Immune checkpoint inhibitor-induced Type 1 diabetes: a systematic review and meta-analysis.

AIM: To conduct a systematic review and meta-analysis to understand the timing and factors associated with anti-programmed cell death protein-1 (PD-1)/anti-programmed cell death protein-1 ligand (PD-L1) inhibitor-induced Type 1 diabetes. METHODS: We searched MEDLINE, EMBASE, SCOPUS and Cochrane databases (August 2000-2018) for studies of any design on immune checkpoint inhibitors. A total of 71 cases were reviewed from 56 publications. Comparisons were made using Fisher's exact and Student's t-tests. RESULTS: The mean ± sd age at Type 1 diabetes presentation was 61.7±12.2 years, 55% of cases were in men, and melanoma (53.5%) was the most frequent cancer. The median time to Type 1 diabetes onset was 49 (5-448) days with ketoacidosis in 76% of cases. The average ± sd HbA1c concentration was 62 ± 0.3 mmol/mol (7.84±1.0%) at presentation. All cases had insulin deficiency and required permanent exogenous insulin treatment. Half of the cases had Type 1 diabetes-associated antibodies at presentation, and those with antibodies had a more rapid onset (P=0.005) and higher incidence of diabetic ketoacidosis (P=0.02) compared to people without antibodies. CONCLUSIONS: Many people developed Type 1 diabetes within 3 months of initial PD-1/PD-L1 inhibitor exposure. People presenting with Type 1 diabetes-associated antibodies had a more rapid onset and higher incidence of ketoacidosis than those without antibodies. Healthcare providers caring for people receiving these state-of-the-art therapies need to be aware of this potential severe adverse event.

Validation of a rapid type 1 diabetes autoantibody screening assay for community-based screening of organ donors to identify subjects at increased risk for the disease.

The Network for Pancreatic Organ donors with Diabetes (nPOD) programme was developed in response to an unmet research need for human pancreatic tissue obtained from individuals with type 1 diabetes mellitus and people at increased risk [i.e. autoantibody (AAb)-positive] for the disease. This necessitated the establishment of a type 1 diabetes-specific AAb screening platform for organ procurement organizations (OPOs). Assay protocols for commercially available enzyme-linked immunosorbent assays (elisas) determining AAb against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA-2A) and zinc transporter-8 (ZnT8A) were modified to identify AAb-positive donors within strict time requirements associated with organ donation programmes. These rapid elisas were evaluated by the international islet AAb standardization programme (IASP) and used by OPO laboratories as an adjunct to routine serological tests evaluating donors for organ transplantation. The rapid elisas performed well in three IASPs (2011, 2013, 2015) with 98-100% specificity for all three assays, including sensitivities of 64-82% (GADA), 60-64% (IA-2A) and 62-68% (ZnT8A). Since 2009, nPOD has screened 4442 organ donors by rapid elisa; 250 (5·6%) were identified as positive for one AAb and 14 (0.3%) for multiple AAb with 20 of these cases received by nPOD for follow-up studies (14 GADA+, two IA-2A(+) , four multiple AAb-positive). Rapid screening for type 1 diabetes-associated AAb in organ donors is feasible, allowing for identification of non-diabetic, high-risk individuals and procurement of valuable tissues for natural history studies of this disease.

Similar biological activity in skin prick test for Oralair® (8200 BAU) and Grazax® (6200 BAU) reinforces effective SLIT dosing level.

In Europe, allergen extracts are standardized based on skin prick wheal size in 20-30 allergic subjects. To understand the biological activity of clinically effective Sublingual immunotherapy, we used this method to determine the biological activity of solution and tablet Timothy grass pollen (TIM) extracts, compared to an FDA-approved extract (Reference) of 10 000 BAU/ml. Blinded, quadruplicate skin prick tests with concentrate and three serial half-log dilutions allowed the construction of a semilogarithmic regression line per extract. Bioequivalent allergy units (BAU) values were obtained from the comparison with reference. Extracts and dilutions showed a neat linear dose response (all: R2 > 0.98) in 33 rhinitis patients. Relative potencies: Staloral® 12 000 BAU/ml, Soluprick® 10 300 BAU/ml, Oralair® 8200 BAU, and Grazax® 6200 BAU. Even though all extract concentrates differed in wheal size (P = 0.01-0.001), Grazax® producing a 25% smaller wheal size than Oralair® , and the biological activity of these clinically effective TIM tablets led in the same range (6200-8200 BAU; 0.92-1.23 cm2 ). SLIT dose-finding studies for other pollens might start with allergen extracts producing 1.1 cm2 wheal surface.

An experimental study on the influence of trace impurities on ionization of atmospheric noble gas dielectric barrier discharges.

While the influence of trace impurities in noble gas discharges is well established in theoretical work, experimental approaches are difficult. Particularly the effects of trace concentrations of N2 on He discharges are complicated to investigate due to the fact that for He 5.0 the purity of He is only 99.999%. This corresponds to a residual concentration of 10 ppm, thereof 3 ppm of N2, in He. Matters are made difficult by the fact that He DBD plasmajets are normally operated under an ambient atmosphere, which has a high abundance of N2. This work tackles these problems from two sides. The first approach is to operate a DBD plasmajet under a quasi-controlled He atmosphere, therefore diminishing the effect of atmospheric N2 and making a defined contamination with N2 possible. The second approach is using Ar as the operating gas and introducing propane (C3H8) as a suitable substitute impurity like N2 in He. As will be shown both discharges in either He or Ar, with their respective impurity show the same qualitative behaviour.

Objectifying the conjunctival provocation test: photography-based rating and digital analysis.

BACKGROUND: Patients with allergic rhinoconjunctivitis are susceptible to both nasal and ocular symptoms. The conjunctival provocation test (CPT) is an established diagnostic procedure used in allergic rhinoconjunctivitis, particularly to document a patient's current reactivity to allergens. To date, there are no international guidelines defining the CPT. No approved evaluation method exists for interpreting CPT results. This paper aims to establish the digital analysis of macroimages as an objective, validated and standardized method for interpreting CPT results. METHODS: In a clinical immunotherapy trial with 155 patients, treatment progress was documented based on the CPT. Local investigators used a symptom score to grade tearing, reddening and the patients' subjective perception of symptoms (mucosal irritation). A central observer rated conjunctival hyperemia via digital photography. Digital image analysis software was utilized to determine conjunctival hyperemia. RESULTS: Spearman's correlation between the local investigators' and the central observer's ratings was r = 0.729 (p < 0.001); the percentage of total agreement was 48% (based on 739 photos). Digital image analysis (based on 48 photos) had a high percentage of total agreement with the central observer's ratings (69%) but a low percentage of total agreement with the investigators' ratings (38%). The corresponding correlations were r = 0.264 and 0.064, respectively. CONCLUSION: Photography-based rating by a central observer may represent a valuable supplement to the local investigator's assessment for making an objective evaluation of CPT results. Digital image analysis possesses the potential of being an objective evaluation method compared to the wide-spread subjective evaluation by the investigators.

Spin-coating process evolution and reproducibility for power-law fluids.

A distinct development of an exact analytical solution for power-law fluids during the spin-coating process is presented for temporal and spatial thickness evolution, after steady state conditions are attained. This solution leads to the definition of a characteristic time, related to the memory of the initial thickness profile. Previously obtained experimental data, for several rotation speeds and carboxymetilcellulose concentrations in water, are quantitatively analyzed through the evaluation of their characteristic times and compared with theoretical predictions, thus allowing better understanding of thickness profile evolution and of process reproducibility.

Teplizumab treatment may improve C-peptide responses in participants with type 1 diabetes after the new-onset period: a randomised controlled trial.

AIMS/HYPOTHESIS: Type 1 diabetes results from a chronic autoimmune process continuing for years after presentation. We tested whether treatment with teplizumab (a Fc receptor non-binding anti-CD3 monoclonal antibody), after the new-onset period, affects the decline in C-peptide production in individuals with type 1 diabetes. METHODS: In a randomised placebo-controlled trial we treated 58 participants with type 1 diabetes for 4-12 months with teplizumab or placebo at four academic centres in the USA. A central randomisation centre used computer generated tables to allocate treatments. Investigators, patients, and caregivers were blinded to group assignment. The primary outcome was a comparison of C-peptide responses to a mixed meal after 1 year. We explored modification of treatment effects in subgroups of patients. RESULTS: Thirty-four and 29 subjects were randomized to the drug and placebo treated groups, respectively. Thirty-one and 27, respectively, were analysed. Although the primary outcome analysis showed a 21.7% higher C-peptide response in the teplizumab-treated group (0.45 vs 0.371; difference, 0.059 [95% CI 0.006, 0.115] nmol/l) (p = 0.03), when corrected for baseline imbalances in HbA(1c) levels, the C-peptide levels in the teplizumab-treated group were 17.7% higher (0.44 vs 0.378; difference, 0.049 [95% CI 0, 0.108] nmol/l, p = 0.09). A greater proportion of placebo-treated participants lost detectable C-peptide responses at 12 months (p = 0.03). The teplizumab group required less exogenous insulin (p < 0.001) but treatment differences in HbA(1c) levels were not observed. Teplizumab was well tolerated. A subgroup analysis showed that treatment benefits were larger in younger individuals and those with HbA(1c) <6.5% at entry. Clinical responders to teplizumab had an increase in circulating CD8 central memory cells 2 months after enrolment compared with non-responders. CONCLUSIONS/INTERPRETATIONS: This study suggests that deterioration in insulin secretion may be affected by immune therapy with teplizumab after the new-onset period but the magnitude of the effect is less than during the new-onset period. Our studies identify characteristics of patients most likely to respond to this immune therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00378508 FUNDING: This work was supported by grants 2007-502, 2007-1059 and 2006-351 from the JDRF and grants R01 DK057846, P30 DK20495, UL1 RR024139, UL1RR025780, UL1 RR024131 and UL1 RR024134 from the NIH.

Optical monitoring for power law fluids during spin coating.

Optical monitoring is applied, in situ and in real time, to non-newtonian, power law fluids in the spin coating process. An analytical exact solution is presented for thickness evolution that well fits to most measurement data. As result, typical rheological parameters are obtained for several CMC (carboximetilcelullose) concentrations and rotation speeds. Optical monitoring thus precisely indicates applicability of the model to power law fluids under spin coating.

Traumatic wound microbiome workshop.

On May 9-10, 2011, the Walter Reed Army Institute of Research, as the Army Center of Excellence for Infectious Disease, assembled over a dozen leaders in areas related to research into the communities of microorganisms which colonize and infect traumatic wounds. The objectives of the workshop were to obtain guidance for government researchers, to spur research community involvement in the field of traumatic wound research informed by a microbiome perspective, and to spark collaborative efforts serving the Wounded Warriors and similarly wounded civilians. During the discussions, it was made clear that the complexity of these infections will only be met by developing a new art of clinical practice that engages the numerous microbes and their ecology. It requires the support of dedicated laboratories and technologists who advance research methods such as community sequencing, as well as the kinds of data analysis expertise and facilities. These strategies already appear to be bearing fruit in the clinical management of chronic wounds. There are now funding announcements and programs supporting this area of research open to extramural collaborators.

Small-angle neutron scattering by spatially inhomogeneous ferromagnets with a nonzero average uniaxial anisotropy.

Micromagnetic small-angle neutron scattering theory is well established for analyzing spin-misalignment scattering data of bulk ferromagnets. Here, this theory is extended to allow for a global uniaxial magnetic anisotropy (texture) of the material, in addition to the already included random zero-average local anisotropy. Macroscopic cross sections and spin-misalignment response functions are computed analytically for several practically relevant mutual anisotropy and external magnetic field orientations in both parallel and perpendicular scattering geometries for field magnitudes both above and below the rotational saturation. Some of these expressions are tested on published experimental data of magnetic-field-annealed Vitroperm and plastically deformed Ni, allowing determination of the corresponding global uniaxial anisotropy quality factors.

Magnetic order and disorder environments in superantiferromagnetic [Formula: see text] nanoparticles.

Magnetic nanoparticles exhibit two different local symmetry environments, one ascribed to the core and one corresponding to the nanoparticle surface. This implies the existence of a dual spin dynamics, leading to the presence of two different magnetic arrangements governed by different correlation lengths. In this work, two ensembles of [Formula: see text] nanoparticles with mean sizes of 18 nm and 13 nm have been produced to unravel the magnetic couplings established among the magnetic moments located within the core and at the nanoparticle surface. To this end, we have combined neutron diffraction measurements, appropriate to investigate magnetically-ordered spin arrangements, with time-dependent macroscopic AC susceptibility measurements to reveal memory and aging effects. The observation of the latter phenomena are indicative of magnetically-frustrated states. The obtained results indicate that, while the [Formula: see text] magnetic moments located within the nanoparticle core keep the bulk antiferromagnetic commensurate structure in the whole magnetic state, the correlations among the surface spins give rise to a collective frustrated spin-glass phase. The interpretation of the magnetic structure of the nanoparticles is complemented by specific-heat measurements, which further support the lack of incommensurability in the nanoparticle state.

Neutron spin-flip scattering of nanocrystalline cobalt.

We report results of longitudinal (one-dimensional) neutron polarization analysis on polycrystalline bulk Co with an average crystallite size of D = 10 nm. The spin-flip small-angle neutron scattering (SANS) data are analyzed in the approach-to-saturation regime within the framework of micromagnetic theory. In particular, we provide a closed-form expression for the spin-flip SANS cross section [Formula: see text]. From the data analysis, we find a room-temperature value of A = (2.6 ± 0.1) × 10( - 11) J m( - 1) for the exchange-stiffness constant, which agrees well with earlier data.

Autoimmune polyendocrine syndrome type 1 (APS-1) as a model for understanding autoimmune polyendocrine syndrome type 2 (APS-2).

Autoimmune polyendocrine syndromes type 1 and 2 (APS-1 and APS-2) are diverse in regards to their component diseases and immunologic features of pathogenesis. Animal models and human studies highlight the importance of alleles of HLA (human leukocyte antigen)-like molecules determining tissue specific targeting that with the loss of tolerance leads to organ specific autoimmunity. Knowledge of the syndromes and component diseases allows clinicians to recognize and prevent illness prior to morbidity. With the current understanding of the syndromes, a paradigm for diagnosis, screening and treatment can be established. Once genetically susceptible individuals are identified screening for autoantibodies can be performed. Amongst autoantibody positive individuals, monitoring for physiologic decompensation, with a goal of treating prior to morbidity and in some cases mortality, follows. With continued basic and clinical research, therapies aimed at treating the underlying autoimmunity and disease prevention should become possible.

Cervical vasopressin compared with no premedication and blood loss during vaginal hysterectomy: a randomized controlled trial.

OBJECTIVE: To compare blood loss, operative time, postoperative pain medication requirements, and complication rates in patients undergoing vaginal hysterectomy who were randomly assigned to receive preoperative intracervical vasopressin or no intracervical injection. METHODS: Fifty-eight women undergoing vaginal hysterectomy were randomly allocated to receive either eight units of vasopressin intracervically or nothing preoperative from January 2004 to January 2005. A researcher blinded to the study group determined blood loss. The surgeries were performed using uniform steps by senior residents under the direction of two attending surgeons. Multiple preoperative and postoperative values were evaluated, including time to specific points in surgery and use of postoperative pain medication. Independent sample t tests, Fisher exact test, and Pearson chi tests were used to analyze the data. RESULTS: The two groups were similar in terms of age, weight, parity, and ethnicity. There was also no difference in indication for surgery or estimated uterine size. The vasopressin group lost significantly less blood (145.3 mL compared with 266.4 mL control; P=.022). There was a significant difference in the increase in mean blood pressure at 5 minutes after injection (10.4 for the vasopressin group compared with. 2.5 for the control group, P=.043). There was no significant difference in immediate recovery room morphine requirements, but patient-controlled anesthesia usage was significantly higher in the vasopressin group. CONCLUSION: The preoperative injection of intracervical vasopressin leads to decreased blood loss during vaginal hysterectomy. There was, however, a significant increase in postoperative morphine use in patients receiving vasopressin. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00799292 LEVEL OF EVIDENCE: I.

Electrical generators driving microhollow and dielectric barrier discharges applied for analytical chemistry.

Scaling down the size of plasma discharges would reduce the amount of gases, liquids, and consumables required, which in turn would decrease the operating costs. Nevertheless, the application of a specialized plasma generator for microhollow cathode discharges (MHCD) and dielectric barrier discharges are driven with commercially available power sources. Those generators are bulky and expensive and their overall efficiency is poor. This work develops and explains several circuit topologies and design hints to excite MHCD and dielectric barrier discharge (DBD) plasmas with respect to its system with as low as possible input power in a very efficient way. Benefits in sensitivity and life expectancy are shown. The generator for the MHCD needs voltages up to 7 V and consumes up to 5 W. The DBD generator has an input power of 3 W and produces a fast rising output pulse up to 9 kV, which has a time duration of 2 micros. These low-power circuits offer the operation with batteries.

Grain-boundary-induced spin disorder in nanocrystalline gadolinium.

Based on experimental magnetic-field-dependent neutron scattering data, we have calculated the autocorrelation function of the spin misalignment of nanocrystalline (160)gadolinium. The analysis suggests the existence of two characteristic length scales in the spin system: the smaller one is about 5 nm and is attributed to the defect cores of the grain boundaries, whereas the larger length scale is of the order of the average crystallite size D = 21 nm and presumably describes the response of the magnetization to the magnetic anisotropy field of the individual crystallites.

Differences of venous thromboembolic risks in vascular general and trauma surgery patients.

AIM: Venous thromboembolism (VTE) is a common complication in patients undergoing surgery. The risk for VTE is determined by the combination of individual predisposing factors and features of the specific type of surgery. Although the knowledge about VTE has increased enormously during the last years VTE-prophylaxis is still inadequate. The goals of our study were to assess the correctness of the adjusted pharmacological prophylaxis, and the difference of the VTE-risks in the different surgical departments. METHODS: During a three months period, 451 patients were prospective included. These patients were admitted to the Departments of Vascular and General Surgery and of Traumatology of our hospital. Based on the modified Hertfelder's VTE-risk-assessment model, we scored the patients and categorized them into 4 groups: low, moderate, high and very high risk for VTE. We enrolled every admitted patient taking their medical history and reviewing medical documents. RESULTS: The mean cumulative risk value for VTE-risk was 3.68 (median 3.5, minimum: 0, maximum: 13 and standard deviation: 2.206), whereas 20.2% of our patients had a low, 27.2% middle, 21.7% high and 30.9% very high risk. The patients with vascular procedures had significantly higher mean value (5.03, SD 2.2) than the patients with general operations (3.6, SD 2.2) and those who underwent traumatology (3.06, SD 1,8) (P value <0.001). The majority of patients (n=356), (78.9%) received VTE-prophylaxis with low dose of low molecular weight heparin (LMWH). Of the remaining patients, 40 (8.9%) received therapeutic dose and 55 (12.2%) received none VTE-prophylaxis. CONCLUSION: The VTE-risk for surgical patients remains high, despite all efforts for prophylaxis. The main reason may be that risk-assessment is time consuming and not standardized. We demonstrated that VTE-risk for patients in vascular surgery is significantly higher than the VTE-risk for patients in general and trauma surgery. We also showed that the VTE-risk in some patients was underestimated and prophylaxis was inadequate. Therefore, it is recommended to emphasize more on short risk-assessment, adequate prophylaxis and optimal dosage in order to prevent deep venous thrombosis and embolism disease.

Fluoride Ion Release of Self-Adhesive Resin Cements and Their Potential to Inhibit In Situ Enamel and Dentin Demineralization.

OBJECTIVE: This study evaluated in situ the potential of a glass ionomer and self-adhesive resin cements to inhibit enamel and dentin demineralization around indirect restorations exposed to cariogenic challenge. The cumulative fluoride release (CFR) of materials was measured in water and acid. METHODS: Seventy blocks cut from human molars received two indirect composite restorations (one in enamel and another in dentin) luted with Ketac Cem EasyMix (GIC, positive control), SeT (SeT), Maxcem Elite (Max), Smart Cem2 (Smart), and RelyX Unicem 2 (Unicem2). Fourteen volunteers wore palatal appliances containing five blocks exposed to a cariogenic challenge (20% sucrose solution, eight times per day, seven days). Knoop microhardness (KH) at two distances from the margins and three depths from the outer surface determined enamel and dentin demineralization. Disc-shape specimens of materials were immersed in daily-replaced deionized water or lactic acid solutions. KH and CFR data were analyzed by analysis of variance, Games-Howell test, and Tukey test (α=0.05). RESULTS: The overall KH ranking was GIC > SeT > Max > Smart = Unicem2 in both enamel and dentin (">" means p<0.05). SeT was the only resin cement that resulted in enamel and dentin KH comparable to that of GIC at most distances and depths. In water, CFR rank of materials was GIC > SeT = Max > Smart = Unicem2. In acid, the rank was similar, except that Set was significantly superior to Max. CONCLUSION: SeT inhibited demineralization in enamel and dentin quite comparably to GIC. All resin cements released lower cumulative amounts of fluoride than the glass ionomer cement.

Characterization of protein tyrosine kinases from human breast cancer: involvement of the c-src oncogene product.

Tyrosine phosphorylation is an important regulatory mechanism in response to the action of growth factors and oncogenes. Since many oncogenes code for tyrosine kinases, increased or altered oncogene expression may be reflected in increased tyrosine kinase activity. In a recent study (Hennipman et al., Cancer Res., 49: 516-521, 1989), we found that the tyrosine kinase activity of the cytosolic and membrane fractions of malignant human breast tissue was significantly higher compared to the benign or the normal breast tissue. Moreover, the increase in the cytosolic fractions was found to be of prognostic value. In the present study we determined the protein tyrosine kinase (PTK) activity of another 72 breast cancer specimens, and it could be shown again that the PTK activity in all 72 of these tumors was elevated compared to normal controls. We characterized these cytosolic PTKs by anion exchange chromatography using fast protein liquid chromatography, and it could be shown that at least two different forms of PTK exist. Using antibodies against a number of known oncogene products, we could determine that at least 70% of the PTK activity in the cytosol originated from the presence of the c-src oncogene product. Both of the PTK activity peaks seen in the fast protein liquid chromatography patterns could be precipitated with the anti-Src antibody. Furthermore, using the MCF-7 breast cancer cell line, it could be shown that the antibody against c-src also precipitated a part of the cytosolic PTK activity. In normal human peripheral lymphocytes, no precipitation of the cytosolic and membrane PTK activity could be achieved using the anti-Src antibody. Inasmuch as the cytosolic PTK activity parallels the malignancy in breast tumors (Hennipman et al., Cancer Res., 49: 516-521, 1989), and the majority of this activity is precipitated by anti-Src antibodies, the c-src protooncogene may play a key role in the manifestation of breast cancer.

Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms.

UNLABELLED: Essentials von Willebrand factor (VWF) and factor VIII (FVIII) levels are modulated by age and ABO status. The effect of aging and ABO blood type on VWF and FVIII was assessed in 207 normal individuals. Aging and ABO blood type showed combined and bidirectional influences on VWF and FVIII levels. Aging and ABO blood type influence VWF levels through both secretion and clearance mechanisms. SUMMARY: Background The effect of aging and ABO blood type on plasma levels of von Willebrand factor (VWF) and factor VIII (FVIII) have been widely reported; however, a comprehensive analysis of their combined effect has not been performed and the mechanisms responsible for the age-related changes have not been determined. Objectives To assess the influence of aging and ABO blood type on VWF and FVIII levels, and to evaluate the contribution of VWF secretion and clearance to the age-related changes. Methods A cross-sectional observational study was performed in a cohort of 207 normal individuals, whose levels of VWF, FVIII, VWF propeptide (VWFpp), VWFpp/VWF:Ag ratio and blood type A antigen content on VWF (A-VWF) were quantified. Results Aging and ABO blood type exerted interrelated effects on VWF and FVIII plasma levels, because the age-related increase in both proteins was significantly higher in type non-O individuals (ß = 0.011 vs. 0.005). This increase with age in non-O subjects drove the differences between blood types in VWF levels, as the mean difference increased from 0.13 U/mL in the young to 0.57 U/mL in the old. Moreover, A-VWF was associated with both VWF antigen (ß = 0.29; 95% confidence interval [CI], 0.09, 0.50) and VWF clearance (ß = -0.15; 95% CI, -0.25, -0.06). We also documented an effect of ABO blood type on VWF secretion with aging, as old individuals with blood type non-O showed higher levels of VWFpp (mean difference 0.29 U/mL). Conclusions Aging and ABO blood type have an interrelated effect on VWF and FVIII levels, where the effect of one is significantly influenced by the presence of the other.