HIV-2 inhibits HIV-1 gene expression via two independent mechanisms during cellular co-infection.

IMPORTANCE: Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.

Mechanisms by which the cystic fibrosis transmembrane conductance regulator may influence SARS-CoV-2 infection and COVID-19 disease severity.

Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS-CoV-2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe-while susceptible to severe COVID-19-are often spared from the highest levels of virus-associated mortality. To understand features that might influence COVID-19 among patients with cystic fibrosis, we studied relationships between SARS-CoV-2 and the gene responsible for CF (i.e., the cystic fibrosis transmembrane conductance regulator, CFTR). In contrast to previous reports, we found no association between CFTR carrier status (mutation heterozygosity) and more severe COVID-19 clinical outcomes. We did observe an unexpected trend toward higher mortality among control individuals compared with silent carriers of the common F508del CFTR variant-a finding that will require further study. We next performed experiments to test the influence of homozygous CFTR deficiency on viral propagation and showed that SARS-CoV-2 production in primary airway cells was not altered by the absence of functional CFTR using two independent protocols. On the contrary, experiments performed in vitro strongly indicated that virus proliferation depended on features of the mucosal fluid layer known to be disrupted by absent CFTR in patients with CF, including both low pH and increased viscosity. These results point to the acidic, viscous, and mucus-obstructed airways in patients with cystic fibrosis as unfavorable for the establishment of coronaviral infection. Our findings provide new and important information concerning relationships between the CF clinical phenotype and severity of COVID-19.

Accelerating TB diagnosis during the COVID-19 pandemic.

SETTING: The COVID-19 pandemic has caused significant disruption worldwide to economies and healthcare systems, even those with well-developed infrastructure.OBJECTIVE: To examine the effects of COVID-19 on TB diagnosis in Singapore, and to identify any factors that could facilitate early detection of TB among persons screened.DESIGN: To assess the impact of testing and diagnosis of the pandemic on TB, the number of TB-related tests from January 2018 to December 2020 were collected. We also conducted a retrospective case-control study of all adult patients admitted for COVID-19, TB or coinfection from 23 January to 31 May 2020.RESULTS: Nationwide testing for TB from 2018 to 2020 increased by 24.2%. We analysed 253 adult inpatients, of whom 107 (42.3%) were diagnosed with COVID-19, 134 (53.0%) had TB, while 12 (4.7%) had co-infection. Patients with TB were more likely to have chest X-ray abnormalities than those with COVID-19 (89.9% vs. 76.0%; P < 0.01). Patients with TB were more likely to have prolonged cough vs. those with COVID-19 infection (28 vs. 5 days; P < 0.01).CONCLUSION: Early screening for TB, even among patients with COVID-19, could lead to earlier diagnosis and treatment, thereby breaking the chain of transmission.

Head and Neck Region Dermatological Ultraviolet-Related Cancers are Associated with Exfoliation Syndrome in a Clinic-Based Population.

OBJECTIVE: We assessed the relationship between ultraviolet (UV)-associated dermatological carcinomas (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) and exfoliation syndrome (XFS) or exfoliation glaucoma (XFG). DESIGN: Case-control study. PARTICIPANTS: Between 2019 and 2021, 321 participants and control subjects (XFS or XFG = 98; primary open-angle glaucoma [POAG] = 117; controls = 106; ages 50-90 years) were recruited. METHODS: A cross-sectional survey assessing medical history, maximum known intraocular pressure, cup-to-disc ratio, Humphrey visual field 24-2, the propensity to tan or burn in early life, history of BCC or SCC, and XFS or XFG diagnosis. The multivariable models adjusted for age, sex, medical history, eye color, hair color, and likeliness of tanning versus burning at a young age. MAIN OUTCOME MEASURES: History of diagnosed XFS or XFG. RESULTS: Any history of BCC or SCC in the head and neck region was associated with a 2-fold higher risk of having XFS or XFG versus having POAG or being a control subject (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.04-3.89) in a multivariable-adjusted analysis. We observed a dose-response association in which the chance of having XFS or XFG increased by 67% per head and neck BCC or SCC occurrence (OR, 1.67; 95% CI, 1.09-2.56). When we excluded POAG participants, head and neck BCC or SCC was associated with a 2.8-fold higher risk of XFS or XFG (OR, 2.80; 95% CI, 1.12-7.02), and each additional occurrence had a 2-fold higher risk of XFS or XFG (OR, 1.97; 95% CI, 1.09-3.58). The association between head and neck region BCC or SCC and POAG compared with the control subjects was null (OR, 1.42; 95% CI, 0.58-3.48). With BCC or SCC located anywhere on the body, there was a nonsignificantly higher risk of having XFS or XFG compared with having POAG or being a control subject (OR, 1.65; 95% CI, 0.88-3.09). CONCLUSIONS: Head and neck region BCCs or SCCs are associated with a higher risk of having XFS or XFG. These findings support prior evidence that head and neck UV exposure may be a risk factor for XFS.

Histone acetylome-wide associations in immune cells from individuals with active Mycobacterium tuberculosis infection.

Host cell chromatin changes are thought to play an important role in the pathogenesis of infectious diseases. Here we describe a histone acetylome-wide association study (HAWAS) of an infectious disease, on the basis of genome-wide H3K27 acetylation profiling of peripheral blood granulocytes and monocytes from persons with active Mycobacterium tuberculosis (Mtb) infection and healthy controls. We detected >2,000 differentially acetylated loci in either cell type in a Singapore Chinese discovery cohort (n = 46), which were validated in a subsequent multi-ethnic Singapore cohort (n = 29), as well as a longitudinal cohort from South Africa (n = 26), thus demonstrating that HAWAS can be independently corroborated. Acetylation changes were correlated with differential gene expression. Differential acetylation was enriched near potassium channel genes, including KCNJ15, which modulates apoptosis and promotes Mtb clearance in vitro. We performed histone acetylation quantitative trait locus (haQTL) analysis on the dataset and identified 69 candidate causal variants for immune phenotypes among granulocyte haQTLs and 83 among monocyte haQTLs. Our study provides proof-of-principle for HAWAS to infer mechanisms of host response to pathogens.

Black and White Young Adults' Support to Midlife Parents.

OBJECTIVES: Prior research suggests that midlife adults in Black and non-Hispanic White families differ in support patterns to aging parents. It is unclear whether such racial differences exist in young adulthood. We examined Black and White young adults' support to their midlife parents and underlying mechanisms to explain within-racial group, family-level differences. METHOD: Young adults (aged 18-30; Black n = 107 and White n = 351) from the Family Exchanges Study 2 reported how often they provided tangible (practical) and intangible (emotional support and advice) support to each parent. Participants also reported beliefs about obligation to support parents, rewards from helping, and parental needs. RESULTS: On average, Black young adults provided more tangible and intangible support than White young adults. Feelings of reward predicted why young adults in some Black and White families gave more support than those in other families. Parental needs explained tangible support in Black families and intangible support in White families. Within families, rewards and parental needs drove Black offspring to give more intangible support than their siblings, while obligation motivated White offspring. DISCUSSION: Consistent with support patterns evident in older adulthood, Black young adults gave more tangible and intangible support to their midlife parents compared to White young adults. Within-race support patterns were explained by different factors informed by the Multidimensional Intergenerational Support Model. Findings suggest psychological factors contribute to between- and within-racial patterns of exchanges.

The Specificity of the Persistent IgM Neutralizing Antibody Response in Zika Virus Infections among Individuals with Prior Dengue Virus Exposure.

Dengue viruses (DENV) and Zika virus (ZIKV) are related mosquito-borne flaviviruses with similar disease manifestations, vector ecologies, and geographic ranges. The ability to differentiate these viruses serologically is vital due to the teratogenic nature of ZIKV and the potential confounding of preexisting cross-reactive anti-DENV antibodies. Here, we illustrate the kinetics of the IgM neutralizing antibody (NAb) response using longitudinal samples ranging from acute ZIKV infection to late convalescence from individuals with evidence of prior DENV infection. By serially depleting antibody isotypes prior to the neutralization assay, we determined that IgM contributes predominantly to ZIKV neutralization and is less cross-reactive than the IgG NAb. The IgM NAb peaked around 14 days (95% confidence interval [95% CI], 13 to 15) and had a median duration of 257 days (95% CI, 133 to 427). These results demonstrate the persistence of IgM NAb after ZIKV infection and imply its potential role in diagnosis, vaccine evaluation, serosurveillance, and research on flavivirus-host interactions.

PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers.

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP's role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field's progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

Asthma, Sinonasal Disease, and the Risk of Active Tuberculosis.

BACKGROUND: Although asthma is associated with impaired lung immunity, it is unclear whether asthma affects the risk of active tuberculosis (TB). Because the upper and lower airways are immunologically related, sinonasal disease may also modify susceptibility to TB disease. OBJECTIVES: To evaluate whether asthma and sinonasal disease prospectively modulate the risk of active TB in the Singapore Chinese Health Study. METHODS: In this population-based prospective cohort, we recruited 63,257 Chinese adults aged 45 to 74 years from 1993 to 1998 in Singapore, and conducted follow-up I interviews among 52,325 surviving participants from 1999 to 2004. Data on self-reported history of physician-diagnosed sinonasal disease were collected at baseline, and data on asthma and chronic bronchitis were collected at follow-up I interviews. Active TB cases were identified by linkage with the National TB Notification Registry through December 2014. Multivariable Cox proportional hazards regression models were used to estimate the risk of active TB. RESULTS: During a mean follow-up of 17 years from recruitment, there were 1249 cases of active TB, and among them, 678 cases were diagnosed in the 12-year period from follow-up I interviews. We observed reduced risk of active TB in those with a history of asthma at follow-up I (hazard ratio [HR], 0.55; 95% CI, 0.32-0.93) or sinonasal disease at baseline (HR, 0.59; 95% CI, 0.36-0.95). Conversely, history of chronic bronchitis was not associated with risk of TB (HR, 0.95; 95% CI, 0.68-1.31). CONCLUSIONS: Asthma or sinonasal disease may modulate immunological response to reduce the incidence of active TB in the adult population.

Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery.

Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg-1 , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery.

Age-related incidence of desaturation events and the cardiac responses on stroke index, cardiac index, and heart rate measured by continuous bioimpedance noninvasive cardiac output monitoring in infants and children undergoing general anesthesia.

STUDY OBJECTIVE: To assess the effects of desaturation on stroke index (SI), cardiac index (CI), and heart rate (HR) using the ICON continuous noninvasive cardiac output monitor in children undergoing general anesthesia. DESIGN: Retrospective analysis of a prospectively collected data set. SETTING: Pediatric operating rooms in a tertiary academic medical center. PATIENTS: Children younger than 20 years who experienced desaturation while undergoing general anesthesia. INTERVENTION: All records were retrospectively searched for desaturation events defined as a recorded Spo2 ≤ 90%. We compared the data from the prior 4 minutes (baseline) with mild, moderate, and severe levels of desaturation. MEASUREMENTS: The relationship between Spo2 and percent change in SI, CI, and HR from baseline was assessed using a generalized linear model with repeated measures and the least-squares method. MAIN RESULTS: Data from 446 patients were reviewed; 38 events were eligible for analysis after exclusions. There were significant decreases in SI at all saturation ranges below 95%: -6.5% (P < .001) for 85%-95%, -8.9% (P = .002) for 71%-84%, and -11% (P < .001) for ≤70%. Based on the result from the regression, Spo2 was associated with change in SI with borderline significance (P = .053) but not that of HR and CI. There was a strong relationship to desaturation events with young age (P < .001), particularly infants younger than 6 months. CONCLUSION: Events associated with desaturation in children under general anesthesia were significantly associated with decreased SI with a greater effect with lower saturation nadirs. It is unclear if other concurrent events could have also contributed to adverse hemodynamic responses during desaturation. In most children, a compensatory increase in HR generally offsets concurrent decreases in CI. It would appear that bradycardia is a late manifestation of hypoxemia.

The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease.

Recurrent gastrointestinal bleeding is one of the most challenging complications encountered in the management of patients with von Willebrand disease (VWD). The commonest cause is angiodysplasia, but often no cause is identified due to the difficulty in making the diagnosis. The optimal treatment to prevent recurrences remains unknown. We performed a retrospective study of VWD patients with occult or angiodysplastic bleeding within the setting of the von Willebrand Disease Prophylaxis Network (VWD PN) to describe diagnostic and treatment strategies. Centres participating in the VWD PN recruited subjects under their care with a history of congenital VWD and gastrointestinal (GI) bleeding due to angiodysplasia, or cases in which the cause was not identified despite investigation. Patients with acquired von Willebrand syndrome or those for whom the GI bleeding was due to another cause were excluded. Forty-eight patients from 18 centres in 10 countries were recruited. Seven individuals had a family history of GI bleeding and all VWD types except 2N were represented. Angiodysplasia was confirmed in 38%, with video capsule endoscopy and GI tract endoscopies being the most common methods of making the diagnosis. Recurrent GI bleeding in VWD is associated with significant morbidity and required hospital admission on up to 30 occasions. Patients were treated with multiple pharmacological agents with prophylactic von Willebrand factor concentrate being the most efficient in preventing recurrence of the GI bleeding. The diagnosis and treatment of recurrent GI bleeding in congenital VWD remains challenging and is associated with significant morbidity. Prophylactic treatment with von Willebrand factor concentrate was the most effective method of preventing recurrent bleeding but its efficacy remains to be confirmed in a prospective study.

Measurement of phenotype and absolute number of circulating heparin-binding hemagglutinin, ESAT-6 and CFP-10, and purified protein derivative antigen-specific CD4 T cells can discriminate active from latent tuberculosis infection.

The tuberculin skin test (TST) and interferon gamma (IFN-γ) release assays (IGRAs) are used as adjunctive tests for the evaluation of suspected cases of active tuberculosis (TB). However, a positive test does not differentiate latent from active TB. We investigated whether flow cytometric measurement of novel combinations of intracellular cytokines and surface makers on CD4 T cells could differentiate between active and latent TB after stimulation with Mycobacterium tuberculosis-specific proteins. Blood samples from 60 patients referred to the Singapore Tuberculosis Control Unit for evaluation for active TB or as TB contacts were stimulated with purified protein derivative (PPD), ESAT-6 and CFP-10, or heparin-binding hemagglutinin (HBHA). The CD4 T cell cytokine response (IFN-γ, interleukin-2 [IL-2], interleukin-17A [IL-17A], interleukin-22 [IL-22], granulocyte-macrophage colony-stimulating factor [GM-CSF], and tumor necrosis factor alpha [TNF-α]) and surface marker expression (CD27, CXCR3, and CD154) were then measured. We found that the proportion of PPD-specific CD4 T cells, defined as CD154(+) TNF-α(+) cells that were negative for CD27 and positive for GM-CSF, gave the strongest discrimination between subjects with latent and those with active TB (area under the receiver operator characteristic [ROC] curve of 0.9277; P < 0.0001). Also, the proportions and absolute numbers of HBHA-specific CD4 T cells were significantly higher in those with latent TB infection, particularly CD154(+) TNF-α(+) IFN-γ(+) IL-2(+) and CD154(+) TNF-α(+) CXCR3(+). Finally, we found that the ratio of ESAT-6- and CFP-10-responding to HBHA-responding CD4 T cells was significantly different between the two study populations. In conclusion, we found novel markers of M. tuberculosis-specific CD4 cells which differentiate between active and latent TB.

Tumor necrosis factor inhibitor therapy and myocardial infarction risk in patients with psoriasis, psoriatic arthritis, or both.

OBJECTIVES: To stratify MI risk reduction in those treated with a TNF inhibitor for psoriasis only, psoriatic arthritis only, or both psoriasis and psoriatic arthritis. DESIGN: Retrospective cohort study. SETTING: Between January 1, 2004 and November 30, 2010. PARTICIPANTS: At least 3 ICD9 codes for psoriasis (696.1) or psoriatic arthritis (696.0) (without antecedent MI. INTERVENTION: None MAIN OUTCOME MEASURE: Incident MI. RESULTS: When comparing to those not treated with TNF inhibitors (reference group), of those treated with TNF inhibitors: those with psoriasis only (N= 846) had a significant decrease in MI risk (hazard ratio (HR), 0.26; 95% CI, 0.12-0.56); those with psoriatic arthritis only (N= 112) had a non-significant decrease in MI risk (HR, 0.86; 95% CI, 0.28-2.70); those with both psoriasis and psoriatic arthritis (N= 715) had a non-significant decrease in MI risk (HR, 0.76; 95% CI, 0.47-1.24). CONCLUSIONS: In the TNF inhibitor cohort, those with psoriasis only have the strongest association with MI risk reduction, followed by those with psoriatic arthritis only, and then followed by those with both psoriasis and psoriatic arthritis.

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms.

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside analog that, unlike approved anti-human immunodeficiency virus type 1 (HIV-1) nucleoside reverse transcriptase inhibitors, has a 3'-OH and exhibits remarkable potency against wild-type and drug-resistant HIVs. EFdA triphosphate (EFdA-TP) is unique among nucleoside reverse transcriptase inhibitors because it inhibits HIV-1 reverse transcriptase (RT) with multiple mechanisms. (a) EFdA-TP can block RT as a translocation-defective RT inhibitor that dramatically slows DNA synthesis, acting as a de facto immediate chain terminator. Although non-translocated EFdA-MP-terminated primers can be unblocked, they can be efficiently converted back to the EFdA-MP-terminated form. (b) EFdA-TP can function as a delayed chain terminator, allowing incorporation of an additional dNTP before blocking DNA synthesis. In such cases, EFdA-MP-terminated primers are protected from excision. (c) EFdA-MP can be efficiently misincorporated by RT, leading to mismatched primers that are extremely hard to extend and are also protected from excision. The context of template sequence defines the relative contribution of each mechanism and affects the affinity of EFdA-MP for potential incorporation sites, explaining in part the lack of antagonism between EFdA and tenofovir. Changes in the type of nucleotide before EFdA-MP incorporation can alter its mechanism of inhibition from delayed chain terminator to immediate chain terminator. The versatility of EFdA in inhibiting HIV replication by multiple mechanisms may explain why resistance to EFdA is more difficult to emerge.

SAMHD1 has differential impact on the efficacies of HIV nucleoside reverse transcriptase inhibitors.

Sterile alpha motif- and histidine/aspartic acid domain-containing protein 1 (SAMHD1) limits HIV-1 replication by hydrolyzing deoxynucleoside triphosphates (dNTPs) necessary for reverse transcription. Nucleoside reverse transcriptase inhibitors (NRTIs) are components of anti-HIV therapies. We report here that SAMHD1 cleaves NRTI triphosphates (TPs) at significantly lower rates than dNTPs and that SAMHD1 depletion from monocytic cells affects the susceptibility of HIV-1 infections to NRTIs in complex ways that depend not only on the relative changes in dNTP and NRTI-TP concentrations but also on the NRTI activation pathways.

Live birth rates following in vitro fertilization in women with thyroid autoimmunity and/or subclinical hypothyroidism.

OBJECTIVE: To investigate whether the live birth rate following in vitro fertilization (IVF) is affected by thyroid autoimmunity (TAI) and/or subclinical hypothyroidism in subfertile women. DESIGN AND SETTING: Retrospective study in a university infertility clinic. PATIENTS: A total of 627 women without past or current history of thyroid disorder undergoing their first IVF cycle. INTERVENTION: Pre-IVF archived blood serum samples were tested for TAI and thyroid function tests. MAIN OUTCOME MEASURE: Live birth rate. RESULTS: The clinical pregnancy rate, live birth rate and miscarriage rate were similar among women with or without TAI and/or subclinical hypothyroidism using a TSH threshold 4·5 mIU/l. Thyroid autoantibody level did not affect these IVF outcomes. CONCLUSION: The live birth rate and miscarriage rate of women with TAI and/or subclinical hypothyroidism following IVF were not impaired.

Guidance on the dental management of patients with haemophilia and congenital bleeding disorders.

Recommendations for dental preventive strategies and treatment planning were originally developed through consensus meetings by the Scottish Oral Health Group for Medically Compromised Patients and published in 2003 as a Guideline. The United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) Dental Working Party has updated these recommendations following the AGREE II approach (www.agreetrust.org), involving a literature search, a review of national and international guidelines and after seeking the opinions of haemophilia treaters in the United Kingdom by an online survey. Where possible, evidence from the literature is graded according to the 'GRADE' system (www.bcshguidelines.com/bsch_process/evidence_levels_and_grades_of_recommendations/43_grade.html); however, overall there is a lack of robust data and most studies have methodological limitations. The objective of this guidance, which is largely consensus-based, is to assist dental practitioners in primary and secondary care to provide routine dental care for patients of all ages with congenital bleeding diatheses in order to improve overall access to dental care. The guidance may not be appropriate in all cases and individual patient circumstances may dictate an alternative approach. Date for guideline review: May 2016.