Association of Systemic Markers of Inflammation with Signs and Symptoms of Dry Eye Disease and Sjogren's Syndrome in the Dry Eye Assessment and Management (DREAM©) Study.

PURPOSE: To evaluate the possible role of systemic inflammation in dry eye disease (DED) via systemic inflammatory marker associations with DED signs and symptoms, and an analysis of a subgroup with Sjogren's Syndrome (SS). METHODS: Participant serums were analyzed using line immunoassays (LIAs) for the presence of antibodies against 34 systemic inflammatory markers. Using the 2012 American College of Rheumatology definition, the 481 participants were categorized into group 1 (SS; n = 52), group 2 (autoimmune disease not including SS; n = 66), or group 3 (control, i.e. no autoimmune disease; n = 363). RESULTS: 3 markers were positive in ≥10% of participants: Ro52 (19.3%), Scl-70 (15.0%), CN-1A (14.2%). 2 markers were positively associated with symptoms: PM-Scl100 (p = 0.02), Sm (p = 0.009). 5 markers were positively associated with signs: U2SnRNP A', Ro52, La, DNA, Ro60. SS participants showed significantly higher positivity for 4 markers compared to participants with no autoimmune disease: PL-7 (p = 0.02), Ro52 (p < 0.0001), La (p < 0.0001), Ro60 (p < 0.0001). SS participants showed significantly higher positivity for 3 markers compared to participants with another autoimmune disease: Ro52 (p < 0.0001), La (p = 0.002), Ro60 (p < 0.0001). CONCLUSIONS: This study did not show evidence of significant systemic inflammation in participants with moderate-to-severe DED, based on the markers tested. PM-Scl100 and Sm may be associated with more severe DED symptoms. U2SnRNP A', Ro52, La, DNA, and Ro60 may be associated with more severe ocular surface disease. Ro52 and PL-7 may be diagnostic markers for SS. Future research evaluating these relationships and their clinical significance is needed.

Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Gate and Temperature Driven Phase Transitions in Few-Layer MoTe2.

MoTe2 has a stable hexagonal semiconducting phase (2H) as well as two semimetallic phases with monoclinic (1T') and orthorhombic (Td) structures. A structural change can thus be accompanied by a significant change in electronic transport properties. The two semimetallic phases are connected by a temperature driven transition and could exhibit topological properties. Here we make extensive Raman measurements as a function of layer thickness, temperature, and electrostatic doping on few layer 2H-MoTe2 and also on 1T'-MoTe2 and Td-WTe2. Recent work in MoTe2 has raised the possibility of a 2H-1T' transition through technology compatible pathways. It has been claimed that such a transition, of promise for device applications, is activated by electrostatic gating. We investigate this claim and find that few-layer tellurides are characterized by high mobility of Te ions, even in ambient conditions and especially through the variation of external parameters like electric field or temperature. These can generate Te clusters, vacancies at crystalline sites, and facilitate structural transitions. We however find that the purported 2H-1T' transition in MoTe2 cannot be obtained by a pure electrostatic field.

Doping by Design: Enhanced Thermoelectric Performance of GeSe Alloys Through Metavalent Bonding.

Doping is usually the first step to tailor thermoelectrics. It enables precise control of the charge-carrier concentration and concomitant transport properties. Doping should also turn GeSe, which features an intrinsically a low carrier concentration, into a competitive thermoelectric. Yet, elemental doping fails to improve the carrier concentration. In contrast, alloying with Ag-V-VI2 compounds causes a remarkable enhancement of thermoelectric performance. This advance is closely related to a transition in the bonding mechanism, as evidenced by sudden changes in the optical dielectric constant ε∞ , the Born effective charge, the maximum of the optical absorption ε2 (ω), and the bond-breaking behavior. These property changes are indicative of the formation of metavalent bonding (MVB), leading to an octahedral-like atomic arrangement. MVB is accompanied by a thermoelectric-favorable band structure featuring anisotropic bands with small effective masses and a large degeneracy. A quantum-mechanical map, which distinguishes different types of chemical bonding, reveals that orthorhombic GeSe employs covalent bonding, while rhombohedral and cubic GeSe utilize MVB. The transition from covalent to MVB goes along with a pronounced improvement in thermoelectric performance. The failure or success of different dopants can be explained by this concept, which redefines doping rules and provides a "treasure map" to tailor p-bonded chalcogenides.

Scaling and Confinement in Ultrathin Chalcogenide Films as Exemplified by GeTe.

Chalcogenides such as GeTe, PbTe, Sb2 Te3 , and Bi2 Se3 are characterized by an unconventional combination of properties enabling a plethora of applications ranging from thermo-electrics to phase change materials, topological insulators, and photonic switches. Chalcogenides possess pronounced optical absorption, relatively low effective masses, reasonably high electron mobilities, soft bonds, large bond polarizabilities, and low thermal conductivities. These remarkable characteristics are linked to an unconventional bonding mechanism characterized by a competition between electron delocalization and electron localization. Confinement, that is, the reduction of the sample dimension as realized in thin films should alter this competition and modify chemical bonds and the resulting properties. Here, pronounced changes of optical and vibrational properties are demonstrated for crystalline films of GeTe, while amorphous films of GeTe show no similar thickness dependence. For crystalline films, this thickness dependence persists up to remarkably large thicknesses above 15 nm. X-ray diffraction and accompanying simulations employing density functional theory relate these changes to thickness dependent structural (Peierls) distortions, due to an increased electron localization between adjacent atoms upon reducing the film thickness. A thickness dependence and hence potential to modify film properties for all chalcogenide films with a similar bonding mechanism is expected.

Advancing the agenda for people-centred accountability of the private healthcare sector.

The thematic track on accountability of the private and corporate healthcare sectors during the COPASAH Global Symposium aimed to analyse the emergence of the global trend of commercialisation of health systems, and the transition of healthcare from being a public good to a marketable commodity, at the cost of publicly funded healthcare in developing countries. It examined the implications of the lack of state regulation and oversight which has enabled the profit driven private healthcare sector to exploit vulnerable people through overcharging, malpractices and violations of patient's rights. Finally, the session addressed challenges in advocacy of patients' rights and showcased effective campaign strategies used by health activists in different countries to promote accountability of the private healthcare sector. Putting together learnings and insights from this track will help in contributing towards a powerful global counter-narrative, while providing activists with the tools to create awareness and engage with this critical issue.

Superconductor-insulator transition in space charge doped one unit cell Bi2.1Sr1.9CaCu2O8+x.

The superconductor-insulator transition in two dimensions is a prototype continuous quantum phase transition at absolute zero, driven by a parameter other than temperature. Here we reveal this transition in one unit-cell Bi2.1Sr1.9CaCu2O8+x by space charge doping, a field effect electrostatic doping technique. We determine the related critical parameters and develop a reliable way to estimate doping in the nonsuperconducting region, a crucial and central problem in these materials. Finite-size scaling analysis yields a critical doping of 0.057 holes/Cu, a critical resistance of ~6.85 kΩ and a scaling exponent product νz ~ 1.57. These results, together with earlier work in other materials, provide a coherent picture of the superconductor-insulator transition and its bosonic nature in the underdoped regime of emerging superconductivity in high critical temperature superconductors.

Functional Monochalcogenides: Raman Evidence Linking Properties, Structure, and Metavalent Bonding.

Pressure- and temperature-dependent Raman scattering in GeSe, SnSe, and GeTe for pressures beyond 50 GPa and for temperatures ranging from 78 to 800 K allow us to identify structural and electronic phase transitions, similarities between GeSe and SnSe, and differences with GeTe. Calculations help to deduce the propensity of GeTe for defect formation and the doping that results from it, which gives rise to strong Raman damping beyond anomalous anharmonicity. These properties are related to the underlying chemical bonding and consistent with a recent classification of bonding in several chalcogenide materials that puts GeTe in a separate class of "incipient" metals.

Ultrafast dynamics of hot carriers in a quasi-two-dimensional electron gas on InSe.

Two-dimensional electron gases (2DEGs) are at the base of current nanoelectronics because of their exceptional mobilities. Often the accumulation layer forms at polar interfaces with longitudinal optical (LO) modes. In most cases, the many-body screening of the quasi-2DEGs dramatically reduces the Fröhlich scattering strength. Despite the effectiveness of such a process, it has been recurrently proposed that a remote coupling with LO phonons persists even at high carrier concentration. We address this issue by perturbing electrons in an accumulation layer via an ultrafast laser pulse and monitoring their relaxation via time- and momentum-resolved spectroscopy. The cooling rate of excited carriers is monitored at doping level spanning from the semiconducting to the metallic limit. We observe that screening of LO phonons is not as efficient as it would be in a strictly 2D system. The large discrepancy is due to the remote coupling of confined states with the bulk. Our data indicate that the effect of such a remote coupling can be mimicked by a 3D Fröhlich interaction with Thomas-Fermi screening. These conclusions are very general and should apply to field effect transistors (FET) with high-κ dielectric gates, van der Waals heterostructures, and metallic interfaces between insulating oxides.

Community action for health in India: evolution, lessons learnt and ways forward to achieve universal health coverage.

The role of civil society and community-based organizations in advancing universal health coverage and meeting the targets of the 2030 Agenda for Sustainable Development has received renewed recognition from major global initiatives. This article documents the evolution and lessons learnt through two decades of experience in India at national, state and district levels. Community and civil society engagement in health services in India began with semi-institutional mechanisms under programmes focused on, for example, HIV/AIDS, tuberculosis, polio and immunization. A formal system of community action for health (CAH) started with the launch of the National Rural Health Mission in 2005. By December 2018, CAH processes were being implemented in 22 states, 353 districts and more than 200 000 villages in India. Successive evaluations have indicated improved performance on various service delivery parameters. One example of CAH is community-based monitoring and planning, which has been continuously expanded and strengthened in Maharashtra since 2007. This involves regular, participatory auditing of public health services, which facilitates the involvement of people in assessing the public health system and demanding improvements. At district level, CAH initiatives are successfully reaching "last-mile" communities. The Self-Employed Women's Association, a cooperative-based organization of women working in the informal sector in Gujarat, has developed community information hubs that empower clients to access government social and health sector services. CAH initiatives in India are now being augmented by regular activities led and/or participated in by civil society organizations. This is contributing to the democratization of community and civil society engagement in health. Additional documentation on CAH and the further formalization of civil society engagement are needed. These developments provide a valuable opportunity both to improve governance and accountability in the health sector and to accelerate progress towards universal health coverage. Lessons learnt may be applicable to other countries in South-East Asia, as well as to most low- and middle-income countries.

The impacts of corporatisation of healthcare on medical practice and professionals in Maharashtra, India.

A heterogeneous private sector dominates healthcare provision in many middle-income countries. In India, the contemporary period has seen this sector undergo corporatisation processes characterised by emergence of large private hospitals and the takeover of medium-sized and charitable hospitals by corporate entities. Little is known about the operations of these private providers and the effects on healthcare professions as employment shifts from practitioner-owned small and medium hospitals to larger corporate settings. This article uses data from a mixed-methods study in two large cities in Maharashtra, India, to consider the implications of these contemporary changes for the medical profession. Data were collected from semistructured interviews with 43 respondents who have detailed knowledge of healthcare in Maharashtra and from a witness seminar on the topic of transformation in Maharashtra's healthcare system. Transcripts from the interviews and witness seminar were analysed thematically through a combination of deductive and inductive approaches. Our findings point to a restructuring of medical practice in Maharashtra as training shifts towards private education and employment to those corporate hospitals. The latter is fuelled by substantial personal indebtedness, dwindling appeal of government employment, reduced opportunities to work in smaller private facilities and the perceived benefits of work in larger providers. We describe a 'reprofessionalisation' of medicine encompassing changes in employment relations, performance targets and constraints placed on professional autonomy within the private healthcare sector that is accompanied by trends in cost inflation, medical malpractice, and distrust in doctor-patient relationships. The accompanying 'restratification' within this part of the profession affords prestige and influence to 'star doctors' while eroding the status and opportunity for young and early career doctors. The research raises important questions about the role that government and medical professionals' bodies can, and should, play in contemporary transformation of private healthcare and the implications of these trends for health systems more broadly.

Crossover to strange metal phase: quantum criticality in one unit cell Bi2Sr2CaCu2O[Formula: see text].

Transport measurements can be used to determine the phase diagram of high temperature superconductors by detecting variations in temperature dependence of resistance in different regions of the phase diagram. While for bulk measurements several samples with varying chemical doping are used, we continuously vary carrier density in our ultra-thin two-dimensional Bi2Sr2CaCu2O[Formula: see text] device by electrostatic means and the space charge doping method. Here we concentrate on a low-disorder, high quality single unit cell thick sample. We establish the crossover to strange metal from the pseudogap and Fermi liquid phases in the normal state, close to the superconducting dome. By extrapolation we demarcate a critical doping region which is thought to correspond to a quantum phase transition at very low temperature.

Direct Observation of Band Gap Renormalization in Layered Indium Selenide.

Manipulation of intrinsic electronic structures by electron or hole doping in a controlled manner in van der Waals layered materials is the key to control their electrical and optical properties. Two-dimensional indium selenide (InSe) semiconductor has attracted attention due to its direct band gap and ultrahigh mobility as a promising material for optoelectronic devices. In this work, we manipulate the electronic structure of InSe by in situ surface electron doping and obtain a significant band gap renormalization of ∼120 meV directly observed by high-resolution angle resolved photoemission spectroscopy. This moderate doping level (carrier concentration of 8.1 × 1012 cm-2) can be achieved by electrical gating in field effect transistors, demonstrating the potential to design of broad spectral response devices.

"We sold the buffalo to pay for a brain scan" - a qualitative study of rural experiences with private mental healthcare providers in Uttar Pradesh, India.

The majority of persons with mental distress (PWMD) in India do not have access to care, and even those who seek care are pushed to attend private providers, given the weak and largely absent public mental health services framework. The aim of this study was to examine the experiences in help-seeking and with unethical health service provision among persons with mental distress in the Saharanpur and Bijnor districts of Uttar Pradesh. In-depth interviews were conducted with twenty persons with mental distress and their caregivers. Thematic analysis yielded four key findings about help-seeking: first, that it was syncretic and persistent; second, that expenditure for private care was high and often catastrophic; third, that investigations and care provided were pharmacological and predominantly irrational and excessive; and lastly, that help-seeking was abandoned. This study demonstrates that PWMD are particularly vulnerable to exploitation by private providers with illnesses that are stigmatising, poorly understood, chronic, relapsing, and disabling and that often require complex management. Responding to mental distress requires multiple empowering and interacting policy and programme initiatives that must include regulation of private and public providers, resources, and actions to strengthen public and primary mental healthcare and promotion of mental health competence in communities.

Pressure-Induced Phase Transitions in Germanium Telluride: Raman Signatures of Anharmonicity and Oxidation.

Pressure-induced phase transitions in GeTe, a prototype phase change material, have been studied to date with diffraction which is not sensitive to anharmonicity-induced dynamical effects. GeTe is also prone to surface oxidation which may compromise surface sensitive measurements. These factors could be responsible for the lack of clarity about the phases and transitions intervening in the phase diagram of GeTe. We have used high-pressure Raman scattering and ab initio pseudopotential density functional calculations to unambiguously establish the high-pressure phase diagram and identify three phases up to 57 GPa, a low-pressure rhombohedral phase, an intermediate pressure cubic phase, and a high-pressure orthorhombic phase. We detect substantial broadening and softening of Raman modes at low pressure and identify the transition regions and possible intermediate phases.

Mutations in microRNA processing genes in Wilms tumors derepress the IGF2 regulator PLAG1.

Many childhood Wilms tumors are driven by mutations in the microRNA biogenesis machinery, but the mechanism by which these mutations drive tumorigenesis is unknown. Here we show that the transcription factor pleomorphic adenoma gene 1 (PLAG1) is a microRNA target gene that is overexpressed in Wilms tumors with mutations in microRNA processing genes. Wilms tumors can also overexpress PLAG1 through copy number alterations, and PLAG1 expression correlates with prognosis in Wilms tumors. PLAG1 overexpression accelerates growth of Wilms tumor cells in vitro and induces neoplastic growth in the developing mouse kidney in vivo. In both settings, PLAG1 transactivates insulin-like growth factor 2 (IGF2), a key Wilms tumor oncogene, and drives mammalian target of rapamycin complex 1 (mTORC1) signaling. These data link microRNA impairment to the PLAG1-IGF2 pathway, providing new insight into the manner in which common Wilms tumor mutations drive disease pathogenesis.

EGF Receptor and mTORC1 Are Novel Therapeutic Targets in Nonseminomatous Germ Cell Tumors.

Germ cell tumors (GCT) are malignant tumors that arise from pluripotent embryonic germ cells and occur in children and young adults. GCTs are treated with cisplatin-based regimens which, while overall effective, fail to cure all patients and cause significant adverse late effects. The seminoma and nonseminoma forms of GCT exhibit distinct differentiation states, clinical behavior, and response to treatment; however, the molecular mechanisms of GCT differentiation are not fully understood. We tested whether the activity of the mTORC1 and MAPK pathways were differentially active in the two classes of GCT. Here we show that nonseminomatous germ cell tumors (NSGCT, including embryonal carcinoma, yolk sac tumor, and choriocarcinoma) from both children and adults display activation of the mTORC1 pathway, while seminomas do not. In seminomas, high levels of REDD1 may negatively regulate mTORC1 activity. In NSGCTs, on the other hand, EGF and FGF2 ligands can stimulate mTORC1 and MAPK signaling, and members of the EGF and FGF receptor families are more highly expressed. Finally, proliferation of NSGCT cells in vitro and in vivo is significantly inhibited by combined treatment with the clinically available agents erlotinib and rapamycin, which target EGFR and mTORC1 signaling, respectively. These results provide an understanding of the signaling network that drives GCT growth and a rationale for therapeutic targeting of GCTs with agents that antagonize the EGFR and mTORC1 pathways. Mol Cancer Ther; 17(5); 1079-89. ©2018 AACR.

Using community-based evidence for decentralized health planning: insights from Maharashtra, India.

Health planning is generally considered a technical subject, primarily the domain of health officials with minimal involvement of community representatives. The National Rural Health Mission launched in India in 2005 recognized this gap and mandated mechanisms for decentralized health planning. However, since planning develops in the context of highly unequal power relations, formal spaces for participation are necessary but not sufficient. Hence a project on capacity building for decentralized health planning was implemented in selected districts of Maharashtra, India during 2010-13. This process developed on the platform of officially supported community-based monitoring and planning, a process for community feedback and participation towards health system change. A specific project on capacity building for decentralized planning included a structured learning course and workshops for major stakeholders. An evaluation of the project, including in-depth interviews of various participants and analysis of change in local health planning processes, revealed positive changes in intervention areas, including increased capacity of key stakeholders leading to preparation of evidence-based, innovative planning proposals, significant community oriented changes in utilization of health facility funds, and inclusion of community-based proposals in village, health facility-based block and district plans. Transparency related to planning increased along with responsiveness of health providers to community suggestions. A key lesson is that active facilitation of decentralized health planning and influencing the health system to expand participation, are essential to ensure changes in planning. Effective strategies included: identifying people's health service related priorities through community-based monitoring, capacity building of diverse stakeholders regarding local health planning, and advocacy to enable participation of community-based actors in the planning process. This combination of strategies draws upon the framework of 'empowered participatory governance' which necessitates combining a degree of 'countervailing power' and acceptance of participation by the system, for new forms of governance to emerge.

Comprehensive phase diagram of two-dimensional space charge doped Bi2Sr2CaCu2O8+x.

The phase diagram of hole-doped high critical temperature superconductors as a function of doping and temperature has been intensively studied with chemical variation of doping. Chemical doping can provoke structural changes and disorder, masking intrinsic effects. Alternatively, a field-effect transistor geometry with an electrostatically doped, ultra-thin sample can be used. However, to probe the phase diagram, carrier density modulation beyond 1014 cm-2 and transport measurements performed over a large temperature range are needed. Here we use the space charge doping method to measure transport characteristics from 330 K to low temperature. We extract parameters and characteristic temperatures over a large doping range and establish a comprehensive phase diagram for one-unit-cell-thick BSCCO-2212 as a function of doping, temperature and disorder.