Predicting the polyethylene wear rate in pin-on-disc experiments in the context of prosthetic hip implants: deriving a data-driven model using machine learning methods.

Pin-on-disc (PoD) experiments are widely used to quantify and rank wear of different material couples for prosthetic hip implant bearings. However, polyethylene wear results obtained from different PoD experiments are sometimes difficult to compare, which potentially leaves information inaccessible. We use machine learning methods to implement several data-driven models, and subsequently validate them by quantifying the prediction error with respect to published experimental data. A data-driven model can supplement results from PoD wear experiments, and enables predicting polyethylene wear of new PoD experiments based on its operating parameters. It also reveals the relative contribution of individual PoD operating parameters to the resulting polyethylene wear, thus informing design of experiments, and potentially reducing the need for time consuming PoD wear measurements.

Friction between a polyethylene pin and a microtextured CoCrMo disc, and its correlation to polyethylene wear, as a function of sliding velocity and contact pressure, in the context of metal-on-polyethylene prosthetic hip implants.

The longevity of metal-on-polyethylene prosthetic hip implant bearings, in which a polished CoCrMo femoral head articulates with a polyethylene liner, is limited by mechanical instability or inflammation resulting from osteolysis caused by polyethylene wear debris. We use pin-on-disc experiments to measure friction and wear of a polyethylene pin that articulates with different microtextured CoCrMo surfaces, covering a wide range of operating conditions including sliding velocity and contact pressure. We determine how the lubrication regime changes as a function of operating conditions, and show that the microtexture accelerates the transition from boundary to elastohydrodynamic lubrication. Additionally, we illustrate that the microtexture could enable tailoring the hip implant to the specific patient needs based on activity level, gender, and age.

Using a patterned microtexture to reduce polyethylene wear in metal-on-polyethylene prosthetic bearing couples.

The longevity of metal-on-polyethylene prosthetic hip joint bearings, in which a CoCrMo femoral head articulates with a polyethylene liner, is often limited by polyethylene wear and osteolysis caused by polyethylene wear particles. Current approaches to reduce polyethylene wear include improving the mechanical properties of the polyethylene liner, and/or manufacturing ultra-smooth articulating surfaces. In contrast, this experimental work shows that adding a patterned microtexture of concave "dimples" to a polished CoCrMo surface significantly reduces polyethylene wear by promoting the formation of an elastohydrodynamic lubricant film, which reduces contact between the CoCrMo and polyethylene bearing surfaces. Using a gravimetric method to measure polyethylene pin wear during pin-on-disc experiments, it was demonstrated that microtextured CoCrMo caused reduced polyethylene wear compared to polished CoCrMo surfaces. Wear was quantified for different polyethylene materials currently used in commercial prosthetic hip joint bearings, and for several microtexture geometries. It was also documented by correlating polyethylene wear with surface topography measurements that the patterned microtexture reduced contact between the articulating bearing surfaces.

Implications of subcutaneous or intravenous delivery of trastuzumab; further insight from patient interviews in the PrefHer study.

BACKGROUND: The 2 Cohort randomised PrefHer trial examined the preferences of HER2+ve primary breast cancer patients for intravenous (IV) or subcutaneous (SC) delivery of trastuzumab via a Single Injectable Device (SID) or hand-held syringe (HHS). The novel approach and design of the study permitted an in-depth exploration of patients' experiences, the impact that different modes of delivery had on patients' well-being and implications for future management. METHODS: The preferences, experiences and general comments of patients in the PrefHer study were collected via specific semi-structured interview schedules. Exploratory analyses of data were conducted using standard methodology. The final question invited patients to make further comments, which were divided into 9 thematic categories - future delivery, compliments, time/convenience, practical considerations, pain/discomfort, study design, side-effects, psychological impact, and perceived efficacy. RESULTS: 267/467 (57%) patients made 396 additional comments, 7 were neutral, 305 positive and 86 negative. The three top categories generating the largest number of comments were compliments and gratitude about staff and being part of PrefHer (75/396; 19%), the potential future delivery of SC trastuzumab (73/396; 18%), and practical considerations about SC administration (60/396; 15%). CONCLUSIONS: Eliciting patient preferences about routes of administration of drugs via comprehensive interviews within a randomised cross-over trial yielded rich and important information. The few negative comments made demonstrated a need for proper staff training in SC administration Patients were grateful to have been part of the trial, and would have liked to continue with SC delivery. The possibility of home administration in the future also seemed acceptable. EUDRACT NUMBER: 2010-024099-25.

Patients' and oncologists' views on the treatment and care of advanced ovarian cancer in the U.K.: results from the ADVOCATE study.

BACKGROUND: Most patients presenting with advanced ovarian cancer (AOC) eventually relapse. Symptom palliation, maintenance of quality of life (QoL) and prolongation of life are primary therapeutic goals. METHODS: Sixty-six U.K. oncologists completed an online survey about AOC management. Two hundred and two patients were interviewed about care, treatment experiences and expectations. RESULTS: Prior to diagnosis, 34% (69 out of 202) of women had > or =3 symptoms associated with AOC. Twenty-one per cent (43 out of 202) thought poor symptom recognition by general practitioners (GPs) delayed diagnosis. Amelioration of side effects experienced was variable, for example, only 54% (68 out of 127) distressed by alopecia had received sufficient information about it. Clinicians were asked 'What minimum gain in progression-free survival (PFS) would make you feel it worthwhile to offer maintenance therapy?'; 48% (24 out of 50) indicated 5-6 months, but 52% (26 out of 50) believed patients would find PFS of 3-4 months acceptable. When patients were presented with hypothetical scenarios, 33% (52 out of 160) would require 1-2 months extra life, 6% (10 out of 160) 3-4 months, 31% (49 out of 160) 5-6 months, and 31% (49 out of 160) > or =7 months. However, 86% (173 out of 202) would accept treatment that improved QoL without prolongation of life. When asked what was most important, 33% (67 out of 201) said QoL, 9% (19 out of 201) length of life and 57% (115 out of 201) said both were equally important. CONCLUSION: Clinicians' and patients' experiences, expectations and priorities about OC management may differ.

ARIX: a randomised trial of acupuncture v oral care sessions in patients with chronic xerostomia following treatment of head and neck cancer.

BACKGROUND: Radiation treatment of head and neck cancer can cause chronic xerostomia which impairs patients' quality of life. The study reported here examined the efficacy of acupuncture in alleviating xerostomia symptoms especially dry mouth. PATIENTS AND METHODS: A total of 145 patients with chronic radiation-induced xerostomia >18 months after treatments were recruited from seven UK cancer centres. The study employed a randomised crossover design with participants receiving two group sessions of oral care education and eight of acupuncture using standardised methods. Patient-reported outcome (PROs) measures were completed at baseline and weeks 5, 9, 13, 17, and 21. The primary outcome was improvement in dry mouth. OBJECTIVE: saliva measurements were also carried out. RESULTS: Acupuncture compared with oral care, produced significant reductions in patient reports of severe dry mouth (OR = 2.01, P = 0.031) sticky saliva (OR = 1.67, P = 0.048), needing to sip fluids to swallow food (OR = 2.08, P = 0.011) and in waking up at night to drink (OR = 1.71, P = 0.013). There were no significant changes in either stimulated or unstimulated saliva measurements over time. CONCLUSION: Eight sessions of weekly group acupuncture compared with group oral care education provide significantly better relief of symptoms in patients suffering from chronic radiation-induced xerostomia.

Thymidine kinase 1 immunoassay: a potential marker for breast cancer.

Previous research indicates that thymidine kinase I (TKI) possesses value as a tool for both prognosis and diagnosis in breast cancer. However, drawbacks to the existing radioassay for thymidine kinase have frustrated its clinical use. To overcome these drawbacks, we developed a monoclonal antibody to TK1. We have assessed this antibody for a linear antibody-antigen response and for reproducibility using ELISA techniques. We also have evaluated this antibody for TKI specificity as determined by Western blot. To test the accuracy of this monoclonal antibody further, we treated human MCF-7 breast cancer cells with tamoxifen and measured decreasing TKI activity and protein levels with the radioassay and with our monoclonal antibody in an ELISA, respectively. We then used the radioassay and our monoclonal antibody to measure TK1 activity and protein levels, respectively, in 218 serum samples of postoperative breast cancer patients and found a correlation between the two assays. Our results demonstrated that the TK1 immunoassay not only had a linear, reproducible, and specific response but accurately measured TK1 levels in both MCF-7 breast cancer cells and serum. Thus, our monoclonal antibody may demonstrate potential for practical use in a clinical setting for the management of breast cancer.

A method for the automated mapping of laboratory results to LOINC.

LOINC is emerging as the standard for laboratory result names, and there is great interest in mapping legacy terms from laboratory systems to it. However, the mapping task is non-trivial, requiring significant resource commitment and a good understanding of the LOINC identifying attributes for the laboratory result names. Because the number of results in a laboratory system may range from around 500 to 2000 or more, manual, one-by-one matching, even with the aid of the RELMA matching tool provided by LOINC, is time consuming and laborious. Moreover, human variation may introduce mapping inconsistencies or errors. Through our experience mapping the results from a variety of laboratory systems to LOINC, an automated mapping method has been developed and is described in this paper. This method allows for data from the laboratory information system to be provided in a manner familiar to the submitting technician, and makes use of parsing and logic rules, combined with synonyms, attribute relationships and mapping frequency data, to perform automated matching to LOINC.

Mitochondrial DNA regions HVI and HVII population data.

Data from 1393 unrelated individuals have been compiled from eight population groups: African Americans, Africans (Sierra Leone), U.S. Caucasians, Austrians, French, Hispanics, Japanese, and Asian Americans. The majority of the mtDNA sequences were observed only once within each population group (i.e., ranging from a low of 60.3% (35/58) of the Asian American sequences to a high of 85.3% (93/109) of the French sequences). Genetic diversity ranged from 0.990 in the African sample to 0.998 in African Americans. Random match probability ranged from 2.50% in the Asian American sample to 0.52% in U.S. Caucasians. The average number of nucleotide differences between individuals in a database is greatest for the African American and African samples (14.1 and 13.1, respectively), and the least variable are the Caucasians (ranging from 7.2 to 8.4). Substitutions are the predominate polymorphism, and at least 92% of the substitutions are transitions. The most prevalent transversions are As substituted for Cs and Cs substituted for As. For most population groups these transversions occurred predominately in the HVI region; however, the African, African American, and Hispanic samples also demonstrated a large portion of their C to A and A to C transversions in the HVII region (at sites 186 and/or 189). Most insertions occur in the HVII region at sites 309.1 and 315.1, within a stretch of C's. Insertions of an additional C are common in all population groups. The sequence data were converted to SSO mtDNA types and compared with population data on Caucasians, Africans, Asians, Japanese, and Mexicans described by Stoneking et al. [M. Stoneking, D. Hedgecock, R.G. Higuchi, L. Vigilant, H.A. Erlich, Population variation of human mtDNA control region sequences detected by enzymatic amplification and sequence-specific oligonucleotide probes, Am. J. Hum. Genet. 48 (1991) 370-382] using an R x C contingency table test. Differences between major population groups (i.e., between African, Caucasian, and Asian) are quite evident, and similar ethnic population groups carried similar SSO polymorphism frequencies. There were only a few SSO types that showed significant differences between subpopulation groups. The SSO data alone can not be used to describe the population genetics with complete sequence data. However, the results of the SSO comparisons are similar to other analyses, and differences in sequence data in regions HVI and HVII are greater between major population groups than between subgroups.

Effect of reference database on frequency estimates of polymerase chain reaction (PCR)-based DNA profiles.

A variety of general, regional, ancestral and ethnic databases is available for the polymerase chain reaction (PCR)-based loci LDLR, GYPA, HBGG, D7S8, Gc, DQA1, and D1S80. Generally, we observed greater differences in frequency estimations of DNA profiles between racial groups than between ethnic or geographic subgroups. Analysis revealed few forensically significant differences within ethnic subgroups, particularly within general United States groups, and multi-locus frequency estimates typically differ by less than a factor of ten. Using a database different from the one to which a target profile belongs tends to overestimate rarity. Implementation of the general correction of homozygote frequencies for a population substructure, advised by the 1996 National Research Council report, The Evaluation of Forensic DNA Evidence, has a minimal effect on profile frequencies. Even when it is known that both the suspect and all possible perpetrators must belong to the same isolated population, the special correction for inbreeding, which was proposed by the 1996 National Research Council report for this special case, has a relatively modest effect, typically a factor of two or less for 1% inbreeding. The effect becomes more substantial (exceeding a factor of ten) for inbreeding of 3% or more in multi-locus profiles rarer than about one in a million.

Estimating minimum allele frequencies for DNA profile frequency estimates for PCR-based loci.

In order that there can be confidence that DNA profile frequency estimates will not place undue bias against a defendant, 2 methods are described for estimating minimum allele frequency bounds for PCR-based loci. One approach estimates minimum allele frequencies for VNTR and STR loci using sample size and the observed heterozygosity at a locus, while the second approach, appropriate for loci typed with allele-specific oligonucleotide probes, is based only on sample size. The use of a minimum allele frequency enables compensation for sparse sampling of infrequent alleles in population databases.

Description and analysis of allele distribution for four VNTR markers in French and French Canadian populations.

Allele distributions were determined for several VNTR loci in the general French Caucasian population, a French regional population from Brittany and in three French Canadian populations, residing either in Montréal or in one of two other regions in Québec. Allele distributions are highly polymorphic in all populations sampled. Despite a well-documented genetic founder effect in one of the populations, no disequilibrium was detected over all genotypes, within and between loci, for the data bases in this study. Moreover, there were no forensically significant differences observed between estimated frequencies of 1,964 Caucasian and non-Caucasian target DNA profiles estimated in any of the groups.

A reassessment of frequency estimates of PvuII-generated VNTR profiles in a Finnish, an Italian, and a general U.S. Caucasian database: no evidence for ethnic subgroups affecting forensic estimates.

Recently, Krane et al. addressed the effect of estimating various target DNA profile frequencies in Finnish, Italian, and general U.S. Caucasian databases. They observed that, when using an "inappropriate ethnic," or noncognate, database (e.g., a Finnish target profile frequency estimated in an Italian database, and vice versa), estimates were less common than when the target profile frequencies were estimated using their own ethnic, or cognate, database, and these estimates differed by more than one order of magnitude. These differences were attributed to the effects of subgroups. We demonstrate that the differences can be ascribed to statistical artifacts that induce large biases and correlations. Additionally, we show that the differences of estimates of any specific DNA profile frequency based on allelic size frequencies from different databases become smaller when the fixed-bin rather than a +/- 2.5% floating-bin approach is used.

Greater differences in forensic DNA profile frequencies estimated from racial groups than from ethnic subgroups.

A National Research Council (NRC) report asserted that genetic diversity between subgroups within a race is greater than between races. While this is counterintuitive to the basic tenets of human population genetics, the forensic application of statistical estimates of DNA profile frequencies has been questioned. The general approach used for estimating DNA profile frequencies by the majority of North American forensic laboratories is the use of the product rule on fixed bin allele frequencies derived from general population group databases. An informal analysis of the differences in frequency estimates within Hinf I-generated RFLP data determined in three ethnically distinct population groups--Norwegians, Spanish, and Turks--and in Caucasians and Blacks from the United States is presented. The VNTR loci analyzed are D2S44, D7S21, and D12S11. The data demonstrate that the assertion by the NRC is unfounded and that major population group databases, in lieu of subpopulation databases, can be used to provide estimates of DNA profile frequencies without consequences of wrongful bias.

Evaluation of Hinf I-generated VNTR profile frequencies determined using various ethnic databases.

Concerns have been raised about hypothetical problems arising from the use of statistics for determining the likelihood of occurrence of DNA profiles for forensic purposes. A major contention is that reference databases based on subgroups of a major population category rather than on general (or major) population groups, might yield large differences in the estimated likelihood of occurrence of DNA profiles. This hypothetical issue is based on the assertion by some people that the differences among subgroups within a race would be greater than between races (at least for forensic purposes). To evaluate the effects of the above concern the likelihood of occurrence of 615 Hinf I-generated target DNA profiles was estimated using fixed bin frequencies from various ethnic databases and the multiplication rule. Based on the data in this study, differences in allele frequencies at a particular locus do not have substantial effects on VNTR profile frequency estimates when subgroup reference databases from within a major population group are compared. In contrast, the greatest variation in statistical estimates occurs across-major population groups. Therefore, the assertion, by some critics that the differences among subgroups within a race would be greater than between races (at least for forensic purposes), is unfounded. The data in the study support that comparisons across major population groups provide valid estimates of DNA profile frequencies without forensically significant consequences. The data do not support the need for alternate procedures, such as the ceiling principle approach, for deriving statistical estimates of DNA profile frequencies.

The assessment of frequency estimates of Hae III-generated VNTR profiles in various reference databases.

The likelihood of occurrence of 1964 Hae III-generated target DNA profiles was estimated using fixed bin frequencies from various regional and ethnic databases and the multiplication rule. The databases generally were from the following major categories: Black, Caucasian, Hispanic, Oriental, and American Indian. It was found that subdivision, either by ethnic group or by U.S. geographic region, within a major population group did not substantially affect forensic estimates of the likelihood of occurrence of a DNA profile. As expected, the greatest variation in estimates for within-group estimates was among American Indian databases. Because the greatest variation in statistical estimates occurs across-major population groups, in most cases, there will be no unfair bias applying general population database estimates. Therefore, based on empirical data, there is no demonstrable need for using alternate approaches, such as the ceiling approach, to derive statistical estimates. The current practice of using general population databases and the multiplication rule provides valid estimates of the likelihood of occurrence of a DNA profile.

A comparison of the fixed bin method with the floating bin and direct count methods: effect of VNTR profile frequency estimation and reference population.

When the results of a forensic comparison of highly polymorphic variable number tandem repeat (VNTR) loci fail to exclude a suspect as a possible contributor of biological evidence, it is desirable to convey to the trier of fact the significance of the match. Furthermore, in a forensic context, it is desirable that the estimated frequency of occurrence be conservative, that is, that any uncertainty in the estimate will favor the accused. Using an empirical approach with a data base of 2046 individuals belonging to one of four population groups, this study examined the effect of the method used to estimate frequency of occurrence of a VNTR profile from a reference data base, and the consequences of using a data base that may not represent the circumstances of the crime. The fixed bin method was at least as conservative as the floating bin and genotype counting (direct counting) methods. Secondly, for forensic purposes, profile frequency estimates from different reference populations do not deviate greatly. VNTR profiles are rare in any of the data bases.

The forensic significance of various reference population databases for estimating the rarity of variable number of tandem repeat (VNTR) loci profiles.

The likelihood of occurrence of 1,964-HaeIII-generated target DNA profiles was estimated using fixed bin VNTR frequencies from various Caucasian, Black, and Hispanic databases and the product rule. The data in this study demonstrate that for forensic purposes there are smaller differences in statistical estimates of DNA profile frequencies among subgroup databases than among estimates across major population databases. This observation does not support the premise asserted by the NCR Report (1992) that the differences among subgroups within a race would be greater than between races (at least for forensic purposes). Therefore, the data do not support the need for alternative procedures, such as the ceiling principle approach (NRC Reports, 1992), for deriving statistical estimates of DNA profile frequencies. Comparisons across major population groups provide reasonable, reliable, and meaningful estimates of DNA profile frequencies without forensically significant consequences.

Fixed-bin analysis for statistical evaluation of continuous distributions of allelic data from VNTR loci, for use in forensic comparisons.

The detection of DNA polymorphisms by RFLP analysis is having a major impact on identity testing in forensic science. At present, this approach is the best effort a forensic scientist can make to exclude an individual who has been falsely associated with an evidentiary sample found at a crime scene. When an analysis fails to exclude a suspect as a potential contributor of an evidentiary sample, a means should be provided to assess suitable weight to the putative match. Most important, the statistical analysis should not place undue weight on a genetic profile derived from an unknown sample that is attributed to an accused individual. The method must allow for limitations in conventional agarose-submarine-gel electrophoresis and Southern blotting procedure, limited sample population data, possible subpopulation differences, and potential sampling error. A conservative statistical method was developed based on arbitrarily defined fixed bins. This approach permits classification of continuous allelic data, provides for a simple and portable data-base system, and is unlikely to underestimate the frequency of occurrence of a set of alleles. This will help ensure that undue weight is not placed on a sample attributed to an accused individual.

Tracking the violent criminal offender through DNA typing profiles--a national database system concept.

Implementation of standard methods for the conduct of restriction fragment length polymorphism analysis into the protocols of United States crime laboratories offers an unprecedented opportunity for the establishment of a national computer database system to enable interchange of DNA typing information. The FBI Laboratory, in concert with crime laboratory representatives, has taken the initiative in planning and implementing such a database system. The Combined DNA Index System (CODIS) will be composed of three sub-indices: a statistical database, which will contain frequencies of DNA fragment alleles in various population groups; an investigative database which will enable linkage of violent crimes through a common subject; and a convicted felon database that will serve to maintain DNA typing profiles for comparison to profiles developed from violent crimes where the suspect may be unknown.