Importance and vulnerability of the world's water towers.

Mountains are the water towers of the world, supplying a substantial part of both natural and anthropogenic water demands1,2. They are highly sensitive and prone to climate change3,4, yet their importance and vulnerability have not been quantified at the global scale. Here we present a global water tower index (WTI), which ranks all water towers in terms of their water-supplying role and the downstream dependence of ecosystems and society. For each water tower, we assess its vulnerability related to water stress, governance, hydropolitical tension and future climatic and socio-economic changes. We conclude that the most important (highest WTI) water towers are also among the most vulnerable, and that climatic and socio-economic changes will affect them profoundly. This could negatively impact 1.9 billion people living in (0.3 billion) or directly downstream of (1.6 billion) mountainous areas. Immediate action is required to safeguard the future of the world's most important and vulnerable water towers.

Perceptions of online surgical-focused learning amongst surgeons during the COVID pandemic: A scoping review 2020-22.

INTRODUCTION: During the COVID pandemic many centres adopted e-learning as a tool to adhere to social distancing recommendations while continuing to provide ongoing postgraduate medical education. We aimed to complete this scoping review in order to map experience and perceptions amongst surgeons and surgical trainees to remote learning during the COVID pandemic. METHODS: Using Arksey and O'Malley's five step model for conducting a scoping review, a systematic search strategy was undertaken across three online databases SCOPUS, MEDLINE and Web of Science. Only original articles in English in the field of postgraduate education in surgery were included. RESULTS: 44 studies were selected for review. Of these 44, 21 were studies of perception of a newly developed e-learning tool/platform. 17 were surveys of surgeon's attitudes towards e-learning during the COVID pandemic. The remaining 6 studies were studies of knowledge or skills acquired through new e-learning, which included a survey of experience. The United States was the most common country of origin with General Surgery the most represented surgical speciality. Response rates across all three study subgroups were on average >60%. Surgeon's experience of e-learning was reported in only positive terms in 86% (n = 38/44) of studies. CONCLUSIONS: This paper is informative in that it focuses specifically on surgeons' perceptions of a e-learning tools used in addition to skills or knowledge gained. Positive e-learning experience reported in these studies may lead to more blended learning curriculums being developed, deployed and evaluated going forward.

Advances in e-learning in undergraduate clinical medicine: a systematic review.

BACKGROUND: E-learning is recognised as a useful educational tool and is becoming more common in undergraduate medical education. This review aims to examine the scope and impact of e-learning interventions on medical student learning in clinical medicine, in order to aid medical educators when implementing e-learning strategies in programme curricula. METHODS: A systematic review compliant with PRISMA guidelines that appraises study design, setting and population, context and type of evaluations. Specific search terms were used to locate articles across nine databases: MEDLINE/PubMed, ScienceDirect, EMBASE, Cochrane Library, ERIC, Academic Search Complete, CINAHL, Scopus and Google Scholar. Only studies evaluating e-learning interventions in undergraduate clinical medical education between January 1990 and August 2021 were selected. Of the 4,829 papers identified by the search, 42 studies met the inclusion criteria. RESULTS: The 42 studies included varied in scope, cognitive domain, subject matter, design, quality and evaluation. The most popular approaches involved multimedia platforms (33%) and case-based approaches (26%), were interactive (83%), asynchronous (71%) and accessible from home (83%). Twelve studies (29%) evaluated usability, all of which reported positive feedback. Competence in use of technology, high motivation and an open attitude were key characteristics of successful students and preceptors. CONCLUSIONS: Medical education is evolving consistently to accommodate rapid changes in therapies and procedures. In today's technologically adept world, e-learning is an effective and convenient pedagogical approach for the teaching of undergraduate clinical medicine.

Integrating threshold concepts with reflective practice: Discussing a theory-based approach for curriculum refinement in dental education.

INTRODUCTION: The theory of threshold concepts (TCs) is a burgeoning area of educational research and curriculum reform. This study describes and reviews the TCs literature, describes the differences between TCs and threshold learning outcomes (TLOs) and seeks to promote discussion on using an integrated reflective practice approach to facilitate the translation of TCs into fulfilment of TLOs. A worked example is included in this study to explore the challenges inherent in this task but also the learning gains to be made for both staff and students in this endeavour. INTERSECTION OF REFLECTIVE CLINICAL PRACTICE AND THRESHOLD CONCEPTS: Reflection is intrinsic to all aspects of learning and is a vital characteristic of developing competence in the health professions. Further, the need for explicit teaching and assessment of reflection in health professions education is recognised. We suggest that the identification of TCs can help to scaffold reflective processes in dentistry and argue that TCs may achieve a bridging function between theory and practice when used in conjunction with reflective writing and dialogue. This study provides a discussion of the complexities and challenges involved as well as an explicit example of the process involved for 1 TC in 1 particular discipline-removable prosthodontics. DISCUSSION: Reflective practice is recognised by the authors as a pedagogical tool to support the acquisition of threshold concepts. An example is provided of integrating reflective practice tasks with identified TCs in curricula which shows the potential of reflective dialogue and discourse as vehicles to make TCs explicit as well as facilitate the attainment of threshold learning outcomes or graduate attributes. This is an ongoing process, and although the fully revised curriculum is not ready to be translated to other contexts, we suggest it is beneficial to start working towards the integration of reflective practice tasks and identified TLOs as part of curriculum refinement-rather than adding to a crowded curriculum. We suggest such an integrated approach can harness the challenges inherent in discipline-specific contexts to bridge the theory-practice nexus for students and permit staff greater flexibility in the teaching and assessment of such traditionally difficult areas. SUMMARY: We propose a way of thinking about curriculum change by integrating threshold concepts with the explicit use and assessment of reflective practice tasks as a means to achieve threshold learning outcomes and professional attributes identified by accrediting bodies. We provide an overview of the literature in this area and an example of our approach in linking reflective practice with newly identified threshold concepts in our School. We welcome further discussion, debate and collaboration in this area.

Cerebrospinal fluid and plasma oxytocin concentrations are positively correlated and negatively predict anxiety in children.

The neuropeptide oxytocin (OXT) exerts anxiolytic and prosocial effects in the central nervous system of rodents. A number of recent studies have attempted to translate these findings by investigating the relationships between peripheral (e.g., blood, urinary and salivary) OXT concentrations and behavioral functioning in humans. Although peripheral samples are easy to obtain in humans, whether peripheral OXT measures are functionally related to central OXT activity remains unclear. To investigate a possible relationship, we quantified OXT concentrations in concomitantly collected cerebrospinal fluid (CSF) and blood samples from child and adult patients undergoing clinically indicated lumbar punctures or other CSF-related procedures. Anxiety scores were obtained in a subset of child participants whose parents completed psychometric assessments. Findings from this study indicate that plasma OXT concentrations significantly and positively predict CSF OXT concentrations (r=0.56, P=0.0064, N=27). Moreover, both plasma (r=-0.92, P=0.0262, N=10) and CSF (r=-0.91, P=0.0335, N=10) OXT concentrations significantly and negatively predicted trait anxiety scores, consistent with the preclinical literature. Importantly, plasma OXT concentrations significantly and positively (r=0.96, P=0.0115, N=10) predicted CSF OXT concentrations in the subset of child participants who provided behavioral data. This study provides the first empirical support for the use of blood measures of OXT as a surrogate for central OXT activity, validated in the context of behavioral functioning. These preliminary findings also suggest that impaired OXT signaling may be a biomarker of anxiety in humans, and a potential target for therapeutic development in individuals with anxiety disorders.

Toxicology study assessing efficacy and safety of repeated administration of lipid/DNA complexes to mouse lung.

For gene therapy to improve lung function in cystic fibrosis (CF) subjects, repeated administration of the gene transfer agent over the lifetime of patients is likely to be necessary. This requirement limits the utility of adenoviral and adeno-associated viral vectors (both previously evaluated in CF gene therapy trials) because of induced adaptive immune responses that render repeated dosing ineffective. For CF gene therapy trials, non-viral vectors are currently the only viable option. We previously showed that the cationic lipid formulation GL67A is the most efficient of several non-viral vectors analysed for airway gene transfer. Here, we assessed the efficacy and safety of administering 12 inhaled doses of GL67A complexed with pGM169, a CpG-free plasmid encoding human CFTR complementary DNA, into mice. We show that repeated administration of pGM169/GL67A to murine lungs is feasible, safe and achieves reproducible, dose-related and persistent gene expression (>140 days after each dose) using an aerosol generated by a clinically relevant nebuliser. This study supports progression into the first non-viral multidose lung trial in CF patients.

Restoration of PPP2CA expression reverses epithelial-to-mesenchymal transition and suppresses prostate tumour growth and metastasis in an orthotopic mouse model.

BACKGROUND: Emergence of castration-resistance in prostate cancer (PCa) is invariably associated with aggressive and metastatic disease. Previously, we reported promotion of castration-resistance upon downregulation of PPP2CA (encoding catalytic subunit of protein phosphatase 2A (PP2A), α-isoform); however, its role in PCa growth and metastasis remained undetermined. METHODS: PPP2CA was overexpressed/silenced in PCa cells by stable transfection. Gene expression was examined by reverse transcription polymerase chain reaction, immunoblot and immunofluorescence analyses, and transcriptional activity measured by luciferase-based promoter-reporter assay. Effect on PCa phenotype was studied in vitro and in orthotopic mouse model, and immunohistochemical/histological analyses performed to assess proliferation/apoptosis and confirm metastatic lesions. RESULTS: An inverse association of PPP2CA expression was observed with epithelial-to-mesenchymal transition (EMT) and aggressive PCa phenotype. PPP2CA restoration resulted in decreased nuclear accumulation and transcriptional activity of ß-catenin/NF-κB, and restitution of their activity abrogated PPP2CA-induced EMT reversal and suppression of PCa invasiveness. Akt mediated PPP2CA loss-induced nuclear accumulation of ß-catenin/NF-κB through inactivation of Gsk3-ß and IκB-α, respectively. Animal studies revealed a suppressive effect of PPP2CA expression on PCa growth and metastasis. CONCLUSIONS: Our findings suggest that PPP2CA downregulation serves as a molecular link between gain of castration-resistance and aggressive PCa phenotype, and its restoration could be an effective preventive/therapeutic approach against the advanced disease.

The chiral structure of porous chitin within the wing-scales of Callophrys rubi.

The structure of the porous three-dimensional reticulated pattern in the wing scales of the butterfly Callophrys rubi (the Green Hairstreak) is explored in detail, via scanning and transmission electron microscopy. A full 3D tomographic reconstruction of a section of this material reveals that the predominantly chitin material is assembled in the wing scale to form a structure whose geometry bears a remarkable correspondence to the srs net, well-known in solid state chemistry and soft materials science. The porous solid is bounded to an excellent approximation by a parallel surface to the Gyroid, a three-periodic minimal surface with cubic crystallographic symmetry I4132, as foreshadowed by Stavenga and Michielson. The scale of the structure is commensurate with the wavelength of visible light, with an edge of the conventional cubic unit cell of the parallel-Gyroid of approximately 310 nm. The genesis of this structure is discussed, and we suggest it affords a remarkable example of templating of a chiral material via soft matter, analogous to the formation of mesoporous silica via surfactant assemblies in solution. In the butterfly, the templating is achieved by the lipid-protein membranes within the smooth endoplasmic reticulum (while it remains in the chrysalis), that likely form cubic membranes, folded according to the form of the Gyroid. The subsequent formation of the chiral hard chitin framework is suggested to be driven by the gradual polymerisation of the chitin precursors, whose inherent chiral assembly in solution (during growth) promotes the formation of a single enantiomer.

Pre-clinical evaluation of three non-viral gene transfer agents for cystic fibrosis after aerosol delivery to the ovine lung.

We use both large and small animal models in our pre-clinical evaluation of gene transfer agents (GTAs) for cystic fibrosis (CF) gene therapy. Here, we report the use of a large animal model to assess three non-viral GTAs: 25 kDa-branched polyethyleneimine (PEI), the cationic liposome (GL67A) and compacted DNA nanoparticle formulated with polyethylene glycol-substituted lysine 30-mer. GTAs complexed with plasmids expressing human cystic fibrosis transmembrane conductance regulator (CFTR) complementary DNA were administered to the sheep lung (n=8 per group) by aerosol. All GTAs gave evidence of gene transfer and expression 1 day after treatment. Vector-derived mRNA was expressed in lung tissues, including epithelial cell-enriched bronchial brushing samples, with median group values reaching 1-10% of endogenous CFTR mRNA levels. GL67A gave the highest levels of expression. Human CFTR protein was detected in small airway epithelial cells in some animals treated with GL67A (two out of eight) and PEI (one out of eight). Bronchoalveolar lavage neutrophilia, lung histology and elevated serum haptoglobin levels indicated that gene delivery was associated with mild local and systemic inflammation. Our conclusion was that GL67A was the best non-viral GTA currently available for aerosol delivery to the sheep lung, led to the selection of GL67A as our lead GTA for clinical trials in CF patients.

Circular dichroism in biological photonic crystals and cubic chiral nets.

Nature provides impressive examples of chiral photonic crystals, with the notable example of the cubic so-called srs network (the label for the chiral degree-three network modeled on SrSi2) or gyroid structure realized in wing scales of several butterfly species. By a circular polarization analysis of the band structure of such networks, we demonstrate strong circular dichroism effects: The butterfly srs microstructure, of cubic I4(1)32 symmetry, shows significant circular dichroism for blue to ultraviolet light, that warrants a search for biological receptors sensitive to circular polarization. A derived synthetic structure based on four like-handed silicon srs nets exhibits a large circular polarization stop band of a width exceeding 30%. These findings offer design principles for chiral photonic devices.

Progress and prospects: the design and production of plasmid vectors.

Plasmid DNA (pDNA) expression vectors are fundamental to all forms of non-viral gene transfer. In this review, we discuss principles of pDNA design and production including the impact of bacterially derived sequences on transgene expression and minicircle approaches to minimize their effects. The impact of inclusion of DNA elements such as scaffold matrix attachment regions (S/MARs), transcription factor (TF)-binding sites and tissue-specific promoters are described. The benefits of eliminating CG dinucleotides (CpGs) from the pDNA are also considered.

Interwoven metal-organic framework on a periodic minimal surface with extra-large pores.

Interpenetration (catenation) has long been considered a major impediment in the achievement of stable and porous crystalline structures. A strategy for the design of highly porous and structurally stable networks makes use of metal-organic building blocks that can be assembled on a triply periodic P-minimal geometric surface to produce structures that are interpenetrating-more accurately considered as interwoven. We used 4,4',4"-benzene-1,3,5-triyl-tribenzoic acid (H(3)BTB), copper(II) nitrate, and N,N'-dimethylformamide (DMF) to prepare Cu(3)(BTB)(2)(H(2)O)(3).(DMF)(9)(H(2)O)(2) (MOF-14), whose structure reveals a pair of interwoven metal-organic frameworks that are mutually reinforced. The structure contains remarkably large pores, 16.4 angstroms in diameter, in which voluminous amounts of gases and organic solvents can be reversibly sorbed.

Tamoxifen blocks chloride channels. A possible mechanism for cataract formation.

Tamoxifen is an antiestrogen frequently used in the treatment of breast cancer and is currently being assessed as a prophylactic for those at high risk of developing tumors. We have found that tamoxifen and its derivatives are high-affinity blockers of specific chloride channels. This blockade appears to be independent of the interaction of tamoxifen with the estrogen receptor and therefore reflects an alternative cellular target. One of the clinical side effects of tamoxifen is impaired vision and cataract. Chloride channels in the lens of the eye were shown to be essential for maintaining normal lens hydration and transmittance. These channels were blocked by tamoxifen and, in organ culture, tamoxifen led to lens opacity associated with cataracts at clinically relevant concentrations. These data suggest a molecular mechanism by which tamoxifen can cause cataract formation and have implications for the clinical use of tamoxifen and related antiestrogens.

Tangled (up in) cubes.

The 'simplest' entanglements of the graph of edges of the cube are enumerated, forming two-cell {6, 3} (hexagonal mesh) complexes on the genus-one two-dimensional torus. Five chiral pairs of knotted graphs are found. The examples contain non-trivial knotted and/or linked subgraphs [(2, 2), (2, 4) torus links and (3, 2), (4, 3) torus knots].

Welfare dental intervention improves employment and quality of life.

Chronic, untreated oral disease adversely affects one's systemic health, quality of life, and economic productivity. This study evaluated the effect of rehabilitative dental treatment on the oral-health-related quality of life and employment of welfare recipients. Three hundred and seventy-seven participants in a novel welfare dental program received oral examinations, questionnaires, and rehabilitative dental treatment. Seventy-nine percent of participants exhibited improvement in their oral-health-related quality-of-life scores following dental treatment. Improved OHIP-14 change scores were associated with being Caucasian or African-American, initial poor general health, severity of treatment urgency, worse baseline oral-health-related quality-of-life scores, subsequent patient satisfaction with the Dental Program, and resolution of their chief complaint (all p < 0.04). Those who completed their dental treatment were twice as likely to achieve a favorable/neutral employment outcome (OR = 2.01, 95%CI = 1.12, 3.62). Thus, oral health improved the quality of life and employment outcome for this welfare population.

A randomized controlled trial of early surgery in Duchenne muscular dystrophy.

We performed a randomized controlled trial of early surgical treatment of contractures in 20 boys with Duchenne muscular dystrophy, age 4-6 yr. Surgery consisted of release of hip flexors, removal of iliotibial bands, and lengthening of tendo Achilles bilaterally. All patients were monitored for at least 12 months post-randomization, and assessed quantitatively for muscle strength and function. Surgery corrected the deformities, but had no beneficial effect on strength or function. Indeed, data in the second year showed more rapid deterioration of function in some of the operated boys. There appeared to be continued evolution of pathology following surgery, as assessed by sequential muscle ultrasound and muscle biopsy. We cannot recommend this type of surgery as a routine treatment.

A randomized comparative study of two methods for controlling Tendo Achilles contracture in Duchenne muscular dystrophy.

A 30-month prospective randomized study of 27 Scandinavian boys with confirmed diagnosis of Duchenne muscular dystrophy was done to compare the effect of passive stretching combined with the use of night splints (group A) or passive stretching (group B) on the evolution of Tendo Achilles contractures. Assessments were based on the methodology of Scott et al. (Muscle Nerve 1982;5:291-301)Analysis of the pattern and mechanism of dropout was done to eliminate bias between the two groups. Logistic regression showed that Tendo Achilles contracture was the most important variable (P=0.0020) for dropout. Methods of statistical analysis for longitudinal data avoiding induced serial correlations were used in the analysis. The expected annual change in Tendo Achilles contracture was found to be 23% less in group A than in group B after equalization for total muscle strength (%MRC).

Longitudinal data analysis: an application to construction of a natural history profile of Duchenne muscular dystrophy.

A 30-month prospective study of 27 Scandinavian boys with confirmed diagnosis of Duchenne muscular dystrophy was carried out to construct profiles of the natural history of the disease. Assessments which included measures of voluntary muscle strength and function were done at 3 monthly intervals except for the first and second which were separated by 1 month. Recently developed statistical methods for analysis of longitudinal data with repeated observations on the same individual were used avoiding the problem of induced serial correlations. This allowed for the construction of both reference and prediction profiles for the variables %MRC, motor ability, walking time for 10 m and the sum of myometry of seven muscle groups.

Validation of self-reported complications by bone marrow transplantation survivors.

Self-administered questionnaires are commonly used to measure exposures and outcomes in epidemiological research and thus need good validity. With increasing numbers of cancer survivors, there is interest in the ongoing assessment of therapy-related complications. A medical record validation of patient-reported complications following bone marrow transplantation (BMT) was performed using a self-administered questionnaire. The study population consisted of 100 patients who had undergone BMT at the City of Hope. The following self-reported complications were validated using medical records: ocular, endocrine, cardiovascular, musculoskeletal, pulmonary, gastrointestinal, neurological, graft-versus-host disease, and subsequent cancers. Using information from medical records as the standard, sensitivities ranged from 52.9% for subsequent cancers to 100% for avascular necrosis and hypothyroidism. Specificities ranged from 75.4% for ocular complications to 100% for avascular necrosis. There was intermediate to excellent agreement (kappa = 0. 4-1.0) for all complications evaluated. Thus, the agreement between self-reporting and medical records was good for complications with clear diagnostic criteria that are easily communicated to the patient, but was diminished for complications with non-established diagnostic criteria (xerophthalmia) or a fluctuating course (peripheral neuropathies and hypertension). Overall these results suggest that cancer survivors can self-report serious complications with an acceptable level of accuracy in epidemiological research.

Congenital herpes infection: placental and umbilical cord findings.

BACKGROUND: Herpes simplex virus (HSV) fetal infections are rare, and the routes through which the virus reaches the fetus are insufficiently documented. CASE: We describe a case of congenital HSV ascending infection in an infant whose membranes were intact until cesarean delivery. The pathologic findings were remarkable for a mild lymphoplasmocytic funisitis and the presence of positive viral staining of cells in the subamniotic connective tissue, amniotic epithelium, and umbilical cord. Antigen-positive cells within the extraplacental membranes were mostly located in an area presumably adjacent to the cervix before birth. In the umbilical cord, positive viral staining was confined to cells in the subamniotic mesenchyma away from the perivascular mesenchyma of the central portion of the cord. CONCLUSION: Immunohistochemistry using herpes-specific antibodies, coupled with routine histologic examination, allows early diagnosis of congenital HSV infection and documentation of the ascending route of infection when the membranes are intact.