In China, there is a massive rural–urban migration and the childr

In China, there is a massive rural–urban migration and the children

of migrants are often unregistered residents (a ‘floating population’). Aim.  This pilot study aimed to profile the oral health of migrant children in South China’s principal city of migration and identify its socio-demographic/behavioural determinants. Design.  An epidemiological survey was conducted in an area of Guangzhou among 5-year-old migrant children (n = 138) who received oral examinations SB525334 according to the World Health Organization criteria. Parents’ oral health knowledge/attitude, child practices, and impact of children’s oral health on their quality-of-life (QoL) were assessed. Results.  The caries rate and mean (SD) dmft were 86% and 5.17 (4.16), respectively, higher than those national statistics for both rural and urban areas (P < 0.05). Oral hygiene was satisfactory (DI-S < 1.0) in 3% of children. Oral health impacts on QoL were considerable; 60% reported one or more impacts. 58% variance in ‘dmft’ was explained by ‘non-local-born’, ‘low-educated parents’, ‘bedtime feeding’, ‘parental unawareness of fluoride’s effect and importance of teeth’, and ‘poor oral hygiene’ (all P < 0.05). ‘Non-local-born’ and ‘dmft’ indicated poor oral health-related QoL (both P < 0.05), accounting for 32% of variance. Conclusion.  Oral health is poor among

rural–urban migrant children and requires effective interventions in targeted sub-groups. “
“International Journal of Paediatric Dentistry 2013; 23: 77–83 Background.  In Chile, no information is available regarding the soluble fluoride (F) content in the toothpastes commercialized for children and the country’s guidelines MAPK Inhibitor Library recommend the use of F in toothpastes in an age-dependent concentration. No global consensus has been reached on this TCL subject. Aim.  To determine the soluble F concentration in dentifrices for children sold in Chile and to discuss Chilean guidelines and professional recommendations of use. Design.  Three samples of twelve different dentifrices were purchased from drugstores. Toothpastes were analysed in duplicate using an ion-specific electrode. The concentrations of total

F (TF) and total soluble F (TSF) were determined (μg F/g). Results.  Measured TF was consistent with that declared by the manufacturer in eight products. Two dentifrices showed lower TF and two higher F concentrations than declared. A toothpaste, marketed as low-F (450 ppm), showed F concentration threefold higher. Most dentifrices exhibited TSF concentrations similar to the TF content, except one sample that displayed considerably lower TSF than TF. Recommendations on F toothpastes use in children widely vary from country to country. Conclusions.  Most dentifrices for children match F content in the labelling, but recommendations are not supported by the best evidence available on the benefit/risk of F toothpastes use. “
“The distribution of fluoride and calcium in plaque after the use of fluoride dentifrices has not yet been determined.

In China, there is a massive rural–urban migration and the childr

In China, there is a massive rural–urban migration and the children

of migrants are often unregistered residents (a ‘floating population’). Aim.  This pilot study aimed to profile the oral health of migrant children in South China’s principal city of migration and identify its socio-demographic/behavioural determinants. Design.  An epidemiological survey was conducted in an area of Guangzhou among 5-year-old migrant children (n = 138) who received oral examinations Alisertib according to the World Health Organization criteria. Parents’ oral health knowledge/attitude, child practices, and impact of children’s oral health on their quality-of-life (QoL) were assessed. Results.  The caries rate and mean (SD) dmft were 86% and 5.17 (4.16), respectively, higher than those national statistics for both rural and urban areas (P < 0.05). Oral hygiene was satisfactory (DI-S < 1.0) in 3% of children. Oral health impacts on QoL were considerable; 60% reported one or more impacts. 58% variance in ‘dmft’ was explained by ‘non-local-born’, ‘low-educated parents’, ‘bedtime feeding’, ‘parental unawareness of fluoride’s effect and importance of teeth’, and ‘poor oral hygiene’ (all P < 0.05). ‘Non-local-born’ and ‘dmft’ indicated poor oral health-related QoL (both P < 0.05), accounting for 32% of variance. Conclusion.  Oral health is poor among

rural–urban migrant children and requires effective interventions in targeted sub-groups. “
“International Journal of Paediatric Dentistry 2013; 23: 77–83 Background.  In Chile, no information is available regarding the soluble fluoride (F) content in the toothpastes commercialized for children and the country’s guidelines PI3K inhibitor recommend the use of F in toothpastes in an age-dependent concentration. No global consensus has been reached on this Vorinostat clinical trial subject. Aim.  To determine the soluble F concentration in dentifrices for children sold in Chile and to discuss Chilean guidelines and professional recommendations of use. Design.  Three samples of twelve different dentifrices were purchased from drugstores. Toothpastes were analysed in duplicate using an ion-specific electrode. The concentrations of total

F (TF) and total soluble F (TSF) were determined (μg F/g). Results.  Measured TF was consistent with that declared by the manufacturer in eight products. Two dentifrices showed lower TF and two higher F concentrations than declared. A toothpaste, marketed as low-F (450 ppm), showed F concentration threefold higher. Most dentifrices exhibited TSF concentrations similar to the TF content, except one sample that displayed considerably lower TSF than TF. Recommendations on F toothpastes use in children widely vary from country to country. Conclusions.  Most dentifrices for children match F content in the labelling, but recommendations are not supported by the best evidence available on the benefit/risk of F toothpastes use. “
“The distribution of fluoride and calcium in plaque after the use of fluoride dentifrices has not yet been determined.

heterostrophus genomic DNA as template Reactions with pairs 3 an

heterostrophus genomic DNA as template. Reactions with pairs 3 and 4 were carried out using pATBS-NEO (M. Ronen, PhD thesis, Technion, 2011) plasmid DNA as template. Round-II used, to construct the 5′ side of the final sequence, the products of pairs 1, 3 as template and FP1, NLC37 as primers; for the second half, the products of pairs 2 buy LY294002 and 4 as template and NLC38, RP2 as primers. The two final products were integrated into the Δskn7 genome by double-crossover recombination, resulting in reconstruction of the complete

neomycin resistance cassette replacing the entire predicted coding region of ChAP1. Fungal protoplasts were prepared and transformants selected for neomycin and hygromycin resistances as described (Turgeon et al., 2010; Turgeon et al., 1987; Wirsel et al., 1996). To assay gene expression, cultures were grown in liquid CMX with shaking Ibrutinib purchase (200 r.p.m.) for 4 days at 22 °C, the mycelium centrifuged and transferred to fresh CMX with 20 mM final concentration of hydrogen peroxide and incubated at 22 °C for 30 min. RNA isolation was done as described in (Shanmugam

et al., 2010). For cDNA synthesis, 2 μg of RNA was used for reverse transcription with random primers following the protocol supplied with the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems). Abundance of transcripts was measured by quantitative real-time PCR in a 7300 cycler (Applied Biosystems), with 15 μL reaction volumes, using Quanta Biosciences SYBR mix with two technical replicates for each PCR reaction. Data shown are means of three biological replicate experiments. The C. heterostrophus actin gene was used as ‘housekeeping’ gene to normalize the amount of cDNA. The primers used for real-time PCR are shown in Table 2. Calculation of CT values was done using Applied Biosystems software dataassist. Solid CMX was amended with 20 mM hydrogen peroxide, 0.4 M potassium Thymidylate synthase chloride, 0.75 M sorbitol, 30 μM menadione or 25 mM calcofluor white stain (CWS). Control was solid CMX without additives. All plates were incubated

under 16 h light–8 h dark at 22 °C for 6 days, and colonies were photographed. Sorbitol, calcofluor white stain, menadione, and MES hydrate were purchased from Sigma-Aldrich. Hydrogen peroxide was purchased from Carlo Erba. Potassium chloride was purchased from MERCK. Murashige and Skoog medium was purchased from Duchefa Biochemie. Maize plants (Royalty, local hybrid, purchased from Ben Shachar, Tel Aviv) were grown in hydroponic culture for 12 days in a medium containing 2.15 g L−1 of Murashige & Skoog medium (0.5 MS), 0.25 mM MES, adjusted to pH 5.7 with KOH. Plants – with their roots – were attached to a tray and kept moist. The second leaf was inoculated with 7-μL droplets of 0.02% Tween 20 in ddW containing about 500 C. heterostrophus spores. Trays were closed in plastic bags to keep the plants moist. Lesions were measured after 2 days.

fragilis does not

significantly increase the presence of

fragilis does not

significantly increase the presence of DNA strand breaks. This is in contrast to what was observed in a B. fragilis recA mutant, where the absence of the RecA protein led to an increase in the presence of single- and double-strand breaks in DNA (Steffens et al., 2010). The recQ mutant strains showed varying levels of increased sensitivity to metronidazole (Table 2). At 60 min, the wild type survived 1.32-fold, 41.88-fold and 23.18-fold better than mutants RecQ1, RecQ2 and RecQ3, respectively. These results confirmed that these proteins are needed for cell survival following metronidazole damage in B. fragilis, although their exact roles have not yet been elucidated. The extreme sensitivity of strain RecQ2 to metronidazole highlights the fact that the absence of this particular homologue (and/or the downstream Tpr protein) causes significant stress in the bacterium, as evidenced X-396 clinical trial by elongated cells and defective growth. The E-test results confirmed that the mutants were more sensitive to metronidazole, with B. fragilis minimum inhibitory concentration values of

0.25 μg mL−1 for strain 638R, compared with 0.125 μg mL−1 for strains RecQ1 and RecQ3, and <0.016 μg mL−1 for RecQ2. This suggests that a RecA-positive background supports metronidazole damage repair in the absence of RecQ1 and RecQ3, but is insufficient in the absence of RecQ2 and possibly its downstream gene product. In this Dehydratase study, it Romidepsin cost has been shown that mutations in the RecQ helicases

render B. fragilis more sensitive to metronidazole and that these proteins are, therefore, important for the cellular response to metronidazole-induced cell damage. The most sensitive mutant strain, RecQ2, exhibited severe growth defects, defective cell division and aberrant cell morphology, possibly due to polar effects on ORF638R_3782, which encodes a putative TPR protein and may be implicated in cell division. Further studies are needed to establish the precise function of each RecQ homologue in maintaining B. fragilis viability following metronidazole challenge. This study was supported by grants from the Wellcome Trust (070375/Z/03/Z), the South African Medical Research council and a South Africa–Sweden Collaborative Research Grant (through the National Research Foundation). C.E.N. acknowledges a grant from the Swedish Research Council (348-2006-6862). We thank A.A. Salyers and N.B. Shoemaker (Urbana, IL) for providing the pLYL01 and pGERM plasmids, and acknowledge G. Blakely for useful discussions. Fig. S1. Confirmation of insertional mutation of recQ genes. Fig. S2. Visualization of Bacteroides fragilis cells using fluorescence microscopy. Fig. S3. Visualization of DNA double- and single-strand breaks. Table S1. Primers used in this study. Table S2. RecQ homologues from the Bacteroides groupNB.

Interventions have been mostly implemented to individual parts of

Interventions have been mostly implemented to individual parts of the medicines management system, without important collaborations between research and practice. Implementing interventions in an isolated manner may provide minimal effects as observed in previous studies.[61,69] Health care is a complex

system with an overarching aim of improving patient health outcomes. Isolated, spontaneous reactions to serious critical incidents without rigorous evaluations of the interactions between various units of the system only yield multiplicity of similar interventions with slight and ineffective modifications. Indeed, a systematic review and meta-analysis of interventions in primary care demonstrated the weakness of the evidence for effectiveness of interventions aimed at reducing hospital admissions or preventable drug-related morbidity.[96] Selleckchem PLX4032 With an aging population, availability learn more of innovative but more expensive therapeutic agents, and tight healthcare budgets, optimising existing interventions becomes necessary. In the recently published Pharmacist-led Information Technology

Complex Intervention (PINCER) Study, simple feedback plus PINCER (an educational outreach and dedicated support) in general practice, patients in the intervention group were significantly less likely to have experienced a range of medication errors.[74] This intervention demonstrated the benefit of collaborative interventions to improve the safety of medication use in primary care and Sclareol ultimately improve patient health outcomes. This review has provided an international perspective on the safety of medication use in primary care across the medication management system.

Targeting the more susceptible population groups and the most dangerous aspects of the system may be more effective to error prevention in primary care. Collaborative implementation of existing interventions may offer time- and cost-effective options to improving medication safety and patients’ health outcome in primary care. The authors declare no conflict of interest. This work was supported by a University of Hertfordshire studentship with support from Merck Sharp & Dohme Limited. The authors wish to thank Merck Sharp & Dohme for their support. “
“Z. Yasmin, A. Gomes, G. Calabrese, R. Kayyali, S. Nabhani-Gebara Kingston University, London, UK The aim of this study was to gauge community pharmacists’ current experience and perceptions of electronic cigarettes. Seventy-three per cent of the pharmacists are currently selling electronic cigarettes with 20% indicating that patients have reported adverse events linked to their use. Community pharmacists believe that electronic cigarettes are being purchased for smoking cessation aid and to prevent relapse. Community pharmacists are looking forward to the MHRA regulation of electronic cigarettes as a smoking cessation tool to assure users about quality and safety.

Obviously, the spine is a modifiable compartment whose neck lengt

Obviously, the spine is a modifiable compartment whose neck length can be controlled by afferent activity and which can regulate the spread of the [Ca2+]i rise evoked at the synapse and perhaps prevent further spreading into the parent dendrite (Korkotian & Segal, 2007); it can also control the access of synaptic molecules into the sphere of the spine head. One category of molecule which is delivered into and out of the synapse in relation

to activity is the ionotrophic AMPA-subtype glutamate receptor. LTP is assumed STI571 research buy to involve the addition of glutamate receptors into the postsynaptic density, and LTD results from the removal of AMPA receptors from the spine head. Recently it has been suggested (Korkotian & Segal, 2007; Ashby et al., 2006) that the spine neck is a barrier to the diffusion of glutamate receptors into the synapse. Whether this barrier is determined by the calcium signal delivered to the dendrite or by the diffusion of receptor molecules is less learn more critical; the outcome is that spine neck restricts access of glutamate receptors to the synapse. Consequently, synapses on the parent dendritic shaft should produce larger synaptic currents than those in the spine head, and the length of the spine will determine synapse efficacy. In addition to the influx of calcium through NMDA-gated channels, voltage-gated calcium channels and GluR1-gated,

GluR2-lacking channels, the spines are endowed with calcium stores of the ryanodine type, which are activated by influx of calcium or by direct activation of the ryanodine receptors (e.g. by caffeine). These stores have been linked Sinomenine recently to the spine apparatus, en enigmatic structure in the spine neck, via synaptopodin, a molecule found to be in close association with the spine apparatus (Vlachos et al., 2009). Synaptopodin and the spine apparatus have been found primarily in large, mature spines. Thus, it is likely that synaptopodin regulates the levels of ambient [Ca2+]i, which is raised transiently by influx of calcium ions. It is likely that large spines, where a larger influx of calcium is expected, need the

stores in order to regulate excess amount of [Ca2+]i. Whether synaptopodin contributes to the stability of the spine is not entirely clear, as time-lapse imaging of synaptopodin and spines show that neither entity is stable over time (Vlachos et al., 2009). Regardless of their plastic properties, spines have been shown to constitute an independent physical compartment in which [Ca2+]i can rise to high levels, independent of the parent dendrite, suggesting that the spine protects the parent neuron from uncontrolled rises in [Ca2+]i, which may otherwise activate apoptotic processes leading to cell death (Schonfeld-Dado et al., 2009). In spiny neurons, shaft synapses are more likely to be harmful to the parent neuron than spine synapses.

If there is a question about the patient’s capacity to make an in

If there is a question about the patient’s capacity to make an informed decision, this should be assessed using Inhibitor Library the principles in the Mental Capacity Act 2005 [28]. Patients presenting at the clinic may be at different stages of readiness to take therapy [29] and clinicians’ first task is to assess their readiness, by means of open questions rather than closed, before supporting and furthering patients’ decisions on therapy. However, if a patient presents in circumstances that necessitate starting ART immediately, for example with certain AIDS diagnoses or very low CD4 cell counts, then doctors should prescribe ART and provide support

for the patient’s adherence, especially through the first few weeks. Recognizing symptoms that patients attribute to ART side effects might avoid loss of adherence and deterioration of trust in the patient–provider relationship [30, 31].

A ‘perceptions and practicalities’ approach should be used to tailor support to meet the needs of the individual, to identify both the perceptual factors (such as beliefs about ART) and practical factors (such as capacity and resources) influencing adherence [8,32]. Supporting patients requires good communication not just between clinician and patient but also between all healthcare staff involved with their care, including those in their HIV services, their GP and any clinicians involved in management of co-morbid conditions. Patients should be offered copies of letters about them sent to their GP and other physicians. CX-4945 The advantages of HIV status disclosure to the patient’s GP should be discussed and considered best practice, as several situations require consensual clinical decision-making. A patient’s decision not to disclose their

status to their GP should, however, always be respected, subject to the clinician’s duty to protect vulnerable individuals. “
“Some fungi cause disease in humans and plants, while others have demonstrable potential for the control of insect pests. PRKACG In addition, fungi are also a rich reservoir of therapeutic metabolites and industrially useful enzymes. Detailed analysis of fungal biochemistry is now enabled by multiple technologies including protein mass spectrometry, genome and transcriptome sequencing and advances in bioinformatics. Yet, the assignment of function to fungal proteins, encoded either by in silico annotated, or unannotated genes, remains problematic. The purpose of this review is to describe the strategies used by many researchers to reveal protein function in fungi, and more importantly, to consolidate the nomenclature of ‘unknown function protein’ as opposed to ‘hypothetical protein’– once any protein has been identified by protein mass spectrometry.

Once synthesized, nitrogenase activity of A brasilense, as well

Once synthesized, nitrogenase activity of A. brasilense, as well as of other Rhodospirillales, is reversibly inactivated in vivo by or anaerobiosis. This inactivation involves ADP-ribosylation of the Fe-protein (dinitrogenase reductase) catalyzed by dinitrogenase

reductase ADP-ribosyltransferase (DraT) and is reversed, upon exhaustion, by dinitrogenase Fludarabine ic50 reductase activating glycohydrolase (DraG) (Cassan & Garcia de Salamone, 2008). The activities of both DraT and DraG enzymes are regulated according to the levels of ammonium through direct interactions with the PII proteins GlnB and GlnZ. DraG interacts with GlnZ both in vivo and in vitro, and DraT interacts with GlnB in vivo (Huergo et al., 2009). Bacteria have developed mechanisms to maintain cell viability during starvation and resume growth when nutrients become available. These include among others phase variation (Kussell et al., 2005). Phase variation has been proposed as an important mechanism by which microorganisms adapt to environmental changes, such as those existing in the soil rhizosphere (Van den Broek et al., 2005). In phase variation, the expression of a given

gene is either in an ‘ON’ or an ‘OFF’ mode, with these changes usually being reversible. Phase variation has been defined as a random event that occurs at high frequency, involves changes in the DNA, and leads to a phenotypically heterogeneous population (Van der Woude & Baumler, 2004; Wisniewski-Dye & Vial, 2008). Several studies with Azospirillum have identified and characterized phenotypic variants. In A. lipoferum 4B, phenotypic LBH589 chemical structure variation was associated with loss of a 750-kb plasmid (Vial et al., 2006). In A. brasilense Sp245, a spontaneous variant was shown to lose plasmids p40, p85, and p120; however, it gained a new plasmid of more than 300 MDa (Katsy et al., 2002). Phenotypic variants of A. brasilense Sp7 also showed altered plasmid composition, as well as changes

in LPS structure (Petrova et al., 2005). New phenotypic variants of A. brasilense Sp7 were retrieved recently, after exposure of the parental strain mainly to starvation, but also after colonization of maize roots (Lerner et al., 2010). Two Etofibrate variants, Sp7E and Sp7EPS, were found to produce significantly higher EPS concentrations relative to the Sp7 parental strain and were LPS-defective. The variants were also shown to carry alterations in DNA rearrangement, EPS monosaccharide composition, and OMP profile as compared to the parental strain (Lerner et al., 2010). Importantly, the variants differed from the parental strain in cell pigmentation (Fig. 3), susceptibility to stresses, antibiotics, and capability of biofilm formation (Lerner et al., 2010). Future studies may determine how phenotypic variation is associated with survival in bacterial inoculants, root colonization, and plant growth promotion.

1 The WHO European Region has been free of autochthonous polio ca

1 The WHO European Region has been free of autochthonous polio cases from 1998, and certification by the WHO in 2002 of this condition led to a modification in vaccine administration. The oral polio vaccine (OPV) has gradually been replaced with the enhanced potency inactivated polio vaccine (IPV), safer than DNA Synthesis inhibitor OPV because it is not associated with the rare

risk of vaccine-associated paralytic poliomyelitis (VAPP).3 In Italy, there is an increased and continuous inflow of refugees from countries where poliomyelitis is still present and this may represent a risk of the wild poliovirus strains being introduced. The Italian region of Puglia (Southern Italy) can be deemed a “border region” because, due to its geographic position, it has to face daily arrivals of refugees. The aim of this study was to evaluate the poliomyelitis immunization level, by titration BKM120 mouse of the neutralizing antibody, in a sample of refugees of various nationalities

residing in the Asylum Seeker Center in Bari Palese in Puglia. The study was carried out during 2008 and involved 573 refugees, 520 (90.8%; 95% CI = 88–92.9) males and 53 (9.2%; 95% CI = 7.1 − 12) females. Of these, 546 (95.3%; 95% CI = 93.1 − 96.8) were from Africa and 27 (4.7%; 95% CI = 3.2 − 6.9) from Asia. In particular, 20 residents (3.5%; 95% CI = 2.2 − 5.4) were from Afghanistan and 67 (11.7%; 95% CI = 9.2 − 14.7) from Nigeria. The average age of the population sample was 24.3 (SD = 5.4; range 1–50). Signed informed consent to the study was Adenosine triphosphate obtained from each participant. A 10 mL blood sample was obtained by venipuncture and the serum was separated by centrifugation. Each serum sample was coded and stored at −20°C. The immunity against poliomyelitis was evaluated as described previously.4 Demographic data from the Asylum Center database and the laboratory exam results were analyzed with the statistical software Epi-Info 6.00. Fisher’s exact test was used in the analysis of the difference between proportions. A value of p < 0.05 was considered as significant. An

antibody titer ≥1:8 was found in 571 subjects (99.6%) for poliovirus type 1, in 572 subjects (99.8%) for poliovirus type 2, and in 570 subjects (99.5%) for poliovirus type 3 (Table 1). All the subjects with an antibody titer less than 1:8 were males from Africa: specifically, a 20-year-old Nigerian with antibody titer less than 1:4 for the three types of poliovirus; two Somalis, aged 26 and 20, had antibody titers of 1:4 and 1:8, respectively. The levels of antibody titer did not significantly differ between Africans and Asians (Table 1). Our survey results revealed excellent immunization levels in the immigrants, in line with other studies in Europe in the last 15 years.5,6 However, we cannot exclude the existence of low-immunity pockets in the immigrant population just because they were not detected in our study.

In addition, data from the SMART trial indicate that episodic use

In addition, data from the SMART trial indicate that episodic use of antiretroviral therapy according to CD4 cell count is associated with increased risk of SNA events, a finding that appeared consistently across a broad range of CD4 cell counts [17]. Several limitations apply to the present study. Above all, the retrospective nature of these data (even with the data verification process that took place within the cohort) and the limited number of potential predisposing

variables that we were able to analyse mean that caution DAPT is required in the interpretation of the results. Ascertainment bias should be addressed in the discussion of retrospective data. Nevertheless, given the nature and relevance of the clinical events analysed and the systematic revision of the clinical charts that was performed at all participant sites, we believe that there was a very low chance of missing or misinterpreting the identified cases. In addition, each of the sites acted as the primary provider for medical care of the patients, so the risk of missing these kinds of events was probably

MAPK inhibitor very low. A relatively low number of SNA events were identified in this cohort, and thus only strong associations were likely to be identified, and analysis of different types of events should be regarded as exploratory. In addition, as few sites have participated in this first project of the LATINA cohort, these results should not be used to extrapolate the situation to the entire Latin American region. We focused the analysis on the influence of immune deficiency on SNA events, and thus we believe that the results obtained for cART-associated variables should be interpreted with caution, as CD4 cell count is in the causal path between treatment and outcome. Nevertheless, we believe that these findings contribute to growing knowledge pentoxifylline regarding the relevance of SNA events as a global problem, providing information on a region for

which little information has been published to date. In summary, we found that SNA events are prevalent among HIV-infected subjects in Latin America and we found significant evidence supporting an association between immune deficiency and the risk of SNA events, when events were considered either together or separately according to type. These results contribute to a large body of evidence that supports the need to better understand the potential benefit of earlier use of cART. Randomized trials will probably be needed to enable definitive conclusions to be drawn about the impact of these findings on current antiretroviral treatment recommendations. We gratefully acknowledge James D. Neaton for his valuable assistance with the final version of the manuscript. Author contributions: W.H.B., M.H.L., L.C.O., A.L.R. and V.G.V.