Natural antibody repertoires: development and functional role in inhibiting allergic airway disease.

In this review we discuss the effects of microbial exposure on the B cell repertoire. Neonatal exposure to conserved bacterial carbohydrates and phospholipids permanently reprograms the natural antibody repertoire directed toward these antigens by clonal expansion, alterations in clonal dominance, and increased serum antibody levels. These epitopes are present not only in bacterial cell walls, but also in common environmental allergens. Neonatal immunization with bacterial polysaccharide vaccines results in attenuated allergic airway responses to fungi-, house dust mite-, and cockroach-associated allergens in mouse models. The similarities between mouse and human natural antibody repertoires suggest that reduced microbial exposure in children may have the opposite effect, providing a potential mechanistic explanation for the hygiene hypothesis. We propose that understanding the effects of childhood infections on the natural antibody repertoire and the mechanisms of antibody-mediated immunoregulation observed in allergy models will lead to the development of prevention/interventional strategies for treatment of allergic asthma.

A transcriptionally distinct subset of influenza-specific effector memory B cells predicts long-lived antibody responses to vaccination in humans.

Seasonal influenza vaccination elicits hemagglutinin (HA)-specific memory B (Bmem) cells, and although multiple Bmem cell populations have been characterized, considerable heterogeneity exists. We found that HA-specific human Bmem cells differed in the expression of surface marker FcRL5 and transcriptional factor T-bet. FcRL5+T-bet+ Bmem cells were transcriptionally similar to effector-like memory cells, while T-betnegFcRL5neg Bmem cells exhibited stem-like central memory properties. FcRL5+ Bmem cells did not express plasma-cell-commitment factors but did express transcriptional, epigenetic, metabolic, and functional programs that poised these cells for antibody production. Accordingly, HA+ T-bet+ Bmem cells at day 7 post-vaccination expressed intracellular immunoglobulin, and tonsil-derived FcRL5+ Bmem cells differentiated more rapidly into antibody-secreting cells (ASCs) in vitro. The T-bet+ Bmem cell response positively correlated with long-lived humoral immunity, and clonotypes from T-bet+ Bmem cells were represented in the secondary ASC response to repeat vaccination, suggesting that this effector-like population predicts influenza vaccine durability and recall potential.

Neonatal Exposure to Commensal-Bacteria-Derived Antigens Directs Polysaccharide-Specific B-1 B Cell Repertoire Development.

B-1 B cells derive from a developmental program distinct from that of conventional B cells, through B cell receptor (BCR)-dependent positive selection of fetally derived precursors. Here, we used direct labeling of B cells reactive with the N-acetyl-D-glucosamine (GlcNAc)-containing Lancefield group A carbohydrate of Streptococcus pyogenes to study the effects of bacterial antigens on the emergent B-1 B cell clonal repertoire. The number, phenotype, and BCR clonotypes of GlcNAc-reactive B-1 B cells were modulated by neonatal exposure to heat-killed S. pyogenes bacteria. GlcNAc-reactive B-1 clonotypes and serum antibodies were reduced in germ-free mice compared with conventionally raised mice. Colonization of germ-free mice with a conventional microbiota promoted GlcNAc-reactive B-1 B cell development and concomitantly elicited clonally related IgA+ plasma cells in the small intestine. Thus, exposure to microbial antigens in early life determines the clonality of the mature B-1 B cell repertoire and ensuing antibody responses, with implications for vaccination approaches and schedules.

Glycan-Reactive Innate-like B Cells and Developmental Checkpoints.

Using an Ig H chain conferring specificity for N-acetyl-d-glucosamine (GlcNAc), we developed transgenic (VHHGAC39 TG) mice to study the role of self-antigens in GlcNAc-reactive B-1 B cell development. In VHHGAC39 TG mice, GlcNAc-reactive B-1 B cell development during ontogeny and in adult bone marrow was normal. However, adult TG mice exhibited a block at transitional-2 immature B cell stages, resulting in impaired allelic exclusion and accumulation of a B cell subset coexpressing endogenous Ig gene rearrangements. Similarly, VHHGAC39 B cell fitness was impeded compared with non-self-reactive VHJ558 B TG cells in competitive mixed bone marrow chimeras. Nonetheless, adult VHHGAC39 mice immunized with Streptococcus pyogenes produce anti-GlcNAc Abs. Peritoneal cavity B cells transferred from VHHGAC39 TG mice into RAG-/- mice also exhibited robust expansion and anti-GlcNAc Ab production. However, chronic treatment of young VHHGAC39 mice with GlcNAc-specific mAbs leads to lower GlcNAc-binding B cell frequencies while increasing the proportion of GlcNAc-binding B1-a cells, suggesting that Ag masking or clearance of GlcNAc Ags impedes maturation of newly formed GlcNAc-reactive B cells. Finally, BCR H chain editing promotes expression of endogenous nontransgenic BCR alleles, allowing potentially self-reactive TG B cells to escape anergy or deletion at the transitional stage of precursor B cell development. Collectively, these observations indicate that GlcNAc-reactive B cell development is sensitive to the access of autologous Ags.

B-1 B Cell-Derived Natural Antibodies against N-Acetyl-d-Glucosamine Suppress Autoimmune Diabetes Pathogenesis.

Environmental factors and host microbiota strongly influence type 1 diabetes (T1D) progression. We report that neonatal immunization with group A Streptococcus suppresses T1D development in NOD mice by promoting clonal expansion of N-acetyl-d-glucosamine (GlcNAc)-specific B-1 B cells that recognize pancreatic ß cell-derived Ags bearing GlcNAc-containing posttranslational modifications. Early exposure to Lancefield group A cell-wall carbohydrate Ags increased production of GlcNAc-reactive serum Abs and enhanced localization of innate-like GlcNAc-specific B cells to pancreatic tissue during T1D pathogenesis. We show that B-1 B cell-derived GlcNAc-specific IgM engages apoptosis-associated ß cell Ags, thereby suppressing diabetogenic T cell activation. Likewise, adoptively transferring GlcNAc-reactive B-1 B cells significantly delayed T1D development in naive recipients. Collectively, these data underscore potentially protective involvement of innate-like B cells and natural Abs in T1D progression. These findings suggest that previously reported associations of reduced T1D risk after GAS infection are B cell dependent and demonstrate the potential for targeting the natural Ab repertoire in considering therapeutic strategies for T1D.

Binuclear Lantern Complexes of All First-Row 3d Metals Scandium to Zinc: Metal-Metal Bond Lengths and Bond Orders, with Measures of Intrinsic Metal-Metal Bond Strength.

The B3LYP and M06-L functionals with the cc-pVTZ basis set are used to study lantern-type binuclear complexes of all the first-row (3d block) metals scandium to zinc in various low-energy spin states, out of which the ground states are predicted. These complexes are studied as models using mostly the unsubstituted formamidinate ligand. For each metal, metal-metal (MM) bond lengths are related to the formal MM bond orders (zero to five), derived by MO analysis and by electron counting. The predicted ground-state spin multiplicities and MM bond lengths of the model complexes generally agree fairly well with available experimental results on substituted analogues. Finally, values of the formal shortness ratio and Wiberg index for the MM bonds in all of these complexes in all spin states studied are categorized into ranges according to the MM bond orders 0 to 5 in steps of 0.5. The trends shown validate their use in estimating intrinsic metal-metal bond strength regardless of the metal.

Chemical Bonding Topology of Metal-Centered Polygonal Wheels: Two-Dimensional Analogues of Metallaboranes Related to Benzene and Cyclopentadienide.

The anion [Au@Ru5(CO)15(µ-CO)4]- has a pentagonal wheel structure that can be derived from a hypothetical pentagonal ruthenium carbonyl cluster Ru5(CO)20 by insertion of a gold atom in the center, thereby splitting the original Ru5 pentagon in Ru5(CO)20 into five AuRu2 triangles. The six electrons used to form 3c-2e bonds in three of the five AuRu2 triangles suggest a relationship to the aromatic sextet of the likewise pentagonal cyclopentadienide anion. Furthermore, the pentagonal wheel framework of [Au@Ru5(CO)15(µ-CO)4]- can be derived from a pentagonal bipyramid, such as that found in the deltahedral borane anion B7H72-, by bringing the two C5 axial vertices together at the center of the equatorial pentagon. Similarly, the hexagonal wheel complexes Ni@P6R6 and Pd@Pd6(µ-N═CtBu2)6 with six triangular faces can be derived from a hexagonal bipyramid, such as that found in the dirhenaborane (η5-Me5C5)2Re2B6H4Cl2, by bringing the two C6 axial vertices together at the center of the equatorial hexagon. A reasonable chemical bonding model for the hexagonal wheel complexes has three-fold symmetry with 3c-2e bonds in three of these six triangular faces analogous to the C═C double bonds in a Kekulé structure of benzene.

Aromaticity in P8 allotropes and (CH)8 analogues: significance of their 40 valence electrons?

The currently unknown phosphorus allotrope P8 is of interest since its 40 total valence electrons is a "magic number" corresponding to a filled 1S21P61D101S21F142P6 shell such as found in the relatively stable main group element clusters Al13- and Ge94-. However, P8 still remains as an elusive structure not realized experimentally. The lowest energy P8 structure by a margin of ∼9 kcal mol-1 is shown by density functional theory to be a cuneane analogue with no PP double bonds and two each of P5, P4, and P3 rings. Higher energy P8 structures are polycyclic systems having at most a single PP double bond. These P8 systems are not "carbon copies" of the corresponding (CH)8 hydrocarbons with exactly one hydrogen atom bonded to each carbon atom. Thus the lowest energy (CH)8 structure is cyclooctatetraene with four CC bonds followed by benzocyclobutene with three CC bonds. The cuneane (CH)8 structure is a relatively high energy isomer lying ∼36 kcal mol-1 above cyclooctatetraene. The cubane P8 and (CH)8 structures are even higher energy structures, lying ∼37 and ∼74 kcal mol-1 in energy above the corresponding global minima. Our results demonstrate differences in medium sized aggregates of elemental phosphorus and isolobal hydrocarbon species.

Polyhedral Ferraboranes with Iron Carbonyl Vertices: Carbonyl Migration Processes in the Iron Tetracarbonyl Derivatives.

The structures and energetics of the neutral Bn-1Hn-1Fe(CO)x (x = 4, 3) and the dianions [Bn-1Hn-1Fe(CO)3]2- (n = 6-14) have been investigated by density functional theory. The low-energy structures of the tricarbonyl dianions [Bn-1Hn-1Fe(CO)3]2- are all found to have closo deltahedral structures in accordance with their 2n+2 skeletal electrons. The low-energy structures of the neutral tricarbonyls Bn-1Hn-1Fe(CO)3 (n = 6-14) with only 2n skeletal electrons are based on capped (n-1)-vertex closo deltahedra (n = 6, 7, 8) or isocloso deltahedra with a degree 6 vertex for the iron atom. The closo 8- and 9-vertex deltahedra are also found in low-energy Bn-1Hn-1Fe(CO)3 structures relating to the nondegeneracy of their frontier molecular orbitals. Carbonyl migration occurs in most of the low-energy structures of the tetracarbonyls Bn-1Hn-1Fe(CO)4. Thus, migration of a carbonyl group from an iron atom to a boron atom gives closo Bn-2Hn-2(BCO)(µ-H)Fe(CO)3 structures with a BCO vertex and a hydrogen atom bridging a B-B deltahedral edge. In other low-energy Bn-1Hn-1Fe(CO)4 structures, a carbonyl group is inserted into the central n-vertex FeBn-1 deltahedron to give a Bn-1Hn-1(CO)Fe(CO)3 structure with a central (n+1)-vertex FeCBn-1 deltahedron that can be an isocloso deltahedron or a µ3-BH face-capped n-vertex FeCBn-2 closo deltahedron. Other low-energy Bn-1Hn-1Fe(CO)4 structures include Bn-1Hn-1Fe(CO)2(µ-CO)2 structures with two of the carbonyl groups bridging FeB2 faces (n = 6, 7, 10) or Fe-B edges (n = 12) or structures in which a closo Bn-1Hn-1 ligand (n = 6, 7, 10, 12) is bonded to an Fe(CO)4 unit with exclusively terminal carbonyl groups through B-H-Fe bridges.

Gasless laparoscopy in rural India-registry outcomes and evaluation of the learning curve.

BACKGROUND: A program of gasless laparoscopy (GL) has been implemented in rural North-East India. To facilitate safe adoption, participating rural surgeons underwent rigorous training prior to independent clinical practice. An online registry was established to capture clinical data on safety and efficacy and to evaluate initial learning curves for gasless laparoscopy. METHODS: Surgeons who had completed the GL training program participated in the online RedCap Registry. Patients included in the registry provided informed consent for the use of their data. Data on operative times, conversion rates, perioperative complications, length of stay, and hospital costs were collected. Fixed reference cumulative sum (CUSUM) model was used to evaluate the learning curve based on operative times and conversion rates published in the literature. RESULTS: Four surgeons from three rural hospitals in North-East India participated in the registry. The data were collected over 12 months, from September 2019 to August 2020. One hundred and twenty-three participants underwent GL procedures, including 109 females (88.6%) and 14 males. GL procedures included cholecystectomy, appendicectomy, tubal ligation, ovarian cystectomy, diagnostic laparoscopy, and adhesiolysis. The mean operative time was 75.3 (42.05) minutes for all the surgeries. Conversion from GL to open surgery occurred in 11.4% of participants, with 8.9% converted to conventional laparoscopy. The main reasons for conversion were the inability to secure an operative view, lack of operating space, and adhesions. The mean length of stay was 3 (2.1) days. The complication rate was 5.7%, with one postoperative death. The CUSUM analysis for GL cholecystectomy showed a longer learning curve for operative time and few conversions. The learning curve for GL tubal ligation was relatively shorter. CONCLUSION: Gasless laparoscopy can be safely implemented in the rural settings of Northeast India with appropriate training programs. Careful case selection is essential during the early stages of the surgical learning curve.

A low-density single nucleotide polymorphism panel for brown trout (Salmo trutta L.) suitable for exploring genetic diversity at a range of spatial scales.

The rivers of southern England and northern France which drain into the English Channel contain several genetically unique groups of trout (Salmo trutta L.) that have suffered dramatic declines in numbers over the past 40 years. Knowledge of levels and patterns of genetic diversity is essential for effective management of these vulnerable populations. Using restriction site-associated DNA sequencing (RADseq) data, we describe the development and characterisation of a panel of 95 single nucleotide polymorphism (SNP) loci for trout from this region and investigate their applicability and variability in both target (i.e., southern English) and non-target trout populations from northern Britain and Ireland. In addition, we present three case studies which demonstrate the utility and resolution of these genetic markers at three levels of spatial separation:(a) between closely related populations in nearby rivers, (b) within a catchment and (c) when determining parentage and familial relationships between fish sampled from a single site, using both empirical and simulated data. The SNP loci will be useful for population genetic and assignment studies on brown trout within the UK and beyond.

Trivalent Polyhedra as Duals of Borane Deltahedra: From Molecular Endohedral Germanium Clusters to the Smallest Fullerenes.

The duals of the most spherical closo borane deltahedra having from 6 to 16 vertices form a series of homologous spherical trivalent polyhedra with even numbers of vertices from 8 to 28. This series of homologous polyhedra is found in endohedral clusters of the group 14 atoms such as the endohedral germanium cluster anions [M@Ge10]3- (M = Co, Fe) and [Ru@Ge12]3- The next members of this series have been predicted to be the lowest energy structures of the endohedral silicon clusters Cr@Si14 and M@Si16 (M = Zr, Hf). The largest members of this series correspond to the smallest fullerene polyhedra found in the endohedral fullerenes M@C28 (M = Zr, Hf, Th, U). The duals of the oblate (flattened) ellipsoidal deltahedra found in the dirhenaboranes Cp*2Re2Bn-2Hn-2 (Cp* = η5-Me5C5; 8 ≤ n ≤ 12) are prolate (elongated) trivalent polyhedra as exemplified experimentally by the germanium cluster [Co2@Ge16]4- containing an endohedral Co2 unit.

Effect modifiers influencing the periodontal healing of the adjacent second molar following mandibular third molar removal.

DATA SOURCES: Studies were selected, using appropriate key words, from the following databases: Cochrane Central Register of Controlled Trials; Medline (via Pubmed); Scopus/Elsevier; and Embase. A manual search was also conducted of five periodontology and oral and maxillofacial surgery journals. It was not clarified what proportion of studies included were derived from which source. STUDY SELECTION: Inclusion criteria included prospective studies and randomised controlled trials published in English, with a minimum 6-month follow-up reporting on parameters of periodontal healing distal to the mandibular second molar following removal of M3M in human subjects. These parameters included pocket probing depth (PPD) reduction and final depth (FD), clinical attachment loss (CAL) reduction and FD, alveolar bone defect (ABD) change and FD. Given prognostic indictors and interventions were investigated, the studies were screened using PICO and PECO (Population, Intervention, Exposure, Comparison, Outcome). Cohen's kappa statistic measured the level of agreement between 2 selecting authors (0.96 stage 1 screening, 1.00 stage 2 screening). Disagreements were resolved with a tie-breaker 3rd author. Ultimately, from 918 studies, 17 met the inclusion criteria and 14 were included in the meta-analysis. Studies were excluded on the basis of same patient pools, non-representative outcomes of interest, insufficient follow-up period, and unclear results. DATA EXTRACTION AND SYNTHESIS: The 17 studies meeting the inclusion criteria underwent validity assessment and data extraction, including risk of bias analysis. Meta-analysis was performed to calculate mean difference and standard error for each outcome measure. If these were unavailable, a correlation coefficient was calculated. Meta-regression was used on different subgroups to determine factors affecting periodontal healing. For all analyses, statistical significance was determined as p < 0.05. Statistical variability in outcomes beyond the expected was estimated using I2 analyses, with a value >50% indicating significant heterogeneity. RESULTS: The periodontal parameters investigated yielded the following results after meta-analysis: overall PPD reduction of 1.06 mm at 6 months and 1.67 mm at 12 months; final PPD of 3.81 mm at 6 months; CAL change of 0.69 mm at 6 months; final CAL of 4.28 mm at 6 months and 4.37 mm at 12 months; ABD reduction of 2.62 mm at 6 months; ABD of 3.2 mm at 6 months. The authors found no statistically significant effect on periodontal healing from the following confounding factors: age; M3M angulation (specifically, mesioangular impaction); optimisation of periodontal health prior to surgery; scaling and root planing of the distal second molar at the time of surgery; post-operative antibiotics or chlorhexidine prophylaxis. There were statistically significant correlations between baseline PPD and final PPD. There was improved PPD reduction at 6 months with a three-sided flap compared to others, and regenerative materials and bone grafts improved all periodontal parameters. CONCLUSIONS: Although M3M removal results in modest improvement in periodontal health distally of the second mandibular molar, periodontal defects remain onwards of 6 months. There is limited evidence suggesting a three-sided flap is more beneficial than an envelope flap in PPD reduction at 6 months. Regenerative materials and bone grafts result in significant improvements across all periodontal health parameters. The most important predictive factor in final PPD of the distal second mandibular molar is baseline PPD.

Triplet Spin-State Capped Deltahedral Structures Rather than Singlet Spin-State Oblatocloso Structures as Energetically Favored Dimanganaborane Structures.

Density functional studies show that the singlet spin-state flattened oblatocloso deltahedral structures found experimentally in the dimetallaboranes Cp*2Re2Bn-2Hn-2 (Cp* = Me5C5; n = 8-12) of the third row group 7 element rhenium are not favored for analogous dimetallaboranes Cp2Mn2Bn-2Hn-2 (n = 8-14) of its first row congener manganese. Instead, the energetically preferred structures for the dimanganaboranes are higher spin-state triplet and quintet spin-state structures. This appears to be related to the lower ligand field splittings in complexes of the first row transition-metal manganese relative to analogous complexes of the third row transition-metal rhenium. The lowest-energy Cp2Mn2Bn-2Hn-2 (n = 8-13) structures typically have a central MnBn-2 closo deltahedron with one face capped by the second CpMn unit. However, for the 14-vertex Cp2Mn2B12H12 system the lowest-energy structures consist of B12 icosahedra with faces capped by both CpMn units. The thermochemistry of cluster buildup reactions of the type Cp2Mn2Bn-2Hn-2 + BH → Cp2Mn2Bn-1Hn-1 suggests that the 11- and 13-vertex structures are likely to be favored products in reactions of cyclopentadienylmanganese derivatives with borane sources. The paramagnetism of the predicted triplet and quintet spin states for the lowest-energy dimanganaboranes Cp2Mn2Bn-2Hn-2 (n = 8-14) suggests possible applications in novel magnetic materials.

Improvement in walking impairment following surgical and endovascular revascularization: Insights from VOYAGER PAD.

BACKGROUND: Peripheral artery disease (PAD) affects 200 million people worldwide and is associated with impaired quality of life, increased morbidity, and mortality. Supervised exercise therapy (SET) and lower-extremity revascularization (LER) are both proven strategies to improve patient symptoms. Short and long-term functional outcomes after LER for symptomatic PAD in a large, international cohort have not previously been described. METHODS: The VOYAGER PAD trial (ClinicalTrials.gov identifier: NCT02504216) enrolled subjects after LER for symptomatic PAD (Rutherford category 2-6). Participants completed the Walking Impairment Questionnaire (WIQ) at baseline, 1, 3 and 6 months, and every 6 months thereafter. The primary outcome analysis was degree of difficulty walking two blocks at each of the aforementioned time points. Difficulty walking three blocks and climbing one flight of stairs at these time points was also analyzed. Data about supervised and home exercise therapy before or after revascularization were not collected in the VOYAGER PAD trial. RESULTS: Of the 5614 VOYAGER PAD participants completing the WIQ at baseline, three-quarters presented with claudication and one-quarter with critical limb ischemia. Of these, the majority (62% with claudication and 74% with CLI) reported inability or much difficulty walking two blocks prior to LER. Walking improved after LER regardless of revascularization strategy, but one-fifth with claudication and one-third with CLI reported continued inability or much difficulty walking two blocks 1 month after LER. Participants who reported improved walking ability 1 month after LER experienced a durable functional result out to 3 years. Although the proportion of participants reporting significant baseline difficulty climbing one flight of stairs or walking three blocks differed, the trend in immediate and sustained improvement after LER was similar to that observed for walking two blocks. CONCLUSION: In this large, international cohort undergoing LER for symptomatic PAD, nearly two-thirds reported inability or much difficulty walking two blocks at baseline. Although many participants reported improved walking ability after LER, a substantial proportion remained severely disabled. These observations may help motivate providers, patients, and medical systems to improve awareness and engagement in SET referral after LER.

Planar Networks of Boron Triangles: Analogies to Benzene and Other Planar Aromatic Hydrocarbons.

The lowest energy structures for Bn species (n = 6 to 23 except for 20) observed experimentally in the gas phase with a mass spectrometer are planar networks of boron triangles. Such networks are considered to consist of trigonal planar sp2-hybridized boron atoms having perpendicular p orbitals similar to the carbon atoms in benzene and other planar aromatic hydrocarbons. Electron bookkeeping for reasonable chemical bonding topologies of wheel-like structures such as B@Bn-1 (n = 6-9) leads to two π-electrons for B6 and B7+ similar to the cyclopropenyl cation and six π-electrons for B82- and B9- similar to benzene. Related chemical bonding topology analyses for low-energy oval B10 and B11- structures as well as for larger planar boron triangle networks with 12, 13, and 14 boron atoms suggest six π-electrons in such structures. Planar networks of boron triangles having 16-19 boron atoms are shown to be systems with 10 π-electrons similar to naphthalene. Similarly, low-energy planar B22 and B23- structures are shown to be 4 π-electron systems 1analogous to linear anthracene and angular phenanthrene, respectively. Intermediate B15- and B21- systems are shown to be systems with 4k rather than 4k + 2 π-electrons with 8 and 12 π-electrons, respectively. Structures based on planar networks of boron triangles are strongly energetically disfavored for B20 relative to a nonplanar decagonal antiprism structure with ideal D10d symmetry.

Substituent, Solvent, and Dispersion Effects on the Zwitterionic Character and Dimerization Thermochemistry of the Group 6 Fulvene Metal Tricarbonyl Complexes.

Dimerizations of fulvene metal tricarbonyl complexes of the type (C5H4CRR')M(CO)3 (R, R' = MeO, Me, H; M = Cr, Mo, W) to form a metal-metal bond and a new carbon-carbon bond, thereby giving binuclear cyclopentadienyl metal carbonyl derivatives, are predicted to be thermochemically favored but to have significant activation energies ranging from ΔE = 19 to 42 kcal/mol. However, the introduction of dimethylamino but not methoxy substituents onto the exocyclic carbon atom changes the situation drastically so that the monomers [C5H4CH(NMe2)]M(CO)3 and [C5H4C(NMe2)2]M(CO)3 become strongly thermochemically favored, lying ΔE = 43 kcal/mol (M = W) to 63 kcal/mol (M = Cr) below their corresponding dimers. In such dimethylamino-substituted (fulvene)M(CO)3 derivatives, the M-C distance to the exocyclic fulvene carbon is lengthened beyond the bonding distance to give a zwitterionic structure with a pentahapto fulvene ligand. Such M-C distances in (fulvene)M(CO)3 complexes, which have preferred zwitterionic structures, increase with increasing solvent polarity (i.e., dielectric constant) until a saturation point is reached.

Adapting sanitary inspections for the monitoring of small drinking water supplies in Iceland.

Sanitary inspections (SIs) are checklists of questions used to identify actual and potential sources and pathways of drinking water contamination. Though the importance of SI adaptation to local contexts is widely acknowledged, there is currently limited guidance on how this should be undertaken in practice. During this research, World Health Organization (WHO) draft template SI forms for spring and borehole supplies were adapted for use in Iceland based on a series of desk reviews and field tests, an approach which may guide other future SI adaptation processes. SI results were collected from 25 spring supplies and nine borehole supplies in three regions of Iceland using adapted SI forms. These results were combined with 10-year historical water quality data from the same supplies to explore potential relationships between both data sets. Binary logistic regression test results indicated a statistically significant association (P = 0.025; odds ratio (OR) 1.864, 95% CI 1.080-3.220) between SI Question 3 (Does ponding from surface water occur around the spring/borehole?) receiving a 'High' risk level assignment and at least one historical incidence of water quality noncompliance for the parameters heterotrophic plate count 22 °C, total coliforms, Escherichia coli, and turbidity at the same supply. The significant modifications applied to the starting template during the testing and development of the Icelandic SI form emphasises the importance of a robust adaptation process to ensure SI forms are appropriate for the local context. Results from the analysis of SI and water quality test results demonstrated the potential for these data sets to identify the primary risks at a supply. This information may then be used to direct remedial actions, especially when the amount of relevant data increases over time.

Are there diagnostic alternatives to histopathology in detecting oral cancer?

Background Oral potentially malignant disorders (OPMDs) include erythroplakia, erosive lichen planus, non-homogenous leukoplakia and many others. These lesions may revert to healthy tissues, remain unchanged, or undergo malignant change to oral squamous cell carcinoma (OSCC). Early detection allows early management, which subsequently improves survival rates for OSCC. Current diagnostic practice involves a tissue biopsy with histology. This can be uncomfortable for patients and delays diagnosis. Other, less invasive diagnostic tests are available which can provide immediate results.Objectives Primary objective: to evaluate the diagnostic accuracy of index tests in detecting OSCC and OPMDs. Secondary objective: to determine the relative accuracy of alternative diagnostic tests.Search methods Four online databases including Medline (OVID), Embase (OVID), the US National Institute of Health Ongoing Trials Register (clinicaltrials.gov) and the World Health Organisation International Clinical Trials Registry Platform were searched for ongoing trials to 20 October 2020. Citation searches were conducted, with no language restrictions, and reference lists were reviewed for any additional references.Selection criteria Studies reporting the diagnostic test accuracy of the following index tests were included if used in conjunction with oral examination in determining OPMDs or OSCC: oral spectroscopy, light-based detection, vital staining, saliva and/or blood analysis and oral cytology.Data collection and analysis Titles and abstracts were screened by two designated review authors to determine relevance. A minimum of two authors, both independently and together, assessed the eligibility of the papers and undertook the quality assessment and data extraction. The methodological quality was determined using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Results of each index test in various studies were amalgamated using meta-analysis following the bivariate approach to determine sensitivity and specificity.Results Seventy-nine datasets were included, spanning from 1980 to 2020. A total of 7,942 lesions were examined. These studies assessed diagnostic sensitivity and specificity of tissue biopsy and histology in comparison to oral cytology (24 datasets), oral spectroscopy/light-based detection (24 datasets) and vital staining (22 datasets). Nine datasets evaluated two combined index tests. No eligible diagnostic accuracy studies assessing salivary or blood sample analysis were identified. Two studies were deemed low risk of bias in all categories (patient selection, index tests, reference standards and flow and timing) with 33 studies being low concern for applicability across three sectors. Patient selection, demographics, the index test and reference standard used were appropriate to a secondary care setting. Meta-analysis of eligible index tests showed the following results. Cytological sensitivity was 0.90 (CI 0.82-0.94) and specificity 0.94 (CI 0.88-0.97) from 24 datasets. For oral spectroscopy, sensitivity was 0.87 (CI 0.78-0.93) and specificity 0.50 (CI 0.32-0.68) from 24 datasets. For vital staining, sensitivity was 0.86 (CI 0.79-0.90) and specificity 0.68 (CI 0.58-0.77) from 22 datasets. For combined tests, sensitivity was 0.78 (CI 0.45-0.94) and specificity 0.71 (CI 0.53-0.84) from nine datasets.Conclusion None of the adjunctive tests can presently be recommended in lieu of tissue biopsy and histological assessment. Of the modalities, oral cytology showed the greatest potential based on the high summary estimate values for sensitivity and specificity. Further research is needed into the utility of these alternative diagnostic tests.

Calcitonin gene-related peptide: physiology and pathophysiology.

Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and ß). It belongs to a group of peptides that all act on an unusual receptor family. These receptors consist of calcitonin receptor-like receptor (CLR) linked to an essential receptor activity modifying protein (RAMP) that is necessary for full functionality. CGRP is a highly potent vasodilator and, partly as a consequence, possesses protective mechanisms that are important for physiological and pathological conditions involving the cardiovascular system and wound healing. CGRP is primarily released from sensory nerves and thus is implicated in pain pathways. The proven ability of CGRP antagonists to alleviate migraine has been of most interest in terms of drug development, and knowledge to date concerning this potential therapeutic area is discussed. Other areas covered, where there is less information known on CGRP, include arthritis, skin conditions, diabetes, and obesity. It is concluded that CGRP is an important peptide in mammalian biology, but it is too early at present to know if new medicines for disease treatment will emerge from our knowledge concerning this molecule.