Economic Consequences of Health Status: A Review of the Evidence

The correlation between health and economic performance is extremely robust across communities and over time. Many factors exogenous to income play an important role in determining health status, including a number of geographical, environmental, and evolutionary factors. This suggests the existence of simultaneous impacts of health on wealth and wealth on health. Potential health impacts on national economic performance are explored, and some important unanswered questions are identified.health, economic growth, human capital

The Changing Global Distribution of Malaria: A Review

Organized efforts to reduce the burden of malaria are as old as human societies. Understanding the historical relationships between humankind and malaria is important for natural and social scientists studying the disease, as well as policy makers trying to control it. Malaria once extended widely throughout the old world, reaching as far north as 64ºN latitude and as far south as 32ºS latitude. Today, however, malaria is almost exclusively a problem of the geographical tropics. Analysis of historical changes in malaria prevalence suggests a number of factors which help to determine the likelihood and sustainability of success in malaria control. Among these are geography, evolutionary history of flora and fauna, infrastructure, and land use. It is due to these factors, much more than socio-economic ones, that attempts to control or interrupt transmission of the disease have historically been most successful on islands, in temperate climates, or at high elevations

Economic Consequences of Health Status: A Review of the Evidence

The correlation between health and economic performance is extremely robust across communities and over time. Many factors exogenous to income play an important role in determining health status, including a number of geographical, environmental, and evolutionary factors. This suggests the existence of simultaneous impacts of health on wealth and wealth on health. Potential health impacts on national economic performance are explored, and some important unanswered questions are identified

Disulfonated tetraphenyl chlorin (TPCS2a)–induced photochemical internalisation of bleomycin in patients with solid malignancies: A first-in-man phase I dose escalation clinical trial

BACKGROUND: Photochemical internalisation, a novel minimally invasive treatment, has shown promising preclinical results in enhancing and site-directing the effect of anticancer drugs by illumination, which initiates localised chemotherapy release. We assessed the safety and tolerability of a newly developed photosensitiser, disulfonated tetraphenyl chlorin (TPCS2a), in mediating photochemical internalisation of bleomycin in patients with advanced and recurrent solid malignancies. METHODS: In this phase 1, dose-escalation, first-in-man trial, we recruited patients (aged ≥18 to <85 years) with local recurrent, advanced, or metastatic cutaneous or subcutaneous malignancies who were clinically assessed as eligible for bleomycin chemotherapy from a single centre in the UK. Patients were given TPCS2a on day 0 by slow intravenous injection, followed by a fixed dose of 15 000 IU/m2 bleomycin by intravenous infusion on day 4. After 3 h, the surface of the target tumour was illuminated with 652 nm laser light (fixed at 60 J/cm2). The TPCS2a starting dose was 0·25 mg/kg and was then escalated in successive dose cohorts of three patients (0·5, 1·0, and 1·5 mg/kg). The primary endpoints were safety and tolerability of TPCS2a; other co-primary endpoints were dose-limiting toxicity and maximum tolerated dose. The primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00993512, and has been completed. FINDINGS: Between Oct 3, 2009, and Jan 14, 2014, we recruited 22 patients into the trial. 12 patients completed the 3-month follow-up period. Adverse events related to photochemical internalisation were either local, resulting from the local inflammatory process, or systemic, mostly as a result of the skin-photosensitising effect of TPCS2a. The most common grade 3 or worse adverse events were unexpected higher transient pain response (grade 3) localised to the treatment site recorded in nine patients, and respiratory failure (grade 4) noted in two patients. One dose-limiting toxicity was reported in the 1·0 mg/kg cohort (skin photosensitivity [grade 2]). Dose-limiting toxicities were reported in two of three patients at a TPCS2a dose of 1·5 mg/kg (skin photosensitivity [grade 3] and wound infection [grade 3]); thus, the maximum tolerated dose of TPCS2a was 1·0 mg/kg. Administration of TPCS2a was found to be safe and tolerable by all patients. No deaths related to photochemical internalisation treatment occurred. INTERPRETATION: TPCS2a-mediated photochemical internalisation of bleomycin is safe and tolerable. We identified TPCS2a 0·25 mg/kg as the recommended treatment dose for future trials. FUNDING: PCI Biotech

Statistical Fluctuations of Electromagnetic Transition Intensities in pf-Shell Nuclei

We study the fluctuation properties of E2 and M1 transition intensities among T=0,1 states of A = 60 nuclei in the framework of the interacting shell model, using a realistic effective interaction for pf-shell nuclei with a Ni56 as a core. It is found that the B(E2) distributions are well described by the Gaussian orthogonal ensemble of random matrices (Porter-Thomas distribution) independently of the isobaric quantum number T_z. However, the statistics of the B(M1) transitions is sensitive to T_z: T_z=1 nuclei exhibit a Porter-Thomas distribution, while a significant deviation from the GOE statistics is observed for self-conjugate nuclei (T_z=0).Comment: 8 pages, latex, 3 figures (ps format

Upregulation of mucin glycoprotein MUC1 in the progression to esophageal adenocarcinoma and therapeutic potential with a targeted photoactive antibody-drug conjugate

BACKGROUND: Mucin glycoprotein 1 (MUC1) is a glycosylated transmembrane protein on epithelial cells. We investigate MUC1 as a therapeutic target in Barrett's epithelium (BE) and esophageal adenocarcinoma (EA) and provide proof of concept for a light based therapy targeting MUC1. RESULTS: MUC1 was present in 21% and 30% of significantly enriched pathways comparing BE and EA to squamous epithelium respectively. MUC1 gene expression was x2.3 and x2.2 higher in BE (p=<0.001) and EA (p=0.03). MUC1 immunohistochemical expression increased during progression to EA and followed tumor invasion. HuHMFG1 based photosensitive antibody drug conjugates (ADC) showed cell internalization, MUC1 selective and light-dependent cytotoxicity (p=0.0006) and superior toxicity over photosensitizer alone (p=0.0022). METHODS: Gene set enrichment analysis (GSEA) evaluated pathways during BE and EA development and quantified MUC1 gene expression. Immunohistochemistry and flow cytometry evaluated the anti-MUC1 antibody HuHMFG1 in esophageal cells of varying pathological grade. Confocal microscopy examined HuHMFG1 internalization and HuHMFG1 ADCs were created to deliver a MUC1 targeted phototoxic payload. CONCLUSIONS: MUC1 is a promising target in EA. Molecular and light based targeting of MUC1 with a photosensitive ADC is effective in vitro and after development may enable treatment of locoregional tumors endoscopically

Magnetically responsive microbubbles as delivery vehicles for targeted sonodynamic and antimetabolite therapy of pancreatic cancer

Magnetically responsive microbubbles (MagMBs), consisting of an oxygen gas core and a phospholipid coating functionalised with Rose Bengal (RB) and/or 5-fluorouracil (5-FU), were assessed as a delivery vehicle for the targeted treatment of pancreatic cancer using combined antimetabolite and sonodynamic therapy (SDT). MagMBs delivering the combined 5-FU/SDT treatment produced a reduction in cell viability of over 50% when tested against a panel of four pancreatic cancer cell lines in vitro. Intravenous administration of the MagMBs to mice bearing orthotopic human xenograft BxPC-3 tumours yielded a 48.3% reduction in tumour volume relative to an untreated control group (p<0.05) when the tumour was exposed to both external magnetic and ultrasound fields during administration of the MagMBs. In contrast, application of an external ultrasound field alone resulted in a 27% reduction in tumour volume. In addition, activated caspase and BAX protein levels were both observed to be significantly elevated in tumours harvested from animals treated with the MagMBs in the presence of magnetic and ultrasonic fields when compared to expression of those proteins in tumours from either the control or ultrasound field only groups (p<0.05). These results suggest MagMBs have considerable potential as a platform to enable the targeted delivery of combined sonodynamic/antimetabolite therapy in pancreatic cancer

Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions

International Geomagnetic Reference Field: the 12th generation

The 12th generation of the International Geomagnetic Reference Field (IGRF) was adopted in December 2014 by the Working Group V-MOD appointed by the International Association of Geomagnetism and Aeronomy (IAGA). It updates the previous IGRF generation with a definitive main field model for epoch 2010.0, a main field model for epoch 2015.0, and a linear annual predictive secular variation model for 2015.0-2020.0. Here, we present the equations defining the IGRF model, provide the spherical harmonic coefficients, and provide maps of the magnetic declination, inclination, and total intensity for epoch 2015.0 and their predicted rates of change for 2015.0-2020.0. We also update the magnetic pole positions and discuss briefly the latest changes and possible future trends of the Earth’s magnetic fiel