Identification of patients with Fabry disease using routine pathology results: PATHFINDER (eGFR) study.

AIMS: Lysosomal α-galactosidase A deficiency (Fabry disease (FD)) was considered an X-linked recessive disorder but is now viewed as a variable penetrance dominant trait. The prevalence of FD is 1 in 40 000-117 000 but the ascertainment of late-onset cases and degree of female penetrance makes this unclear. Its prevalence in the general population, especially in patients with abnormal renal function is unclear. This study attempted to identify the prevalence of FD in patients with abnormal renal function results from laboratory databases. METHODS: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of reduced estimated glomerular filtration rate categorised by age on one occasion or more over a 3-year time interval. Patients were recalled and a dried blood spot sample was collected for the determination of α-galactosidase A activity by fluorimetric enzyme assay in men and mass spectrometry assays of α-galactosidase A and lyso-globotriaosylceramide (lyso-GL-3) concentrations in women. RESULTS: Samples were obtained from 1084 patients identified with reduced renal function. No cases of FD were identified in 505 men. From 579 women, one subject with reduced α-galactosidase activity (1.5 µmol/L/h) and increased Lyso-GL-3 (5.5 ng/mL) was identified and shown to be heterozygous for a likely FD pathogenic variant (GLA c.898C>T; p.L300F; Leu300Phe). It was later confirmed that she was a relative of a known affected patient. CONCLUSIONS: Pathology databases hold routine information that can be used to identify patients with inherited errors of metabolism. Biochemical screening using reduced eGFR alone has a low yield for unidentified cases of Fabry Disease.

Issues of theory and method in the analysis of Paleolithic mortuary behavior: A view from Shanidar Cave.

Mortuary behavior (activities concerning dead conspecifics) is one of many traits that were previously widely considered to have been uniquely human, but on which perspectives have changed markedly in recent years. Theoretical approaches to hominin mortuary activity and its evolution have undergone major revision, and advances in diverse archeological and paleoanthropological methods have brought new ways of identifying behaviors such as intentional burial. Despite these advances, debates concerning the nature of hominin mortuary activity, particularly among the Neanderthals, rely heavily on the rereading of old excavations as new finds are relatively rare, limiting the extent to which such debates can benefit from advances in the field. The recent discovery of in situ articulated Neanderthal remains at Shanidar Cave offers a rare opportunity to take full advantage of these methodological and theoretical developments to understand Neanderthal mortuary activity, making a review of these advances relevant and timely.

Demand management of weekend haematology and clinical biochemistry requests.

BACKGROUND: Increasing demand for laboratory testing at weekends is common but little is known about its appropriateness. METHODS: An audit was conducted in a large district hospital of routine haematology and clinical biochemistry requests ordered over two weekends. Appropriateness was assessed by review of ordered tests compared with clinical records by a qualified chemical pathologist. RESULTS: Profiles requested on phlebotomy included full blood count (76%), renal profile (91%), C-reactive protein (41%), liver function tests (18%) and another test in 18%. Phlebotomy was likely unnecessary in 47.5% of episodes while 60.8% of requested assays were graded probably unnecessary or unnecessary. At ward level the number of requests averaged 37 (median 32; range 2-76) totalling 446 separate profiles or assays. There was no difference in phlebotomy requests by ward (P = 0.19). Differences were observed in ordered tests (P = 0.005) which were caused by one outlier ward with a low request rate. CONCLUSIONS: A large number of unnecessary common tests seem to be carried out at weekends as part of the routine care. Implementation of demand management through education and if necessary electronic limitation of requests may be useful to control laboratory workloads.

Newly discovered Neanderthal remains from Shanidar Cave, Iraqi Kurdistan, and their attribution to Shanidar 5.

The Neanderthal remains from Shanidar Cave, excavated between 1951 and 1960, have played a central role in debates concerning diverse aspects of Neanderthal morphology and behavior. In 2015 and 2016, renewed excavations at the site uncovered hominin remains from the immediate area where the partial skeleton of Shanidar 5 was found in 1960. Shanidar 5 was a robust adult male estimated to have been aged over 40 years at the time of death. Comparisons of photographs from the previous and recent excavations indicate that the old and new remains were directly adjacent to one another, while the disturbed arrangement and partial crushing of the new fossils is consistent with descriptions and photographs of the older discoveries. The newly discovered bones include fragments of several vertebrae, a left hamate, part of the proximal left femur, a heavily crushed partial pelvis, and the distal half of the right tibia and fibula and associated talus and navicular. All these elements were previously missing from Shanidar 5, and morphological and metric data are consistent with the new elements belonging to this individual. A newly discovered partial left pubic symphysis indicates an age at death of 40-50 years, also consistent with the age of Shanidar 5 estimated previously. Thus, the combined evidence strongly suggests that the new finds can be attributed to Shanidar 5. Ongoing analyses of associated samples, including for sediment morphology, palynology, and dating, will therefore offer new evidence as to how this individual was deposited in the cave and permit new analyses of the skeleton itself and broader discussion of Neanderthal morphology and variation.

The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya) - Optical dating of early human occupation during Marine Isotope Stages 4, 5 and 6.

The paper presents the results of optical dating of potassium-rich feldspar grains obtained from the Haua Fteah cave in Cyrenaica, northeast Libya, focussing on the chronology of the Deep Sounding excavated by Charles McBurney in the 1950s and re-excavated recently. Samples were also collected from a 1.25 m-deep trench (Trench S) excavated during the present project below the basal level of the Deep Sounding. Optically stimulated luminescence (OSL) data sets for multi-grain, single aliquots of quartz for samples from the Middle Trench were previously published. Re-analyses of these OSL data confirm significant variation in the dose saturation levels of the quartz signal, but allow the most robust OSL ages to be determined for comparison with previous age estimates and with those obtained in this study for potassium-rich feldspars from the Deep Sounding. The latter indicate that humans may have started to visit the cave as early as ∼150 ka ago, but that major use of the cave occurred during MIS 5, with the accumulation of the Deep Sounding sediments. Correlations between optical ages and episodes of "Pre-Aurignacian" artefact discard indicate that human use of the cave during MIS 5 was highly intermittent. The earliest phases of human activity appear to have occurred during interstadial conditions (5e and 5c), with a later phase of lithic discard associated with more stadial conditions, possibly MIS 5b. We argue that the "Pre-Aurignacian" assemblage can probably be linked with modern humans, like the succeeding "Levalloiso-Mousterian" assemblage; two modern human mandibles associated with the latter are associated with a modelled age of 73-65 ka. If this attribution is correct, then the new chronology implies that modern humans using "Pre-Aurignacian" technologies were in Cyrenaica as early as modern humans equipped with "Aterian" technologies were in the Maghreb, raising new questions about variability among lithic technologies during the initial phases of modern human dispersals into North Africa.

Analytical Performance Verification of the Beckman Coulter AU5800 Clinical Chemistry Analyser Against Recognized Quality Specifications Reveals Relevance of Method Harmonization.

BACKGROUND: Analytical performance of 24 Beckman-Coulter AU 5800 methods was verified against recognized quality goals and manufacturer's expected imprecision and bias. METHODS: AU5800 method imprecision, bias, agreement with a comparative method, and linearity were studied using CLSI protocols, commercial control material, patient samples, and linearity test kit solutions. Repeat patient testing and IQC were also used for imprecision. Commutability of control material was tested. Total analytical error (TAE) was estimated for each method and between the tested and the comparative method, the Beckman-Coulter Unicel DxC800. RESULTS: CLSI EP15 total imprecision CV (TCV) < 3.2%. Duplicate patient imprecision CV < 2.8%. IQC imprecision CV < 5.1%, except for low level ALP (CV = 7.4%). Sodium and urate IQC imprecision were higher than manufacturer's specifications. TAE for all methods met accepted quality goals. Correlation between methods was > 0.975, except for Cl (0.971), TP (0.964), and Na (0.948). Average bias versus Unicel DxC800 is high for ALP (17.3%), GGT (37%), LD (20%), TBIL (-23%), and TP (8%) and was confirmed in other laboratories. TAE between methods met allowable total error for 21 analytes. For GGT, between method TAE (23 to 51%) was predictable from expected bias and combined method imprecision. For LD and TP several between method differences were outside boundaries describing expected bias. Linearity was excellent with R2 > 0.997 and deviations met accepted goals. CONCLUSIONS: The Beckman-Coulter AU 5800 demonstrates good linearity, low imprecision, and good correlation with previous methods. Observed between method differences suggest ALP, GGT, LD, TBIL, and TP harmonization should be considered.

The chronostratigraphy of the Haua Fteah cave (Cyrenaica, northeast Libya).

The 1950s excavations by Charles McBurney in the Haua Fteah, a large karstic cave on the coast of northeast Libya, revealed a deep sequence of human occupation. Most subsequent research on North African prehistory refers to his discoveries and interpretations, but the chronology of its archaeological and geological sequences has been based on very early age determinations. This paper reports on the initial results of a comprehensive multi-method dating program undertaken as part of new work at the site, involving radiocarbon dating of charcoal, land snails and marine shell, cryptotephra investigations, optically stimulated luminescence (OSL) dating of sediments, and electron spin resonance (ESR) dating of tooth enamel. The dating samples were collected from the newly exposed and cleaned faces of the upper 7.5 m of the ∼14.0 m-deep McBurney trench, which contain six of the seven major cultural phases that he identified. Despite problems of sediment transport and reworking, using a Bayesian statistical model the new dating program establishes a robust framework for the five major lithostratigraphic units identified in the stratigraphic succession, and for the major cultural units. The age of two anatomically modern human mandibles found by McBurney in Layer XXXIII near the base of his Levalloiso-Mousterian phase can now be estimated to between 73 and 65 ka (thousands of years ago) at the 95.4% confidence level, within Marine Isotope Stage (MIS) 4. McBurney's Layer XXV, associated with Upper Palaeolithic Dabban blade industries, has a clear stratigraphic relationship with Campanian Ignimbrite tephra. Microlithic Oranian technologies developed following the climax of the Last Glacial Maximum and the more microlithic Capsian in the Younger Dryas. Neolithic pottery and perhaps domestic livestock were used in the cave from the mid Holocene but there is no certain evidence for plant cultivation until the Graeco-Roman period.

An evaluation of serum albumin and the sub-scores of the Waterlow score in pressure ulcer risk assessment.

BACKGROUND: From previous work serum albumin is predictive of pressure ulcers over and above the Waterlow score. However the sub-scores of the Waterlow score were not available, and the accuracy of calculation of the total score was poor. This study has used sub-scores and is an order of magnitude larger. OBJECTIVES: To compare serum albumin with Waterlow score as a predictive measure for pressure ulcers. DESIGN: Retrospective analysis of hospital information support system. SETTINGS: A district general hospital in Staffordshire. PARTICIPANTS: Adult non-elective in-patients. METHODS: Logistic regression and receiver operating characteristic. RESULTS: The sub-scores of the Waterlow score were explored. While they constitute a multi-dimensional dataset, many were not found relevant to pressure ulcer risk in this population (non-elective in-patients). Some sub-scores were not recorded correctly, and body mass index (BMI) was particularly badly reported. Age was found to be as predictive of pressure ulcer as the more complex Waterlow score. Serum albumin was at least as good as the Waterlow score in risk assessment of pressure ulcers. Matching patients with pressure ulcers to patients with none, who had identical Waterlow sub-scores, confirmed serum albumin as a robust predictive value in pressure ulcers. CONCLUSION: Risk assessing patients based on their age is as good as the more complex Waterlow score. Additional risk information can be gained from knowing the serum albumin value.

Obstetrics and gynaecology trainees' understanding of intrauterine device/system insertion.

OBJECTIVE: To determine obstetrics and gynaecology trainees' understanding of intrauterine device/system (IUD/IUS) insertion. METHODS: A questionnaire-based survey of obstetrics and gynaecology trainees in the West Midlands region of the UK. RESULTS: Forty-five trainees completed a questionnaire on this topic. High scores were obtained in questions relating to the medical and drug interactions of IUD/IUSs. However, trainees' knowledge of the technicalities of fitting and patient selection was poor. Some 49% of respondents stated that an IUS was effective as emergency contraception and 47% felt that an IUD/IUS was contraindicated in HIV-positive patients. No significant difference was seen between the number of correct answers given by pre- and post-MRCOG trainees for any of the questions. The number of insertions per year was unrelated to knowledge levels. CONCLUSIONS: Obstetrics and gynaecology trainees regularly insert IUD/IUSs, and although their medical knowledge is on the whole very good, many doctors are not aware of best practice advice, in particular regarding the use of the IUS as emergency contraception. Training on contraception and sexual health needs to be incorporated into career obstetrician/gynaecologists' teaching programmes in order to improve their understanding and practice in this area.

An audit of research productivity in clinical biochemistry revisited.

OBJECTIVE: To investigate recent (2011-2015) research productivity in clinical biochemistry and compare it with a previous audit (1994-1998). DESIGN: A retrospective audit of peer-reviewed academic papers published in Medline listed journals. SETTING: UK chemical pathology/clinical biochemistry laboratories and other clinical scientific staff working in departments of pathology. PARTICIPANTS: Medically qualified chemical pathologists and clinical scientists. MAIN OUTCOME MEASURES: Publications were identified from electronic databases for individuals and sites. Analyses were conducted for individuals, sites and regional educational groups. RESULTS: Clinical scientific staff numbers fell by 3.9% and medical staff by 17.4% from 1998 to 2015. Publication rates declined as publication count centiles rose between 1998 and 2015 (e.g. n = 5; 67th→84th centile; p < 0.001). A reduction in productivity was seen in medically qualified staff but less from clinical scientists. Regional staffing was 77 ± 37 (range 30-150) with university hospital laboratory staff accounting for 58 ± 19% (range 30-92%). Medically qualified staff comprised 20 ± 4% of staff with lowest numbers in some London regions. Publication rates varied widely with a median of 155 papers per region (range 98-1035) and 2.82 (1.21-8.62) papers/individual. The skew was attenuated, increasing the publication rate to 6.0 ± 2.73 papers (range 2.29-11.76)/individual after correction for the number of university hospital sites per region and was not related to numbers of trainees. High publication rates were associated with the presence of one highly research-active individual. Their activity correlated over their careers from recruitment to today (r2 = 0.45; p = 0.05). The productivity rates of recent cohorts of trainees are inferior to previous cohorts. CONCLUSIONS: Research remains a minority interest in clinical biochemistry. A small and decreasing proportion of individuals publish 90% of the work. A reduction was seen in clinical scientist and especially medical research productivity. No correlation of training activity with research productivity was seen implying weak links with translational medicine.

Identification of patients with Pompé disease using routine pathology results: PATHFINDER (creatine kinase) study.

AIMS: Adult-onset inherited errors of metabolism can be difficult to diagnose. Some cases of potentially treatable myopathy are caused by autosomal recessive acid α-1,4 glucosidase (acid maltase) deficiency (Pompé disease). This study investigated whether screening of asymptomatic patients with elevated creatine kinase (CK) could improve detection of Pompé disease. METHODS: Pathology databases in six hospitals were used to identify patients with elevated CK results (>2× upper limit of normal). Patients were recalled for measurement of acid α-1,4 glucosidase activity in dried blood spot samples. RESULTS: Samples were obtained from 812 patients with elevated CK. Low α-glucosidase activity was found in 13 patients (1.6%). Patients with neutropaenia (n=4) or who declined further testing (n=1) were excluded. Confirmation plasma specimens were obtained from eight individuals (1%) for a white cell lysosomal enzyme panel, and three (0.4%) were confirmed to have low α-1,4-glucosidase activity. One patient was identified as a heterozygous carrier of an acid α-1,4 glucosidase c.-32-13 G>T mutation. Screening also identified one patient who was found to have undiagnosed Fabry disease and one patient with McArdle's disease. One patient later presented with Pompé's after an acute illness. Including the latent case, the frequency of cases at 0.12% was lower than the 2.5% found in studies of patients with raised CK from neurology clinics (p<0.001). CONCLUSIONS: Screening pathology databases for elevated CK may identify patients with inherited metabolic errors affecting muscle metabolism. However, the frequency of Pompé's disease identified from laboratory populations was less than that in patients referred for neurological investigation.

A Retrospective Observational Study to Determine Baseline Characteristics and Early Prescribing Patterns for Patients Receiving Alirocumab in UK Clinical Practice.

BACKGROUND: Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been previously shown, in the phase III ODYSSEY clinical trial program, to provide significant lowering of low-density lipoprotein cholesterol (LDL-C) and reduction in risk of major adverse cardiovascular events. However, real-world evidence to date is limited. OBJECTIVE: The primary objective was to describe baseline characteristics, clinical history, and prior lipid-lowering therapy (LLT) use of patients initiated on alirocumab in UK clinical practice following publication of health technology appraisal (HTA) body recommendations. Secondary objectives included description of alirocumab use and lipid parameter outcomes over a 4-month follow-up period. METHODS: In this retrospective, single-arm, observational, multicenter study, data were collected for 150 patients initiated on alirocumab. RESULTS: Mean (standard deviation; SD) age of patients was 61.4 (10.5) years and baseline median (interquartile range; IQR) LDL-C level was 4.8 (4.2-5.8) mmol/l. Alirocumab use occurred predominantly in patients with heterozygous familial hypercholesterolemia (HeFH) (n = 100/150, 66%) and those with statin intolerance (n = 123/150, 82%). Most patients started on alirocumab 75 mg (n = 108/150 [72%]) and 35 (23.3%) were up-titrated to 150 mg. Clinically significant reductions in atherogenic lipid parameters were observed with alirocumab, including LDL-C (median [IQR] change from baseline, - 53.6% [- 62.9 to - 34.9], P < 0.001). CONCLUSION: This study highlights the unmet need for additional LLT in patients with uncontrolled hyperlipidemia and demonstrates the clinical utility of alirocumab in early real-world practice, where dosing flexibility is an important attribute of this therapeutic option.

Preoperative axillary staging in breast cancer-saving time and resources.

This study was performed to assess the feasibility and accuracy of ultrasound guided fine needle aspiration biopsy for axillary staging in invasive breast cancer. Data were collected prospectively from June 2005 to June 2006. In all, 197 patients with invasive breast cancer and clinically nonsuspicious axillary lymph nodes were included. Patients with suspicious nodes on ultrasound had fine needle aspiration biopsy. Those with fine needle aspiration biopsy positive for malignancy were planned for axillary nodes clearance otherwise they had sentinel node biopsy. Patients (41) had ultrasound guided fine needle aspiration biopsy. Three cases were excluded for being nonconclusive. Postoperative histology showed 18/38 cases (47.4%) axillary lymph nodes positive and 20/38 cases (52.6%) axillary nodes negative. Ultrasound guided fine needle aspiration biopsy was positive in 8/38 cases (21.1%), negative in 30/38 cases (78.9%). The sensitivity of ultrasound guided fine needle aspiration biopsy was found to be 47.1%, specificity 100%, positive predictability 100%, negative predictability 70%, and overall accuracy 76.3%. Ultrasound guided fine needle aspiration biopsy was found to be more accurate and sensitive when two or more nodes were involved, raising the sensitivity to 80% and negative predictability to 93.3%. Preoperative axillary staging with ultrasound guided fine needle aspiration biopsy in invasive breast cancer patients is very beneficial in diagnosing nodes positive cases. These cases can be planned for axillary lymph nodes clearance straightaway therefore saving patients from undergoing further surgery as well as time and resources.

Differential diagnosis for chronic hypokalaemia.

Doctors will often see patients with chronic hypokalaemia, frequently this is secondary to gastrointestinal losses, diuretics or renal disease. However, in this case report we review a rarer cause of chronic hypokalaemia-Gitelman syndrome (GS).GS is an uncommon genetic disorder which causes primary renal tubular hypokalaemic metabolic alkalosis with secondary hypomagnesaemia and hypocalciuria. Although rare, it is important to remember GS when considering differential diagnoses for chronic hypokalaemia. We report the case of a woman who presented to the ophthalmology department with sclerochoroidal calcification. An ophthalmologist was reviewing the medical literature, which prompted them to investigate for GS. A diagnosis was formed at that time based on the blood and urine chemistry results. However, later we were able to offer the patient genetic testing, which confirmed our provisional diagnosis.

Posttraumatic Deep Vein Thrombosis in Collegiate Athletes: An Exploration Clinical Case Series.

BACKGROUND: Although athletes are typically at low risk for developing venous thromboembolism (VTE), injured and noninjured athletes alike can be exposed to many acquired risk factors, including intense training, dehydration, trauma, immobilization, oral contraceptive use, and long-distance travel. Additionally, the risk of developing VTE might be increased by unidentified genetic clotting disorders. Due to the potential for fatal outcomes, knowledge of VTE pathoetiology and recognition of deep vein thrombosis (DVT) presentation should be an inherent part of the evaluation process for all who attend to athletes, regardless of age and apparent risk profile. OBJECTIVE: To present an exploration clinical case series consisting of 2 otherwise healthy, college-aged female athletes who, despite their ages and relative low risk profiles, experienced DVTs after lower extremity trauma. Each case will be discussed relative to known clinical prediction rules (CPRs) and published evidence. CONCLUSIONS: Collectively, both cases reinforce the need for the attending clinicians to perform a thorough history and pay attention to subtle clinical findings, regardless of the relatively low risk in college-aged athletes. Although the Wells' CPRs for DVT can be used as a diagnostic guideline in the general population, it might not fully address the risks inherent in a young, otherwise healthy athletic population. We propose a risk-screening tool that is based on and modified from our experiences with these 2 patients and the known prediction rules and positive probability influences.

Increased frequency of delayed type hypersensitivity to metals in patients with connective tissue disease.

BACKGROUND: Connective tissue disease (CTD) is a group of inflammatory disorders of unknown aetiology. Patients with CTD often report hypersensitivity to nickel. We examined the frequency of delayed type hypersensitivity (DTH) (Type IV allergy) to metals in patients with CTD. METHODS: Thirty-eight patients; 9 with systemic lupus erythematosus (SLE), 16 with rheumatoid arthritis (RA), and 13 with Sjögren's syndrome (SS) and a control group of 43 healthy age- and sex-matched subjects were included in the study. A detailed metal exposure history was collected by questionnaire. Metal hypersensitivity was evaluated using the optimised lymphocyte transformation test LTT-MELISA(®) (Memory Lymphocyte Immuno Stimulation Assay). RESULTS: In all subjects, the main source of metal exposure was dental metal restorations. The majority of patients (87%) had a positive lymphocyte reaction to at least one metal and 63% reacted to two or more metals tested. Within the control group, 43% of healthy subjects reacted to one metal and only 18% reacted to two or more metals. The increased metal reactivity in the patient group compared with the control group was statistically significant (P<0.0001). The most frequent allergens were nickel, mercury, gold and palladium. CONCLUSIONS: Patients with SLE, RA and SS have an increased frequency of metal DTH. Metals such as nickel, mercury and gold are present in dental restorative materials, and many adults are therefore continually exposed to metal ions through corrosion of dental alloys. Metal-related DTH will cause inflammation. Since inflammation is a key process in CTDs, it is possible that metal-specific T cell reactivity is an etiological factor in their development. The role of metal-specific lymphocytes in autoimmunity remains an exciting challenge for future studies.

Down's syndrome risk estimates demonstrate considerable heterogeneity despite homogeneity of input.

BACKGROUND: Due to concerns about screening quality, Down's syndrome screening laboratories were surveyed to identify the range of variation in risk-calculation software. METHODS: All UK Down's syndrome screening laboratories were sent the confidential survey via the National External Quality Assessment Scheme. This covered the software used, its origin, the risk calculation methodology and the Gaussian population parameters. Laboratories were also given multiples of the median (MoM) data from five representative cases and asked to calculate Down's syndrome risks on their systems. RESULTS: Most parameter sets could be traced to published literature. The range of risk results for identical patient data was wide; the largest differences between lowest and highest risk for a test MoM set were: alpha-fetoprotein (AFP)+human chorionic gonadotrophin (hCG), 1:95 to 1:388 = 408%; AFP+hCG+urine estriol (UE(3)), 1:2011 to 1:7000 = 348%; AFP+free-beta-hCG, 1:280 to 1:1681 = 600%; AFP+free-beta-hCG+UE(3), 1:340 to 1:13000 = 3823%. Two explanations for this variation - the prior age risk result (half-year correction) and the population parameters - are described. CONCLUSIONS: (a) All laboratories should apply half-year correction for maternal age risk calculation. (b) Triple-test parameter variations result in huge variation of risk estimates, and a single national risk threshold of 1 in 250 will be unlikely to improve screening equity unless attention is also paid to standardizing population parameters. Down's syndrome screening has been controversial since it was introduced, and the possibility that more central control (including listing acceptable population parameters) may be necessary to ensure comparability of results is certain to ensure that this controversy continues.