); and c) increased cardiac inflammation (interleukin [IL]-1ß/IL-6 ratio: 19.79 versus 13.57, p = .038; tumor necrosis factor α/IL-6 ratio: 1.73 versus 1.03, p = .019) and oxidative stress (thiobarbituric acid reactive substances: 7.81 versus 7.05, p = .022), which were associated with cardiac steatosis (higher triacylglycerol: 1.09 versus 0.72, p < .001). Cardiac lipogenesis persisted, and elevated blood pressure emerged 2 weeks postexposure. CONCLUSIONS: Acute psychological stress elicits ECS-related cardiac responses associated with persistent, potentially pathological changes in rat cardiovascular biochemistry/function.

Syndrome of inappropriate antidiuretic hormone release secondary to central nervous system coccidioidomycosis with vasculitis.

A man in his 60s presented to the clinic due to night sweats and weight loss following pneumonia. He was found to have hyponatraemia due to a syndrome of inappropriate antidiuretic hormone (SIADH). CT of the thorax was concerning for pulmonary nodules. He was ultimately diagnosed with pulmonary coccidioidomycosis (CM) and started on fluconazole 400 mg daily with improvement in symptoms. Due to the report of headaches, head MRI was conducted which suggested central nervous system (CNS) involvement. Cerebrospinal fluid analysis was consistent with CNS CM and head magnetic resonance angiography confirmed the presence of CNS vasculitis. Fluconazole dose was increased to 800 mg daily which the patient continued to tolerate and showed improvement. This report depicts a case of SIADH associated with CNS CM with vasculitis and demonstrates the importance of high clinical suspicion for SIADH secondary to CNS CM in the setting of hyponatraemia and headache.

Use of PSMA PET/CT to detect prostate cancer metastatic to a preexisting thyroid nodule.

Prostate cancer (PCa) seldom metastasizes to the thyroid gland, and only a limited number of cases are documented in the literature. The application of a relatively recent and highly sensitive imaging technique, prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET/CT), has enhanced the identification of metastatic disease. Nevertheless, as PSMA is expressed in various tissue types, the clinical importance of a PSMA-avid thyroid lesion remains largely uncertain. A minor, yet noteworthy, percentage of these lesions are ultimately determined to be malignant. Here we describe the case of a 70-year-old man with a past medical history of Lynch syndrome who presented to an outpatient oncologic clinic for management of very high risk localized PCa. He developed metastatic recurrence and his disease progressed through several lines of therapy, including immunotherapy and targeted treatments. He was found to have a new, intense PSMA uptake in an existing, previously benign thyroid nodule. Sonographic evaluation revealed changing morphology despite grossly stable size. Repeat biopsy confirmed the unusual finding of PCa metastasis to a known thyroid nodule. The shift in PSMA avidity played a pivotal role in discerning this metastatic deposit. There is a potential risk that such lesions may be inadequately acknowledged. The impact of the patient's Lynch syndrome on this presentation remains uncertain.

To B(enign) or Not to B: functionalisation of variant in a mild form of argininosuccinate lyase deficiency identified through newborn screening.

Argininosuccinate lyase (ASL) deficiency is an autosomal recessive disorder of the urea cycle with a diverse spectrum of clinical presentation that is detectable in newborn screening. We report an 8-year-old girl with ASL deficiency who was detected through newborn screening and was confirmed using biochemical and functional assay. She is compound heterozygous for a likely pathogenic variant NM_000048.4(ASL):c.283C>T (p.Arg95Cys) and a likely benign variant NM_000048.4(ASL): c.1319T>C (p.Leu440Pro). Functional characterisation of the likely benign genetic variant in ASL was performed. Genomic sequencing was performed on the index patient presenting with non-specific symptoms of poor feeding and lethargy and shown to have increased serum and urine argininosuccinic acid. Functional assay using HEK293T cell model was performed. ASL enzymatic activity was reduced for Leu440Pro. This study highlights the role of functional testing of a variant that may appear benign in a patient with a phenotype consistent with ASL deficiency, and reclassifies NM_000048.4(ASL): c.1319T>C (p.Leu440Pro) variant as likely pathogenic.