Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

Divergence beneath the Brillouin sphere and the phenomenology of prediction error in spherical harmonic series approximations of the gravitational field.

The Brillouin sphere is defined as the smallest sphere, centered at the origin of the geocentric coordinate system, that incorporates all the condensed matter composing the planet. The Brillouin sphere touches the Earth at a single point, and the radial line that begins at the origin and passes through that point is called the singular radial line. For about 60 years there has been a persistent anxiety about whether or not a spherical harmonic (SH) expansion of the external gravitational potential,V, will converge beneath the Brillouin sphere. Recently, it was proven that the probability of such convergence is zero. One of these proofs provided an asymptotic relation, called Costin's formula, for the upper bound,EN, on the absolute value of the prediction error,eN, of a SH series model,VN(θ,λ,r), truncated at some maximum degree,N=nmax. When the SH series is restricted to (or projected onto) a particular radial line, it reduces to a Taylor series (TS) in1/r. Costin's formula isEN≃BN-b(R/r)N, whereRis the radius of the Brillouin sphere. This formula depends on two positive parameters:b, which controls the decay of error amplitude as a function ofNwhenris fixed, and a scale factorB. We show here that Costin's formula derives from a similar asymptotic relation for the upper bound,Anon the absolute value of the TS coefficients,an, for the same radial line. This formula,An≃Kn-k, depends on degree,n, and two positive parameters,kandK, that are analogous tobandB. We use synthetic planets, for which we can compute the potential,V, and also the radial component of gravitational acceleration,gr=∂V/∂r, to hundreds of significant digits, to validate both of these asymptotic formulas. Let superscriptVrefer to asymptotic parameters associated with the coefficients and prediction errors for gravitational potential, and superscriptgto the coefficients and predictions errors associated withgr. For polyhedral planets of uniform density we show thatbV=kV=7/2andbg=kg=5/2almost everywhere. We show that the frequency of oscillation (around zero) of the TS coefficients and the series prediction errors, for a given radial line, is controlled by the geocentric angle,α, between that radial line and the singular radial line. We also derive useful identities connectingKV,BV,Kg, andBg. These identities are expressed in terms of quotients of the various scale factors. The only other quantities involved in these identities areαandR. The phenomenology of 'series divergence' and prediction error (whenr < R) can be described as a function of the truncation degree,N, or the depth,d, beneath the Brillouin sphere. For a fixedr⩽R, asNincreases from very low values, the upper error boundENshrinks until it reaches its minimum (best) value whenNreaches some particular or optimum value,Nopt. WhenN>Nopt, prediction error grows asNcontinues to increase. Eventually, whenN≫Nopt, prediction errors increase exponentially with risingN. If we fix the value ofNand allowR/rto vary, then we find that prediction error in free space beneath the Brillouin sphere increases exponentially with depth,d, beneath the Brillouin sphere. Becausebg=bV-1everywhere, divergence driven prediction error intensifies more rapidly forgrthan forV, both in terms of its dependence onNandd. If we fix bothNandd, and focus on the 'lateral' variations in prediction error, we observe that divergence and prediction error tend to increase (as doesB) as we approach high-amplitude topography.

Proof-of-Principle Experiment for Testing Strong-Field Quantum Electrodynamics with Exotic Atoms: High Precision X-Ray Spectroscopy of Muonic Neon.

To test bound-state quantum electrodynamics (BSQED) in the strong-field regime, we have performed high precision x-ray spectroscopy of the 5g-4f and 5f- 4d transitions (BSQED contribution of 2.4 and 5.2 eV, respectively) of muonic neon atoms in the low-pressure gas phase without bound electrons. Muonic atoms have been recently proposed as an alternative to few-electron high-Z ions for BSQED tests by focusing on circular Rydberg states where nuclear contributions are negligibly small. We determined the 5g_{9/2}- 4f_{7/2} transition energy to be 6297.08±0.04(stat)±0.13(syst) eV using superconducting transition-edge sensor microcalorimeters (5.2-5.5 eV FWHM resolution), which agrees well with the most advanced BSQED theoretical prediction of 6297.26 eV.

Measurements of Strong-Interaction Effects in Kaonic-Helium Isotopes at Sub-eV Precision with X-Ray Microcalorimeters.

We have measured the 3d→2p transition x rays of kaonic ^{3}He and ^{4}He atoms using superconducting transition-edge-sensor microcalorimeters with an energy resolution better than 6 eV (FWHM). We determined the energies to be 6224.5±0.4(stat)±0.2(syst) eV and 6463.7±0.3(stat)±0.1(syst) eV, and widths to be 2.5±1.0(stat)±0.4(syst) eV and 1.0±0.6(stat)±0.3(stat) eV, for kaonic ^{3}He and ^{4}He, respectively. These values are nearly 10 times more precise than in previous measurements. Our results exclude the large strong-interaction shifts and widths that are suggested by a coupled-channel approach and agree with calculations based on optical-potential models.

Predicting depression outcomes throughout inpatient treatment using the general and specific personality disorder factors.

BACKGROUND: Clinical intuition suggests that personality disorders hinder the treatment of depression, but research findings are mixed. One reason for this might be the way in which current assessment measures conflate general aspects of personality disorders, such as overall severity, with specific aspects, such as stylistic tendencies. The goal of this study was to clarify the unique contributions of the general and specific aspects of personality disorders to depression outcomes. METHODS: Patients admitted to the Menninger Clinic, Houston, between 2012 and 2015 (N = 2352) were followed over a 6-8-week course of multimodal inpatient treatment. Personality disorder symptoms were assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition Axis II Personality Screening Questionnaire at admission, and depression severity was assessed using the Patient Health Questionnaire-9 every fortnight. General and specific personality disorder factors estimated with a confirmatory bifactor model were used to predict latent growth curves of depression scores in a structural equation model. RESULTS: The general factor predicted higher initial depression scores but not different rates of change. By contrast, the specific borderline factor predicted slower rates of decline in depression scores, while the specific antisocial factor predicted a U shaped pattern of change. CONCLUSIONS: Personality disorder symptoms are best represented by a general factor that reflects overall personality disorder severity, and specific factors that reflect unique personality styles. The general factor predicts overall depression severity while specific factors predict poorer prognosis which may be masked in prior studies that do not separate the two.

Deexcitation Dynamics of Muonic Atoms Revealed by High-Precision Spectroscopy of Electronic K X Rays.

We observed electronic K x rays emitted from muonic iron atoms using superconducting transition-edge sensor microcalorimeters. The energy resolution of 5.2 eV in FWHM allowed us to observe the asymmetric broad profile of the electronic characteristic Kα and Kß x rays together with the hypersatellite K^{h}α x rays around 6 keV. This signature reflects the time-dependent screening of the nuclear charge by the negative muon and the L-shell electrons, accompanied by electron side feeding. Assisted by a simulation, these data clearly reveal the electronic K- and L-shell hole production and their temporal evolution on the 10-20 fs scale during the muon cascade process.

Hand eczema in children referred for patch testing: North American Contact Dermatitis Group Data, 2000-2016.

BACKGROUND: Little is known about the aetiologies and relevant allergens in paediatric patients with hand eczema (HE). OBJECTIVES: To characterize the aetiologies and determine the proportion of positive and currently relevant allergens in children/adolescents (age < 18 years) with HE referred for patch testing. METHODS: A retrospective analysis (2000-2016) of North American Contact Dermatitis Group data was performed. RESULTS: Of 1634 paediatric patients, 237 (14·5%) had involvement of the hands. Final physician diagnoses included allergic contact dermatitis (49·4%), atopic dermatitis (37·1%) and irritant contact dermatitis (16·9%). In multivariable logistic regression models, employment was the only association with increased odds of any HE or primary HE. Children with HE vs. those without HE had similar proportions of positive patch tests (56·1% vs. 61·7%; χ2 -test, P = 0·11). The five most common currently relevant allergens were nickel, methylisothiazolinone, propylene glycol, decyl glucoside and lanolin. In multivariable logistic regression models of the top 20 relevant allergens, HE was associated with significantly higher odds of currently relevant reactions to lanolin, quaternium-15, Compositae mix, thiuram mix, 2-mercaptobenzathiazole and colophony. The allergens with the highest mean significance-prevalence index number were methylisothiazolinone, carba mix, thiuram mix, nickel and methylchloroisothiazolinone/methylisothiazolinone. CONCLUSIONS: Children with HE who were referred for patch testing had a high proportion of positive patch tests, which was similar to the proportion found in children without HE. Children with HE had a distinct and fairly narrow profile of currently relevant allergens.

Absolute energies and emission line shapes of the L x-ray transitions of lanthanide metals.

We use an array of transition-edge sensors, cryogenic microcalorimeters with 4 eV energy resolution, to measure L x-ray emission-line profiles of four elements of the lanthanide series: praseodymium, neodymium, terbium, and holmium. The spectrometer also surveys numerous x-ray standards in order to establish an absolute-energy calibration traceable to the international system of units for the energy range 4 keV to 10 keV. The new results include emission line profiles for 97 lines, each expressed as a sum of one or more Voigt functions; improved absolute energy uncertainty on 71 of these lines relative to existing reference data; a median uncertainty on the peak energy of 0.24 eV, four to ten times better than the median of prior work; and six lines that lack any measured values in existing reference tables. The 97 lines comprise nearly all of the most intense L lines from these elements under broad-band x-ray excitation. The work improves on previous measurements made with a similar cryogenic spectrometer by the use of sensors with better linearity in the absorbed energy and a gold x-ray absorbing layer that has a Gaussian energy-response function. It also employs a novel sample holder that enables rapid switching between science targets and calibration targets with excellent gain balancing. Most of the results for peak energy values shown here should be considered as replacements for the currently tabulated standard reference values, while the line shapes given here represent a significant expansion of the scope of available reference data.

Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive surgery for advanced ovarian cancer.

OBJECTIVES: Intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and interval tumor reductive surgery (TRS) for advanced ovarian cancer is feasible, however, the impact on disease outcomes remains unclear. We compare outcomes of patients treated with IP chemotherapy versus intravenous (IV) chemotherapy following NACT and interval TRS. METHODS: In this retrospective review, patients with advanced ovarian cancer were included if they received NACT followed by optimal interval TRS between 1/2004 and 4/2017. Patients were excluded if they had an ECOG PS >1, received >6 cycles of NACT or postoperative chemotherapy, and/or received bevacizumab during primary therapy. Primary outcomes were progression free survival (PFS) and overall survival (OS). RESULTS: There were 134 patients included in this study, 37 (28%) received IP and 97 (72%) received IV chemotherapy postoperatively. Patients in the IV group were older (median 66.3 vs 59.7 years, p = 0.0039) though there were no differences in BMI, race, BRCA status, stage, or histology. Median PFS was 3 months longer in the IP group (14.5 versus 11.5 months, p = 0.028) however there was no significant difference in OS. On univariate analysis, increasing number of NACT cycles (HR 1.914, 95% CI 1.024-3.497) and residual disease at completion of TRS (HR 1.541, 95% CI 1.042-2.248) were associated with decreased PFS; IP chemotherapy was associated with increased PFS (HR 0.633, 95% CI 0.414-0.944). These associations remained on multivariate analysis. Toxicity was comparable between the groups. CONCLUSIONS: IP after NACT and optimal interval TRS was associated with in improved PFS compared to IV chemotherapy without significant differences in toxicity.

Association of TPH1 and serotonin transporter genotypes with treatment response for suicidal ideation: a preliminary study.

Variants in three genes coding for components of the serotonergic system, the tryptophan hydroxylase 1 (TPH1) rs1799913, serotonin transporter (SLC6A4) 5-HTTLPR, and serotonin receptor 2A (HTR2A) rs6311, were evaluated for association with suicidal ideation (SI) and with recovery from SI in a psychiatric inpatient population. Five hundred and eighty-two adult inpatients, including 390 patients who had SI, collected from December 2012 to April 2016 were assessed. SI recovery, calculated as change in SI between the first two-week period after admission and weeks 5 and 6, was appraised for association with the three variants. In this preliminary study, both TPH1 and 5-HTTLPR genotypes were associated with recovery (TPH1: recessive model, increased recovery with AC genotype, P = 0.026; additive model, increased recovery with AC genotype, P = 0.037; 5-HTTLPR: recessive model, increased recovery with AC, P = 0.043). When patients with comorbid alcohol use disorder (AUD) were removed, given that TPH1 has been associated with alcoholism, the associations of those recovered from SI with TPH1 rs1799913 remained significant for the additive (increased recovery with AC, P = 0.045) and recessive (increased recovery with C-carriers, P = 0.008) models, and with 5-HTTLPR using the dominant model (increased recovery with S'S', P = 0.016). In females, an association of SI recovery with TPH1 rs1799913 was found using a recessive model (increased recovery with C-carriers, P = 0.031), with 5-HTTLPR using additive (increased recovery with L'S', P = 0.048) and recessive (increased recovery with S'S', P = 0.042) models. Additionally, an association of SI with TPH1 rs1799913 was found in females using both additive (increased risk in AC, P = 0.033) and recessive (increased risk in C-carriers, P = 0.043) models, and with 5-HTTLPR using a recessive model (increased risk in S'S', P = 0.030). This study provides evidence that variation in the TPH1 and serotonin transporter genes play key roles in moderating recovery from SI during treatment in an inpatient psychiatric clinic.

Long-term safety and efficacy of trifarotene 50 µg/g cream, a first-in-class RAR-γ selective topical retinoid, in patients with moderate facial and truncal acne.

BACKGROUND: Treatment for both facial and truncal acne has not sufficiently been studied. OBJECTIVES: To evaluate the long-term safety and efficacy of trifarotene in both facial and truncal acne. METHODS: In a multicentre, open-label, 52-week study, patients with moderate facial and truncal acne received trifarotene 50 µg/g cream (trifarotene). Assessments included local tolerability, safety, investigator and physician's global assessments (IGA, PGA) and quality of life (QOL). A validated QOL questionnaire was completed by the patient at Baseline, Week 12, 26 and 52/ET. RESULTS: Of 453 patients enrolled, 342 (75.5%) completed the study. Trifarotene-related treatment-emergent adverse events (TEAEs) were reported in 12.6% of patients, and none was serious. Most related TEAEs were cutaneous and occurred during the first 3 months. Signs and symptoms of local tolerability were mostly mild or moderate and severe signs, and symptoms were reported for 2.2% to 7.1% of patients for the face and 2.5% to 5.4% for the trunk. Local irritation increased during the first week of treatment on the face and up to Weeks 2 to 4 on the trunk with both decreasing thereafter. At Week 12, IGA and PGA success rates were 26.6% and 38.6%, respectively. Success rates increased to 65.1% and 66.9%, respectively at Week 52. Overall success (both IGA and PGA success in the same patient) was 57.9% at Week 52. At Week 52 visit, 92/171 (53.8%) patients who had completed their assessments had scores from 0 to 1 (i.e. no effect of acne on their QOL) vs. 47/208 (22.6%) patients at Baseline visit. CONCLUSION: In this 52-week study, trifarotene was safe, well tolerated and effective in moderate facial and truncal acne.

"Operator syndrome": A unique constellation of medical and behavioral health-care needs of military special operation forces.

OBJECTIVE: U.S. military special operation forces represent the most elite units of the U.S. Armed Forces. Their selection is highly competitive, and over the course of their service careers, they experience intensive operational training and combat deployment cycles. Yet, little is known about the health-care needs of this unique population. METHOD: Professional consultations with over 50 special operation forces operators (and many spouses or girlfriends) over the past 6 years created a naturalistic, observational base of knowledge that allowed our team to identify a unique pattern of interrelated medical and behavioral health-care needs. RESULTS: We identified a consistent pattern of health-care difficulties within the special operation forces community that we and other special operation forces health-care providers have termed "Operator Syndrome." This includes interrelated health and functional impairments including traumatic brain injury effects; endocrine dysfunction; sleep disturbance; obstructive sleep apnea; chronic joint/back pain, orthopedic problems, and headaches; substance abuse; depression and suicide; anger; worry, rumination, and stress reactivity; marital, family, and community dysfunction; problems with sexual health and intimacy; being "on guard" or hypervigilant; memory, concentration, and cognitive impairments; vestibular and vision impairments; challenges of the transition from military to civilian life; and common existential issues. CONCLUSIONS: "Operator Syndrome" may be understood as the natural consequences of an extraordinarily high allostatic load; the accumulation of physiological, neural, and neuroendocrine responses resulting from the prolonged chronic stress; and physical demands of a career with the military special forces. Clinical research and comprehensive, intensive immersion programs are needed to meet the unique needs of this community.

Altered habenula to locus coeruleus functional connectivity in past anorexia nervosa suggests correlation with suicidality: a pilot study.

PURPOSE: Despite anorexia nervosa having the highest mortality rate of mental illnesses, little is known regarding the brain mechanisms involved. Given that lack of interest for food in anorexic patients is related to alterations in the reward system, we tested the hypothesis that patients with past anorexia nervosa (pAN) have altered resting state functional connectivity (RSFC) between the habenula (a major component of the reward system) and its targets. METHODS: RSFC between the habenula and major targets (locus coeruleus, median and dorsal raphe nuclei, substantia nigra, and ventral tegmental area) was studied in 14 psychiatric inpatients with pAN and 14 psychiatric inpatient controls (PC, never-anorexic patients in same clinic, matched for comorbidities). Next, we tested possible correlations between RSFC and suicidal ideation, depression, and anxiety as determined by self-report questionnaires. RESULTS: Left habenula/locus coeruleus RSFC was lower in pAN patients compared to PC. The left habenula/locus coeruleus RSFC was positively correlated with suicidal ideation (past 2 months) in pAN patients, but not in controls. CONCLUSIONS: pAN patients showed long lasting alterations in habenular connectivity. This may have clinical implications, possibly including future evaluation of the habenula as a therapeutic target and the need to carefully monitor suicidality in pAN patients. NO LEVEL OF EVIDENCE: Basic science.

Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles in ChAT-Cre Mouse Lines.

The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT(BAC)-Cre mouse line, created with the bacterial artificial chromosome (BAC) method, and ChAT(IRES)-Cre mouse line, generated with the internal ribosome entry site (IRES) method. ChAT(BAC)-Cre transgenic and wild-type mice did not differ in general locomotor behavior, anxiety measures, drug-induced cataplexy, nicotine-mediated hypolocomotion, or operant food training. However, ChAT(BAC)-Cre transgenic mice did exhibit significant deficits in intravenous nicotine self-administration, which paralleled an increase in vesicular acetylcholine transporter and choline acetyltransferase (ChAT) hippocampal expression. For the ChAT(IRES)-Cre line, transgenic mice exhibited deficits in baseline locomotor, nicotine-mediated hypolocomotion, and operant food training compared with wild-type and hemizygous littermates. No differences among ChAT(IRES)-Cre wild-type, hemizygous, and transgenic littermates were found in anxiety measures, drug-induced cataplexy, and nicotine self-administration. Given that increased cre expression was present in the ChAT(IRES)-Cre transgenic mice, as well as a decrease in ChAT expression in the hippocampus, altered neuronal function may underlie behavioral phenotypes. In contrast, ChAT(IRES)-Cre hemizygous mice were more similar to wild-type mice in both protein expression and the majority of behavioral assessments. As such, interpretation of data derived from ChAT-Cre rodents must consider potential limitations dependent on the line and/or genotype used in research investigations.SIGNIFICANCE STATEMENT Altered baseline and/or nicotine-mediated behavioral profiles were discovered in transgenic mice from the ChAT(BAC)-Cre and ChAT(IRES)-Cre lines. Given that these cre-expressing mice have become increasingly used by the scientific community, either independently with chemicogenetic and optogenetic viral vectors or crossed with other transgenic lines, the current studies highlight important considerations for the interpretation of data from previous and future experimental investigations. Moreover, the current findings detail the behavioral effects of either increased or decreased baseline cholinergic signaling mechanisms on locomotor, anxiety, learning/memory, and intravenous nicotine self-administration behaviors.

The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate-to-severe atopic dermatitis: results from a randomized double-blind placebo-controlled study.

BACKGROUND: ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways. OBJECTIVES: The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily). RESULTS: ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE. CONCLUSIONS: In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

Classifying suicidal behavior with resting-state functional connectivity and structural neuroimaging.

OBJECTIVE: About 80% of patients who commit suicide do not report suicidal ideation the last time they speak to their mental health provider, highlighting the need to identify biomarkers of suicidal behavior. Our goal is to identify suicidal behavior neural biomarkers to classify suicidal psychiatric inpatients. METHODS: Eighty percent of our sample [suicidal (n = 63) and non-suicidal psychiatric inpatients (n = 65)] was used to determine significant differences in structural and resting-state functional connectivity measures throughout the brain. These measures were used in a random forest classification model on 80% of the sample for training the model. RESULTS: The model built on 80% of the patients had sensitivity = 79.4% and specificity = 72.3%. This model was tested on an independent sample (20%; n = 32) with sensitivity = 81.3% and specificity = 75.0% for confirming the generalizability of the model. Altered resting-state functional connectivity features from frontal and middle temporal regions, as well as the amygdala, parahippocampus, putamen, and vermis were found to generalize best. CONCLUSION: This work demonstrates neuroimaging (an unbiased biomarker) can be used to classify suicidal behavior in psychiatric inpatients without observing any clinical features.

Resting-State Functional Connectivity of the Habenula in Mood Disorder Patients With and Without Suicide-Related Behaviors.

The habenula is a small midbrain structure that is important for brain signaling and learning from negative events. Thus, the habenula is strongly connected to both the reward system and motor regions. Increasing evidence suggests a role for the habenula in the etiology of psychiatric disorders, including mood and substance use disorders. However, no studies to date have investigated habenular resting-state functional connectivity (rsFC) in suicide-related behaviors (SB). The authors enrolled 123 individuals with major depressive disorder (MDD) or bipolar disorder and a history of suicide-related behaviors (SB+), 74 individuals with MDD or bipolar disorder and a history of suicidal ideation but no history of SB (SB-), and 75 healthy control subjects (HC). A seed-based approach was used to identify regions showing different rsFC with the habenula followed by region of interest to region of interest post hoc comparisons. Compared with both the SB- and HC groups, the SB+ group showed higher connectivity between the left habenula and the left parahippocampal gyrus, the right amygdala, and the right precentral and postcentral gyri. Patients with mood disorders displayed higher rsFC between the left habenula and left middle temporal gyrus, the left angular gyrus, and the left posterior cingulate cortex, as well as lower rsFC between the right habenula and the left thalamus, when compared with HCs. These findings suggest that the habenula is involved in the neural circuitry of suicide. The higher habenular rsFC found in the SB+ group may mediate a dysfunction in the mechanism that links the habenula with motor activity and contextual associative processing.

Optimization of Time- and Code-Division-Multiplexed Readout for Athena X-IFU.

Readout of a large, spacecraft-based array of superconducting transition-edge sensors (TESs) requires careful management of the layout area and power dissipation of the cryogenic-circuit components. We present three optimizations of our time- (TDM) and code-division-multiplexing (CDM) systems for the X-ray Integral Field Unit (X-IFU), a several-thousand-pixel-TES array for the planned Athena-satellite mission. The first optimization is a new readout scheme that is a hybrid of CDM and TDM. This C/TDM architecture balances CDM's noise advantage with TDM's layout compactness. The second is a redesign of a component: the shunt resistor that provides a dc-voltage bias to the TESs. A new layout and a thicker Pd-Au resistive layer combine to reduce this resistor's area by more than a factor of 5. Third, we have studied the power dissipated by the first-stage SQUIDs (superconducting quantum-interference devices) and the readout noise versus the critical current of the first-stage SqUIDs. As a result, the X-IFU TDM and C/TDM SQUIDs will have a specified junction critical current of 5 µA. Based on these design optimizations and TDM experiments described by Durkin, et al. (these proceedings), TDM meets all requirements to be X-IFU's backup-readout option. Hybrid C/TDM is another viable option that could save spacecraft resources.

Demonstration of Athena X-IFU Compatible 40-Row Time-Division-Multiplexed Readout.

Time-division multiplexing (TDM) is the backup readout technology for the X-ray Integral Field Unit (X-IFU), a 3,168-pixel X-ray transition-edge sensor (TES) array that will provide imaging spectroscopy for ESA's Athena satellite mission. X-0IFU design studies are considering readout with a multiplexing factor of up to 40. We present data showing 40-row TDM readout (32 TES rows + 8 repeats of the last row) of TESs that are of the same type as those being planned for X-IFU, using measurement and analysis parameters within the ranges specified for X-IFU. Singlecolumn TDM measurements have best-fit energy resolution of (1.91 ± 0.01) eV for the Al Kα complex (1.5 keV), (2.10 ± 0.02) eV for Ti Kα (4.5 keV), (2.23 ± 0.02) eV for Mn Kα (5.9 keV), (2.40 ± 0.02) eV for Co Kα (6.9 keV), and (3.44 ± 0.04) eV for Br Kα (11.9 keV). Three-column measurements have best-fit resolution of (2.03 ± 0.01) eV for Ti Kα and (2.40 ± 0.01) eV for Co Kα. The degradation due to the multiplexed readout ranges from 0.1 eV at the lower end of the energy range to 0.5 eV at the higher end. The demonstrated performance meets X-IFU's energy-resolution and energy-range requirements. True 40-row TDM readout, without repeated rows, of kilopixel scale arrays of X-IFU-like TESs is now under development.

Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches.

BACKGROUND: Adalimumab is used to treat several inflammatory diseases, including plaque psoriasis. GP2017 is a proposed adalimumab biosimilar. OBJECTIVES: To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis. METHODS: This 51-week double-blinded, phase III study randomly assigned patients to GP2017 (n = 231) or ref-ADMB (n = 234) 80 mg subcutaneously at week 0, then 40 mg biweekly from week 1. At week 17, patients were rerandomized to switch (n = 126) or continue (n = 253) treatment. The primary end point was patients achieving ≥ 75% improvement in Psoriasis Area and Severity Index (PASI 75) at week 16, with equivalence confirmed if the 95% confidence interval (CI) for the difference in PASI 75 between treatments was ± 18%. The key secondary end point was the change from baseline to week 16 in continuous PASI. Other end points were PASI over time; PASI 50, 75, 90 and100; pharmacokinetics; safety; tolerability and immunogenicity for the switched and continued treatment groups. RESULTS: Equivalent efficacy between GP2017 and ref-ADMB was confirmed for the primary (66·8% and 65·0%, respectively; 95% CI -7·46 to 11·15) and key secondary end points (-60·7% and -61·5%, respectively; 95% CI -3·15 to 4·84). PASI improved over time and was similar between treatment groups at week 16, and the switched and continued groups from weeks 17 to 51. There were no relevant safety or immunogenicity differences between GP2017 and ref-ADMB at week 16, or the switched and continued groups from weeks 17 to 51. No hypersensitivity to adalimumab was reported upon switching. CONCLUSIONS: Following the demonstration of GP2017 biosimilarity to ref-ADMB, switching up to four times between GP2017 and ref-ADMB had no detectable impact on efficacy, safety or immunogenicity.