Deformation conditions during syn-convergent extension along the Cordillera Blanca shear zone, Peru

Strain localization across the brittle-ductile transition is a fundamental process in accommodating tectonic movement in the mid-crust. The tectonically active Cordillera Blanca shear zone (CBSZ), a ~200-km-long normal-sense shear zone situated within the footwall of a discrete syn-convergent extensional fault in the Peruvian Andes, is an excellent field laboratory to explore this transition. Field and microscopic observations indicate consistent top-down-to-the-southwest sense of shear and a sequence of tectonites ranging from undeformed granodiorite through mylonite and ultimately fault breccia along the detachment. Using microstructural analysis, two-feldspar and Ti-in-quartz (TitaniQ) thermometry, recrystallized quartz paleopiezometry, and analysis of quartz crystallographic preferred orientations, we evaluate the deformation conditions and mechanisms in quartz and feldspar across the CBSZ. Deformation temperatures derived from asymmetric strain-induced myrmekite in a subset of tectonite samples are 410 ± 30 to 470 ± 36 °C, consistent with TitaniQ temperatures of 450 ± 60 to 490 ± 33 °C and temperatures \u3e400 °C estimated from microstructural criteria. Brittle fabrics overprint ductile fabrics within ~150 m of the detachment that indicate that deformation continued to lower-temperature (~280–400 °C) and/or higher-strain-rate conditions prior to the onset of pervasive brittle deformation. Initial deformation occurred via high-temperature fracturing and dissolution-precipitation in feldspar. Continued subsolidus deformation resulted in either layering of mylonites into monophase quartz and fine-grained polyphase domains oriented subparallel to macroscopic foliation or the interconnection of recrystallized quartz networks oriented obliquely to macroscopic foliation. The transition to quartz-controlled rheology occurred at temperatures near ~500 °C and at a differential stress of ~16.5 MPa. Deformation within the CBSZ occurred predominantly above ~400 °C and at stresses up to ~71.4 MPa prior to the onset of brittle deformation

Deformation Conditions During Syn-Convergent Extension Along the Cordillera Blanca Shear Zone, Peru

Strain localization across the brittle-ductile transition is a fundamental process in accommodating tectonic movement in the mid-crust. The tectonically active Cordillera Blanca shear zone (CBSZ), a ∼200-km-long normal-sense shear zone situated within the footwall of a discrete syn-convergent extensional fault in the Peruvian Andes, is an excellent field laboratory to explore this transition. Field and microscopic observations indicate consistent top-down-to-the-southwest sense of shear and a sequence of tectonites ranging from undeformed granodiorite through mylonite and ultimately fault breccia along the detachment. Using microstructural analysis, two-feldspar and Ti-in-quartz (TitaniQ) thermometry, recrystallized quartz paleopiezometry, and analysis of quartz crystallographic preferred orientations, we evaluate the deformation conditions and mechanisms in quartz and feldspar across the CBSZ. Deformation temperatures derived from asymmetric strain-induced myrmekite in a subset of tectonite samples are 410 ± 30 to 470 ± 36 °C, consistent with TitaniQ temperatures of 450 ± 60 to 490 ± 33 °C and temperatures \u3e400 °C estimated from microstructural criteria. Brittle fabrics overprint ductile fabrics within ∼150 m of the detachment that indicate that deformation continued to lower-temperature (∼280–400 °C) and/or higher-strain-rate conditions prior to the onset of pervasive brittle deformation. Initial deformation occurred via high-temperature fracturing and dissolution-precipitation in feldspar. Continued subsolidus deformation resulted in either layering of mylonites into monophase quartz and fine-grained polyphase domains oriented subparallel to macroscopic foliation or the interconnection of recrystallized quartz networks oriented obliquely to macroscopic foliation. The transition to quartz-controlled rheology occurred at temperatures near ∼500 °C and at a differential stress of ∼16.5 MPa. Deformation within the CBSZ occurred predominantly above ∼400 °C and at stresses up to ∼71.4 MPa prior to the onset of brittle deformation

Mantle-Derived Helium in Hot Springs of the Cordillera Blanca, Peru: Implications for Mantle-to-Crust Fluid Transfer in a Flat-Slab Subduction Setting

Fault-controlled hot springs in the Cordillera Blanca, Peru provide geochemical evidence of mantle-derived fluids in a modern flat-slab subduction setting. The Cordillera Blanca is an ~200km-long mountain range that contains the highest peaks in the Peruvian Andes, located in an amagmatic reach of the Andean arc. The Cordillera Blanca detachment defines the southwestern edge of the range and records a progression of top-down-to-the-west ductile shear to brittle normal faulting since ~5Ma. Hot springs, recording temperatures up to 78°C, issue along this fault zone and are CO2-rich, near neutral, alkaline-chloride to alkaline-carbonate waters, with elevated trace metal contents including arsenic (≤11ppm). Water δ18OSMOW (-14.2 to -4.9‰) and δDSMOW (-106.2 to -74.3‰), trends in elemental chemistry, and cation geothermometry collectively demonstrate mixing of hot (200-260°C) saline fluid with cold meteoric water along the fault. Helium isotope ratios (3He/4He) for dissolved gases in the waters range from 0.62 to 1.98 RA (where RA=air 3He/4He), indicating the presence of up to 25% mantle-derived helium. Given the long duration since, and large distance to active magmatism in the region, and the possible presence of a tear in the flat slab south of the Cordillera Blanca, we suggest that mantle helium may originate from asthenosphere entering the slab tear, or from the continental mantle-lithosphere, mobilized by metasomatic fluids derived from slab dehydration. © 2015 Elsevier B.V

Temporal trends of population viral suppression in the context of Universal Test and Treat: the ANRS 12249 TasP trial in rural South Africa

Introduction: The universal test-and-treat (UTT) strategy aims to maximize population viral suppression (PVS), that is, the proportion of all people living with HIV (PLHIV) on antiretroviral treatment (ART) and virally suppressed, with the goal of reducing HIV transmission at the population level. This article explores the extent to which temporal changes in PVS explain the observed lack of association between universal treatment and cumulative HIV incidence seen in the ANRS 12249 TasP trial conducted in rural South Africa. Methods: The TasP cluster-randomized trial (2012 to 2016) implemented six-monthly repeat home-based HIV counselling and testing (RHBCT) and referral of PLHIV to local HIV clinics in 2 9 11 clusters opened sequentially. ART was initiated according to national guidelines in control clusters and regardless of CD4 count in intervention clusters. We measured residency status, HIV status, and HIV care status for each participant on a daily basis. PVS was computed per cluster among all resident PLHIV (≥16, including those not in care) at cluster opening and daily thereafter. We used a mixed linear model to explore time patterns in PVS, adjusting for sociodemographic changes at the cluster level. Results: 8563 PLHIV were followed. During the course of the trial, PVS increased significantly in both arms (23.5% to 46.2% in intervention, +22.8, p < 0.001; 26.0% to 44.6% in control, +18.6, p < 0.001). That increase was similar in both arms (p = 0.514). In the final adjusted model, PVS increase was most associated with increased RHBCT and the implementation of local trial clinics (measured by time since cluster opening). Contextual changes (measured by calendar time) also contributed slightly. The effect of universal ART (trial arm) was positive but limited. Conclusions: PVS was improved significantly but similarly in both trial arms, explaining partly the null effect observed in terms of cumulative HIV incidence between arms. The PVS gains due to changes in ART-initiation guidelines alone are relatively small compared to gains obtained by strategies to maximize testing and linkage to care. The achievement of the 90-90-90 targets will not be met if the operational and implementational challenges limiting access to care and treatment, often context-specific, are not properly addressed. Clinical trial number: NCT01509508 (clinicalTrials.gov)/DOH-27-0512-3974 (South African National Clinical Trials Register)

Change and Continuity in the Role of State Attorneys General in the Obama and Trump Administrations

During the Trump Administration, state attorneys general (AGs) have become entrenched as integral policymaking actors in the United States. Their expanding policymaking role fits broader patterns of polarized politics, as partisan coalitions of AGs are increasingly willing to sue the federal government, a trend that gathered steam in the Obama Administration and has reached a crescendo in Trump’s first year. However, state AGs do cooperate, particularly in corporate litigation to address allegedly widespread, illegal behavior. Utilizing a comprehensive dataset of multi-state lawsuits and Supreme Court amicus briefs, we identify continuity and change in how AGs have employed their powers, by examining their activities during the first year of the Trump presidency and placing these activities in the context of previous administrations. This analysis is accompanied by a pair of case studies, one on conflictual AG environmental litigation and another on bipartisan efforts to address the opioid epidemic. Both demonstrate AG’s prominent policymaking power, a power unlikely to abate anytime soon

Modified-release hydrocortisone is associated with lower plasma renin activity in patients with salt-wasting congenital adrenal hyperplasia

OBJECTIVE: Poorly controlled salt-wasting (SW) congenital adrenal hyperplasia (CAH) patients often require high 9α-fluorocortisol doses as they show high levels of 17-hydroxyprogesterone (17OHP), which is a mineralocorticoid (MC)-receptor antagonist. DESIGN: We investigated the renin-angiotensin-aldosterone system in patients with SW-CAH receiving twice daily modified-release hydrocortisone (MR-HC, Efmody) compared with standard glucocorticoid (GC) therapy. METHODS: Data were analyzed from the 6-month, phase 3 study of MR-HC (n = 42) versus standard GC therapy (n = 41). MC replacement therapy remained unchanged throughout the study. Blood pressure, serum potassium, serum sodium, plasma renin activity (PRA), and serum 17OHP and androstenedione concentrations were analyzed at baseline, 4, 12, and 24 weeks. RESULTS: The median serum 17OHP in the morning was significantly lower on MR-HC compared with standard GC at 24 weeks (2.5 nmol L-1 (IQR 8.3) versus 10.5 nmol L-1 (IQR 55.2), P = .001). PRA decreased significantly from baseline to 24 weeks in patients on MR-HC (0.83 ng L-1 s-1 (IQR 1.0) to 0.48 ng L-1 s-1 (IQR 0.61), P = .012) but not in patients on standard GC (0.53 ng L-1 s-1 (IQR 0.66) to 0.52 ng L-1 s-1 (IQR 0.78), P = .613). Serum sodium concentrations increased from baseline to 24 weeks in patients on MR-HC (138.8 ± 1.9 mmol L-1 to 139.3 ± 1.8 mmol L-1, P = .047), but remained unchanged on standard GC (139.8 ± 1.6 mmol L-1 to 139.3 ± 1.9 mmol L-1, P = .135). No significant changes were seen in systolic and diastolic blood pressure and serum potassium levels. CONCLUSION: 6 months of MR-HC therapy decreased PRA and increased sodium levels indicating a greater agonist action of the 9α-fluorocortisol dose, which may be due to the decreased levels of the MC-receptor antagonist 17OHP

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P &lt; 0.001) and PARP inhibitor therapy (P &lt; 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P &lt; 0.018) and WEE1 inhibitor (P &lt; 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P &lt; 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course