A retrospective study on use of palliative care for patients with alcohol related end stage liver disease in United States.

BACKGROUND: Palliative care (PC) has been shown to be beneficial in end stage liver disease (ESLD), yet the hospitalization data for PC utilization is unknown. AIM: To identify the trend of PC utilization for the special population of alcohol-associated ESLD patients, factors affecting its use and ascertain its impact on healthcare utilization. METHODS: We analyzed around 78 million discharges from the 2007-2014 national inpatient sample and 2010-2014 national readmission database including adult patients admitted for decompensated alcohol-associated cirrhosis. We identified patients with PC consultation as a secondary diagnosis. Odds ratios (OR) and means were adjusted for confounders using multivariate regression analysis models. RESULTS: Out of the total 1421849 hospitalizations for decompensated liver cirrhosis, 62782 (4.4%) hospitalizations had a PC consult, which increased from 0.8% (1258) of all alcohol-associated ESLD hospitalizations in 2007 to 6.6% in 2014 (P < 0.01). Patient and hospital characteristics associated with increased odds of PC utilization were advanced age, lower income, Medicaid coverage, teaching institution, urban location, length of stay > 3 d, prolonged ventilation, and administration of total parenteral nutrition (all P < 0.01). Palliative encounters in alcohol-associated ESLD and acute-on-chronic liver failure (ACLF) score were associated with increased odds of discharge to a rehabilitation facility, but significantly lower odds of 30-d readmissions (aOR: 0.35, 95%CI: 0.31-0.41), lower total hospitalization charges and lower mean hospitalization days (all P < 0.01). CONCLUSION: Inpatient PC is sparingly used for patients with decompensated alcohol related liver disease, however it has increased over the past decade. PC consultation is associated with lower 30-d readmission rates on multivariate analysis, and lower hospitalization cost and length of stay in patients with ACLF score ≥ 2.

Integrating skeletal anchorage into fixed and aligner biomechanics.

Routine alignment with fixed appliances and aligners is indeterminate mechanics because equilibrium equations are only applicable to two abutments: teeth, segments, or arches. Orthodontists must depend on compliance and resilience of materials (archwires and aligners) for initial alignment. However, stabilized segments and arches are "large multirooted teeth" that can be moved with determinate mechanics using temporary skeletal anchorage devices. Temporary skeletal anchorage devices have advanced from retromolar implants and inter-radicular miniscrews to extra-alveolar bone screws placed in the basilar bone buccal to the first molars: mandibular buccal shelf and infrazygomatic crest. Extra-alveolar anchorage is determinate mechanics to move teeth, segments, and arches. Retraction and rotation of the lower arch reverses the etiology of Class III open bite malocclusion to correct severe skeletal dysplasia with no extractions or orthognathic surgery.

Success of infrazygomatic crest bone screws: patient age, insertion angle, sinus penetration, and terminal insertion torque.

INTRODUCTION: The aim of this study was to assess the 6-month survival (success) rate for infrazygomatic crest (IZC) bone screws relative to patient age, insertion angle, sinus penetration, and terminal insertion torque. METHODS: One hundred consecutive patients (27 males, 73 females; mean age 25.8 years; age range, 11.0-53.8 years) received IZC temporary anchorage devices (TADs) bilaterally (n = 200). Each TAD was routinely loaded with up to 14 oz (397 g or 389 cN), reactivated monthly, and followed for 6 months. Terminal insertion torque was measured, and radiographs were assessed to determine the length of the TAD engaged in bone and depth of penetration into the maxillary sinus. RESULTS: Compared with nonpenetrating IZC TADs, the mean results for the 96 (48%) TADs that did penetrate the sinus were: 3.23 mm of sinus penetration, 21.3% decrease in terminal insertion torque, and 31.5% less bone contact at the TAD osseous interface. Perforation prevalence increased with age from 35.7% (11-19 years) to 62.5% (>30 years) (P <0.01). Terminal insertion torque increased from 11-19 years to 20-29 years because of increasing bone density with age but then decreased at >30 years because of increased incidence of sinus penetration (P <0.05). Sinus penetration had no significant effect on IZC TAD survival. About 5% of the devices did fail when the final insertion torque was significantly (P <0.05) decreased to 7.37 N-cm compared with the mean torque of 11.63 N-cm for successful TADs. CONCLUSIONS: Both sinus perforation and IZC bone quality increased with age. Sinus penetration did not significantly affect the 6 month survival rate of IZC TADs because the loss of bone quantity at the interface was offset by the age-related increase in bone quality at the IZC site.

Orthodontic bone screws: A quick update and its promising future.

Orthodontic bone screws (OBSs) provide intraoral anchorage by penetrating oral mucosa and seating firmly in basilar bone (BB). Retromolar (prosthetic-type) implants introduced the extra-alveolar (E-A) concept for BB anchorage to move teeth throughout the alveolar process, but the clinical procedures were complex and expensive. Titanium alloy (Ti) miniscrews placed in inter-radicular (I-R) alveolar bone are more convenient and provide some tooth movement potential, but multiple screws are usually required and the devices often interfere with the path of tooth movement. The advantages of BB anchorage and the convenience of miniscrew are combined into the E-A OBS system. These miniscrews are relatively large in diameter (2 mm), and strong (stainless steel), which are placed intraorally in the BB of the infra-zygomatic crest (IZC) and mandibular buccal shelf (MBS). E-A OBSs provide osseous anchorage to retract the dentition and/or rotate either arch. Recovery of impactions is effectively managed with lever arm springs anchored with IZC or MBS bone screws. An emerging frontier is BB anchorage for correcting severe malocclusions with clear aligners. Since the osseous-anchored mechanics are complementary, fixed appliances and clear aligners can be used individually or in tandem to resolve a broad variety of malocclusions. This report summarizes current concepts for conservatively managing complex malocclusions such as severe crowding, skeletal discrepancies, asymmetries and impactions with the OBS system.

A fast and scalable framework for large-scale and ultrahigh-dimensional sparse regression with application to the UK Biobank.

The UK Biobank is a very large, prospective population-based cohort study across the United Kingdom. It provides unprecedented opportunities for researchers to investigate the relationship between genotypic information and phenotypes of interest. Multiple regression methods, compared with genome-wide association studies (GWAS), have already been showed to greatly improve the prediction performance for a variety of phenotypes. In the high-dimensional settings, the lasso, since its first proposal in statistics, has been proved to be an effective method for simultaneous variable selection and estimation. However, the large-scale and ultrahigh dimension seen in the UK Biobank pose new challenges for applying the lasso method, as many existing algorithms and their implementations are not scalable to large applications. In this paper, we propose a computational framework called batch screening iterative lasso (BASIL) that can take advantage of any existing lasso solver and easily build a scalable solution for very large data, including those that are larger than the memory size. We introduce snpnet, an R package that implements the proposed algorithm on top of glmnet and optimizes for single nucleotide polymorphism (SNP) datasets. It currently supports ℓ1-penalized linear model, logistic regression, Cox model, and also extends to the elastic net with ℓ1/ℓ2 penalty. We demonstrate results on the UK Biobank dataset, where we achieve competitive predictive performance for all four phenotypes considered (height, body mass index, asthma, high cholesterol) using only a small fraction of the variants compared with other established polygenic risk score methods.

Components of genetic associations across 2,138 phenotypes in the UK Biobank highlight adipocyte biology.

Population-based biobanks with genomic and dense phenotype data provide opportunities for generating effective therapeutic hypotheses and understanding the genomic role in disease predisposition. To characterize latent components of genetic associations, we apply truncated singular value decomposition (DeGAs) to matrices of summary statistics derived from genome-wide association analyses across 2,138 phenotypes measured in 337,199 White British individuals in the UK Biobank study. We systematically identify key components of genetic associations and the contributions of variants, genes, and phenotypes to each component. As an illustration of the utility of the approach to inform downstream experiments, we report putative loss of function variants, rs114285050 (GPR151) and rs150090666 (PDE3B), that substantially contribute to obesity-related traits and experimentally demonstrate the role of these genes in adipocyte biology. Our approach to dissect components of genetic associations across the human phenome will accelerate biomedical hypothesis generation by providing insights on previously unexplored latent structures.

Failure rates for stainless steel versus titanium alloy infrazygomatic crest bone screws: A single-center, randomized double-blind clinical trial.

OBJECTIVES: To compare failure rates for stainless steel (SS) and titanium alloy (TiA) bone screws (BSs) placed in the infrazygomatic crest (IZC). MATERIALS AND METHODS: A total of 386 consecutive patients (76 male, 310 female; mean age 24.3 years, range 10.3-59.4 years) received IZC BSs (SS or TiA) via a double-blind, split-mouth design. BSs penetrated attached gingiva (AG) or moveable mucosa (MM) with 5 mm of soft tissue clearance. All BSs were immediately loaded and reactivated monthly with ≤14 oz (397 g or 389 cN) applied directly to the upper archwire bilaterally for 6 months to retract the maxilla to correct Class II or bimaxillary protrusion. RESULTS: Of the 772 devices, there were 49 (6.3%) failures: 27 SS (7.0%) and 22 TiA (5.7%). The 1.3% difference was not statistically significant ( P = .07). There was no significant relationship between SS or TiA failures relative to (1) right vs left side, (2) unilateral vs bilateral, or (3) age at failure. Significantly ( P < .05) increased failure rates were noted for SS screws in only two subgroups: AG site (7.4%) and right side (7.8%). Unilateral failure occurred in 21 patients (5.4%), and bilateral failures occurred in 14 of the total 772 patients (1.8%). CONCLUSIONS: The overall success rate of 93.7% indicates that both SS and TiA are clinically acceptable for IZC BSs.

Severe unilateral scissors-bite with a constricted mandibular arch: Bite turbos and extra-alveolar bone screws in the infrazygomatic crests and mandibular buccal shelf.

A 33-year-old woman had a chief complaint of difficulty chewing, caused by a constricted mandibular arch and a unilateral full buccal crossbite (scissors-bite or Brodie bite). She requested minimally invasive treatment but agreed to anchorage with extra-alveolar temporary anchorage devices as needed. Her facial form was convex with protrusive but competent lips. Skeletally, the maxilla was protrusive (SNA, 86°) with an ANB angle of 5°. Amounts of crowding were 5 mm in the mandibular arch and 3 mm in the maxillary arch. The mandibular midline was deviated to the left about 2 mm, which was consistent with a medially and inferiorly displaced mandibular right condyle. Ectopic eruption of the maxillary right permanent first molar to the buccal side of the mandibular first molar cusps resulted in a 2-mm functional shift of the mandible to the left, which subsequently developed into a full buccal crossbite on the right side. Treatment was a conservative nonextraction approach with passive self-ligating brackets. Glass ionomer bite turbos were bonded on the occlusal surfaces of the maxillary left molars at 1 month into treatment. An extra-alveolar temporary anchorage device, a 2 × 12-mm OrthoBoneScrew (Newton A, HsinChu City, Taiwan), was inserted in the right mandibular buccal shelf. Elastomeric chains, anchored by the OrthoBoneScrew, extended to lingual buttons bonded on the lingually inclined mandibular right molars. Cross elastics were added as secondary uprighting mechanics. The maxillary right bite turbos were reduced at 4 months and removed 1 month later. At 11 months, bite turbos were bonded on the lingual surfaces of the maxillary central incisors, and an OrthoBoneScrew was inserted in each infrazygomatic crest. The Class II relationship was resolved with bimaxillary retraction of the maxillary arch with infrazygomatic crest anchorage and intermaxillary elastics. Interproximal reduction was performed to correct the black interdental spaces and the anterior flaring of the incisors. The scissors-bite and lingually inclined mandibular right posterior segment were sufficiently corrected after 3 months of treatment to establish adequate intermaxillary occlusion in the right posterior segments to intrude the maxillary right molars. The anterior bite turbos opened space for extrusion of the posterior teeth to level the mandibular arch, and the infrazygomatic crest bone screws anchored the retraction of the maxillary arch. In 27 months, this difficult malocclusion, with a Discrepancy Index score of 25, was treated to a Cast-Radiograph Evaluation score of 22 and a pink and white esthetic score of 3.

Extra-Alveolar Bone Screws for Conservative Correction of Severe Malocclusion Without Extractions or Orthognathic Surgery.

PURPOSE OF REVIEW: Evaluate management of challenging malocclusions conservatively (no extractions or orthognathic surgery). RECENT FINDINGS: Most malocclusions have a predominately environmental etiology. Optimal esthetics and function are restored by aligning the dentition over the apical base of bone at the appropriate vertical dimension of occlusion (VDO). Extra-alveolar (E-A) anchorage is achieved at three intraoral sites: mandibular buccal shelf (MBS), infrazygomatic crest (IZC), and anterior ramus. MBS and IZC bone screws effectively anchor the conservative correction of severe dental and skeletal malocclusions. All bone screw sites are effective for anchoring lever arms to recover impacted teeth. Rather than extracting teeth, E-A anchorage corrects crowding by retracting the posterior segments to increase arch length. Skeletal malocclusion is corrected by aligning teeth over the apical base of bone and restoring the VDO by retracting and posteriorly rotating the dental arches as segments. Challenging dental and skeletal malocclusions can be treated routinely via determinate mechanics anchored with E-A bone screws.

Medical relevance of protein-truncating variants across 337,205 individuals in the UK Biobank study.

Protein-truncating variants can have profound effects on gene function and are critical for clinical genome interpretation and generating therapeutic hypotheses, but their relevance to medical phenotypes has not been systematically assessed. Here, we characterize the effect of 18,228 protein-truncating variants across 135 phenotypes from the UK Biobank and find 27 associations between medical phenotypes and protein-truncating variants in genes outside the major histocompatibility complex. We perform phenome-wide analyses and directly measure the effect in homozygous carriers, commonly referred to as "human knockouts," across medical phenotypes for genes implicated as being protective against disease or associated with at least one phenotype in our study. We find several genes with strong pleiotropic or non-additive effects. Our results illustrate the importance of protein-truncating variants in a variety of diseases.

Interdisciplinary treatment for a compensated Class II partially edentulous malocclusion: Orthodontic creation of a posterior implant site.

A 36-year-old woman with good periodontal health sought treatment for a compensated Class II partially edentulous malocclusion associated with a steep mandibular plane (SN-MP, 45°), 9 missing teeth, a 3-mm midline discrepancy, and compromised posterior occlusal function. She had multiple carious lesions, a failing fixed prostheses in the mandibular right quadrant replacing the right first molar, and a severely atrophic edentulous ridge in the area around the mandibular left first and second molars. After restoration of the caries, the mandibular left third molar served as anchorage to correct the mandibular arch crowding. The mandibular left second premolar was retracted with a light force of 2 oz (about 28.3 cN) on the buccal and lingual surfaces to create an implant site between the premolars. Modest lateral root resorption was noted on the distal surface of the mandibular left second premolar after about 7 mm of distal translation in 7 months. Six months later, implants were placed in the mandibular left and right quadrants; the spaces were retained with the fixed appliance for 5 months and a removable retainer for 1 month. Poor cooperation resulted in relapse of the mandibular left second premolar back into the implant site, and it was necessary to reopen the space. When the mandibular left fixture was uncovered, a 3-mm deep osseous defect on the distobuccal surface was found; it was an area of relatively immature bundle bone, because the distal aspect of the space was reopened after the relapse. Subsequent bone grafting resulted in good osseous support of the implant-supported prosthesis. The relatively thin band of attached gingiva on the implant at the mandibular right first molar healed with a recessed contour that was susceptible to food impaction. A free gingival graft restored soft tissue form and function. This severe malocclusion with a discrepancy index value of 28 was treated to an excellent outcome in 38 months of interdisciplinary treatment. The Cast-Radiograph Evaluation score was 13. However, the treatment was complicated by routine relapse and implant osseous support problems. Retreatment of space opening and 2 additional surgeries were required to correct an osseous defect and an inadequate soft tissue contour. Orthodontic treatment is a viable option for creating implant sites, but fixed retention is required until the prosthesis is delivered. Bone augmentation is indicated at the time of implant placement to offset expected bone loss. Complex restorative treatment may result in routine complications that are effectively managed with interdisciplinary care.

Epstein-Barr Virus Induces Adhesion Receptor CD226 (DNAM-1) Expression during Primary B-Cell Transformation into Lymphoblastoid Cell Lines.

Epstein-Barr virus (EBV), an oncogenic herpesvirus, infects and transforms primary B cells into immortal lymphoblastoid cell lines (LCLs), providing a model for EBV-mediated tumorigenesis. EBV transformation stimulates robust homotypic aggregation, indicating that EBV induces molecules that mediate cell-cell adhesion. We report that EBV potently induced expression of the adhesion molecule CD226, which is not normally expressed on B cells. We found that early after infection of primary B cells, EBV promoted an increase in CD226 mRNA and protein expression. CD226 levels increased further from early proliferating EBV-positive B cells to LCLs. We found that CD226 expression on B cells was independent of B-cell activation as CpG DNA failed to induce CD226 to the extent of EBV infection. CD226 expression was high in EBV-infected B cells expressing the latency III growth program, but low in EBV-negative and EBV latency I-infected B-lymphoma cell lines. We validated this correlation by demonstrating that the latency III characteristic EBV NF-κB activator, latent membrane protein 1 (LMP1), was sufficient for CD226 upregulation and that CD226 was more highly expressed in lymphomas with increased NF-κB activity. Finally, we found that CD226 was not important for LCL steady-state growth, survival in response to apoptotic stress, homotypic aggregation, or adhesion to activated endothelial cells. These findings collectively suggest that EBV induces expression of a cell adhesion molecule on primary B cells that may play a role in the tumor microenvironment of EBV-associated B-cell malignancies or facilitate adhesion in the establishment of latency in vivo. IMPORTANCE Epstein-Barr virus (EBV) is a common human herpesvirus that establishes latency in B cells. While EBV infection is asymptomatic for most individuals, immune-suppressed individuals are at significantly higher risk of a form of EBV latent infection in which infected B cells are reactivated, grow unchecked, and generate lymphomas. This form of latency is modeled in the laboratory by infecting B cells from the blood of normal human donors in vitro. In this model, we identified a protein called CD226 that is induced by EBV but is not normally expressed on B cells. Rather, it is known to play a role in aggregation and survival signaling of non-B cells in the immune system. Cultures of EBV-infected cells adhere to one another in "clumps," and while the proteins that are responsible for this cellular aggregation are not fully understood, we hypothesized that this form of cellular aggregation may provide a survival advantage. In this article, we characterize the mechanism by which EBV induces this protein and its expression on lymphoma tissue and cell lines and characterize EBV-infected cell lines in which CD226 has been knocked out.

Identification of individuals by trait prediction using whole-genome sequencing data.

Prediction of human physical traits and demographic information from genomic data challenges privacy and data deidentification in personalized medicine. To explore the current capabilities of phenotype-based genomic identification, we applied whole-genome sequencing, detailed phenotyping, and statistical modeling to predict biometric traits in a cohort of 1,061 participants of diverse ancestry. Individually, for a large fraction of the traits, their predictive accuracy beyond ancestry and demographic information is limited. However, we have developed a maximum entropy algorithm that integrates multiple predictions to determine which genomic samples and phenotype measurements originate from the same person. Using this algorithm, we have reidentified an average of >8 of 10 held-out individuals in an ethnically mixed cohort and an average of 5 of either 10 African Americans or 10 Europeans. This work challenges current conceptions of personal privacy and may have far-reaching ethical and legal implications.

Protective Effect of Inflammasome Activation by Hydrogen Peroxide in a Mouse Model of Septic Shock.

OBJECTIVES: To study the effect of a lack of antioxidant defenses during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. SETTING: Laboratory experiments. SUBJECTS: C57Bl6 and glutathione peroxidase 1 knockout mice. INTERVENTION: Murine acute pneumonia model induced by Klebsiella pneumonia. MEASUREMENTS AND MAIN RESULTS: We show here that despite a lack of one of the major antioxidant defense enzymes, glutathione peroxidase 1 knockout mice are protected during lethal pneumonia induced by Klebsiella pneumonia, compared to wild-type mice. Furthermore, this protective effect was suppressed when antioxidant defenses were restored. Infected glutathione peroxidase 1 mice showed an early and significant, albeit transient, increase in the activity of the NOD-like receptor family, pyrin domain containing 3 inflammasome when compared with wild-type mice. The key role of the NOD-like receptor family, pyrin domain containing 3 inflammasome during acute pneumonia was confirmed in vivo when the protective effect was suppressed by treating glutathione peroxidase 1 mice with an interleukin-1 receptor antagonist. Additionally we report, in vitro, that increased concentrations of active caspase-1 and interleukin-1ß are related to an increased concentration of hydrogen peroxide in bacterially infected glutathione peroxidase 1 macrophages and that restoring hydrogen peroxide antioxidant defenses suppressed this effect. CONCLUSIONS: Our findings demonstrate that, contrary to current thinking, an early intervention targeting NOD-like receptor family, pyrin domain containing 3 inflammasome activity induces a timely and efficient activation of the innate immune response during acute infection. Our findings also demonstrate a role for hydrogen peroxide in the mechanisms tightly regulating NOD-like receptor family, pyrin domain containing 3 activation.

Canine-lateral incisor transposition: Controlling root resorption with a bone-anchored T-loop retraction.

A 12-year-old girl presented with a Class II Division 1 malocclusion, complicated by a complete transposition of the maxillary left canine into the position normally occupied by the left lateral incisor. Dental and medical histories were noncontributory. Brackets were bonded on all maxillary teeth, from first molar to first molar, except for the left lateral incisor. Because the lateral incisor was not engaged on the archwire, the tooth was free to physiologically move out of the path of canine root movement. To prepare the site for canine retraction, a coil spring was used to open space between the left central incisor and the first premolar. A 2 × 12-mm stainless steel miniscrew was placed in the infrazygomatic crest, labial to the mesiodistal cusp of the maxillary left first molar. A 0.019 × 0.025-in titanium-molybdenum alloy T-loop, anchored by the miniscrew, was used to retract the canine root over the labial surface of the root of the distally positioned lateral incisor. In 24 months, this difficult malocclusion, with a Discrepancy Index score of 18, was treated to a Cast-Radiograph Evaluation score of 26.

Diagnosis and conservative treatment of skeletal Class III malocclusion with anterior crossbite and asymmetric maxillary crowding.

A man, aged 28 years 9 months, came for an orthodontic consultation for a skeletal Class III malocclusion (ANB angle, -3°) with a modest asymmetric Class II and Class III molar relationship, complicated by an anterior crossbite, a deepbite, and 12 mm of asymmetric maxillary crowding. Despite the severity of the malocclusion (Discrepancy Index, 37), the patient desired noninvasive camouflage treatment. The 3-Ring diagnosis showed that treatment without extractions or orthognathic surgery was a viable approach. Arch length analysis indicated that differential interproximal enamel reduction could resolve the crowding and midline discrepancy, but a miniscrew in the infrazygomatic crest was needed to retract the right buccal segment. The patient accepted the complex, staged treatment plan with the understanding that it would require about 3.5 years. Fixed appliance treatment with passive self-ligating brackets, early light short elastics, bite turbos, interproximal enamel reduction, and infrazygomatic crest retraction opened the vertical dimension of the occlusion, improved the ANB angle by 2°, and achieved excellent alignment, as evidenced by a Cast Radiograph Evaluation score of 28 and a Pink and White dental esthetic score of 3.

Time to detection in liquid culture of sputum in pulmonary MDR-TB does not predict culture conversion for early discharge.

OBJECTIVES: UK guidelines advise that patients with pulmonary MDR-TB are isolated in hospital until the results of sputum cultures are negative (culture conversion), typically after 42 days of incubation with no growth. MDR-TB patients may be isolated ≥42 days longer than is necessary for public safety, which has major implications for patients and hospitals. Our objective was to determine whether analysis of time to detection (TTD) in liquid culture could predict the earliest safe discharge date of MDR-TB patients. PATIENTS AND METHODS: Fifteen pulmonary MDR-TB patients were identified retrospectively from the London TB Register and hospital records. We performed linear regression of TTD against days elapsed between admission and sample date. If the regression line crossed the observed culture-conversion date at TTD = 42 days, the data were deemed to give 'precise prediction' of the earliest safe discharge date. RESULTS: The median length of stay was 91 days (IQR 79-131 days). Culture conversion occurred at a median of 59 days (IQR 46-86 days). Twelve patients were hospitalized beyond culture conversion, with a median overstay of 52 days (IQR 35-68 days). TTD tended to lengthen until culture conversion and, for nearly half of the patients (7/15, 47%), linear regression of TTD against time from admission gave a good fit to the data (r(2) ≥ 0.6) and supported precise prediction. However, data from the remaining patients showed considerable variation, and linear regression did not support prediction of safe discharge. CONCLUSIONS: TTD data from these pulmonary MDR-TB patients did not support a simple clinical prediction tool, but our analysis was limited by the small size of our sample.