Hereditary angio-oedema in the Western Cape Province, South Africa.

BACKGROUND: Hereditary angio-oedema (HAE) is an autosomal dominant condition caused by a deficiency in the C1-esterase inhibitor protein, resulting in increased bradykinin release. It presents clinically with recurrent attacks of angio-oedema, commonly affecting the limbs, face, upper airway and gastrointestinal tract. Little is known about this condition in sub-Saharan Africa. OBJECTIVES: To analyse and report on the clinical presentation and treatment of patients with HAE in the Western Cape Province, South Africa. METHODS: A retrospective analysis was conducted on a series of 60 cases of HAE seen between 2010 and 2015 at the Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, and the Allergy Clinic at Groote Schuur Hospital, Cape Town. The findings in 43 cases of type 1 HAE are described. Parameters assessed included age, gender, age of diagnosis, duration of illness, family history, identifiable triggers, average duration of attack, number of attacks per year and type of attack. RESULTS: A total of 43 patients were included in this study. Of these, 65.1% (28/43) were female. The median age at diagnosis was 20 years (interquartile range (IQR) 10 - 27) and the median duration of illness 10.5 years (IQR 6 - 22). Of the patients, 62.8% (27/43), 32.6% (14/43) and 4.7% (2/43) were of mixed ancestry, white and black African, respectively; 51.2% (22/43) were index cases, with the remaining 48.8% (21/43) diagnoses via family member screening, 12 families making up the majority of the cohort. The mean (standard deviation) duration of an acute attack was 49 (25.8) hours, and 64.3% (27/42), 71.4% (30/42), 14.3% (6/42) and 88.1% (37/42) of patients experienced facial or upper airway, abdominal, external genitalia and limb attacks, respectively. Danazol for long-term prophylaxis was used in 21 patients, while C1-inhibitor concentrate (Berinert) was accessed for short-term prophylaxis in only four patients. Acute life-threating attacks were treated with fresh frozen plasma in 11 patients, and only four accessed icatibant. The mortality rate for the period 2010 - 2015 was 4.5% (2/43). The prevalence of HAE in the Western Cape was estimated to be 1:140 000. CONCLUSIONS: HAE occurs in South Africans of all ethnicities, and life-threatening attacks occur in almost two-thirds of patients. Despite limited therapeutic options and very limited access to gold-standard therapies available in the developed world, our mortality rate is very low, with both the deaths related to inability to access emergency treatment rapidly.

Hereditary angio-oedema in the Western Cape Province, South Africa

Background. Hereditary angio-oedema (HAE) is an autosomal dominant condition caused by a deficiency in the C1-esterase inhibitor protein, resulting in increased bradykinin release. It presents clinically with recurrent attacks of angio-oedema, commonly affecting the limbs, face, upper airway and gastrointestinal tract. Little is known about this condition in sub-Saharan Africa.Objectives. To analyse and report on the clinical presentation and treatment of patients with HAE in the Western Cape Province, South Africa.Methods. A retrospective analysis was conducted on a series of 60 cases of HAE seen between 2010 and 2015 at the Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, and the Allergy Clinic at Groote Schuur Hospital, Cape Town. The findings in 43 cases of type 1 HAE are described.Parameters assessed included age, gender, age of diagnosis, duration of illness, family history, identifiable triggers, average duration of attack, number of attacks per year and type of attack.Results. A total of 43 patients were included in this study. Of these, 65.1% (28/43) were female. The median age at diagnosis was 20 years (interquartile range (IQR) 10 - 27) and the median duration of illness 10.5 years (IQR 6 - 22). Of the patients, 62.8% (27/43), 32.6% (14/43) and 4.7% (2/43) were of mixed ancestry, white and black African, respectively; 51.2% (22/43) were index cases, with the remaining 48.8% (21/43) diagnoses via family member screening, 12 families making up the majority of the cohort. The mean (standard deviation) duration of an acute attack was 49 (25.8) hours, and 64.3% (27/42), 71.4% (30/42), 14.3% (6/42) and 88.1% (37/42) of patients experienced facial or upper airway, abdominal, external genitalia and limb attacks, respectively.Danazol for long-term prophylaxis was used in 21 patients, while C1-inhibitor concentrate (Berinert) was accessed for short-term prophylaxis in only four patients. Acute life-threating attacks were treated with fresh frozen plasma in 11 patients, and only four accessed icatibant. The mortality rate for the period 2010 - 2015 was 4.5% (2/43). The prevalence of HAE in the Western Cape was estimated to be 1:140 000.Conclusions.HAE occurs in South Africans of all ethnicities, and life-threatening attacks occur in almost two-thirds of patients. Despite limited therapeutic options and very limited access to gold-standard therapies available in the developed world, our mortality rate is very low, with both the deaths related to inability to access emergency treatment rapidly

Choledochotomy and primary repair of extrahepatic biliary duct rupture in seven dogs and two cats.

OBJECTIVE: To report clinical findings and outcome in dogs and cats undergoing choledochotomy or primary repair of extrahepatic biliary duct rupture. METHODS: Retrospective study of dogs (n=7) and cats (n=2) that had choledochotomy or primary bile duct repair. RESULTS: Extrahepatic biliary obstruction was confirmed at surgery in all cases. The underlying cause in four dogs and both cats was choledocholithiasis, two dogs had gall bladder mucocoeles with associated bile duct rupture, and one dog had inspissated bile obstructing the bile duct secondary to gall bladder carcinoid tumour. Three dogs and both cats had choledochotomies performed to relieve extrahepatic biliary obstruction, and four dogs with bile duct rupture underwent primary repair of the defect. One dog with a bile duct rupture was re-explored four days postoperatively and had suffered dehiscence of the repair; this rupture was re-repaired. All animals were discharged from the hospital, and did not have clinical recurrence of extrahepatic biliary obstruction. CLINICAL SIGNIFICANCE: Choledochotomy and primary repair of extrahepatic biliary duct rupture were associated with low perioperative morbidity and no mortality in this small cohort of cases. These techniques are reasonable options either alone or in conjunction with other procedures when bile duct patency cannot be re-established by catheterisation or bile duct discontinuity exists.

Comparison of four commercial devices to measure limb circumference in dogs.

We evaluated four measurement devices for obtaining circumferential measurements at four locations on the canine hindlimb and forelimb. We hypothesised that these devices would be consistent and precise in the hands of veterinary professionals with varying experience levels. Circumferential measurements were made in five dogs with no history or clinical evidence of orthopaedic disease. Measurements were obtained in triplicate by three observers at mid-thigh, tibial tuberosity, hock and carpus bilaterally. Results indicated a significantly larger measurement at the left mid-thigh region than the right, with no significant differences between limbs noted at other sites. Measurements with a tape measure and a retractable tape measure resulted in significantly smaller values at each site than an ergonomic measuring tape and a circumference measuring tape. Interobserver variation was 3.6 times higher than intraobserver variation. These results illustrate the importance of consistency when obtaining these measurements. Sequential circumference measurements should be made by the same individual using the same device to decrease measurement variability. Devices were equally precise for repeat measurements although the absolute measurement varied by device.

Effect of bandaging on post-operative swelling after tibial plateau levelling osteotomy.

OBJECTIVE: To compare the effects of bandaging on immediate postoperative swelling using a modified Robert-Jones bandage after tibial plateau levelling osteotomy (TPLO) in dogs. STUDY DESIGN: Prospective case series. METHODS: Dogs undergoing a TPLO were randomly placed into two groups. Group 1 received a modified Robert-Jones bandage postoperatively for a 24 hour period and Group 2 was not bandaged. Hindlimb circumference was measured at the level of the mid-patella, the distal aspect of the tibial crest, the mid-point of the tibial diaphysis and the hock. Measurements were recorded and compared in each group preoperatively and at 24 hours and 48 hours post-operatively. Interobserver variability was compared between the two observers. RESULTS: There was no significant difference in postoperative swelling, as measured by the percentage change in circumference, between bandaged and unbandaged operated limbs after the TPLO at 24 and 48 hours at any site. Some significant differences in measurement at particular sites were observed between the two different observers, but there was a significant linear correlation at all sites between observers. The observer with the least experience consistently had slightly higher measurements at these sites. CLINICAL RELEVANCE: The use of a modified Robert-Jones bandage after TPLO did not prevent statistically significant postoperative swelling, and thus may not be indicated for this purpose. Postoperative bandages placed to control swelling after other small animal orthopaedic procedures should be evaluated individually for efficacy.

Good for women, good for men, bad for people: Simpson's paradox and the importance of sex-specific analysis in observational studies.

Even if a medial intervention has a beneficial effect in both men and women, an observational study that combines data from men and women can lead to the incorrect conclusion that treatment has a harmful effect. This is an example of Simpson's paradox, which although uncommon in practice, does, in fact, occur (Wainer H. Simpson's paradox. Chance 1999;12:43). More importantly, it is likely that in an observational study, a related result will occur; namely, ignoring sex in the analysis will lead to biased results. To better understand why Simpson's paradox and the related result occur, we present a graphic explanation.

The paired availability design for historical controls.

BACKGROUND: Although a randomized trial represents the most rigorous method of evaluating a medical intervention, some interventions would be extremely difficult to evaluate using this study design. One alternative, an observational cohort study, can give biased results if it is not possible to adjust for all relevant risk factors. METHODS: A recently developed and less well-known alternative is the paired availability design for historical controls. The paired availability design requires at least 10 hospitals or medical centers in which there is a change in the availability of the medical intervention. The statistical analysis involves a weighted average of a simple "before" versus "after" comparison from each hospital or medical center that adjusts for the change in availability. RESULTS: We expanded requirements for the paired availability design to yield valid inference. (1) The hospitals or medical centers serve a stable population. (2) Other aspects of patient management remain constant over time. (3) Criteria for outcome evaluation are constant over time. (4) Patient preferences for the medical intervention are constant over time. (5) For hospitals where the intervention was available in the "before" group, a change in availability in the "after group" does not change the effect of the intervention on outcome. CONCLUSION: The paired availability design has promise for evaluating medical versus surgical interventions, in which it is difficult to recruit patients to a randomized trial.

Compliance subsampling designs for comparative research: estimation and optimal planning.

For studies with treatment noncompliance, analyses have been developed recently to better estimate treatment efficacy. However, the advantage and cost of measuring compliance data have implications on the study design that have not been as systematically explored. In order to estimate better treatment efficacy with lower cost, we propose a new class of compliance subsampling (CSS) designs where, after subjects are assigned treatment, compliance behavior is measured for only subgroups of subjects. The sizes of the subsamples are allowed to relate to the treatment assignment, the assignment probability, the total sample size, the anticipated distributions of outcome and compliance, and the cost parameters of the study. The CSS design methods relate to prior work (i) on two-phase designs in which a covariate is subsampled and (ii) on causal inference because the subsampled postrandomization compliance behavior is not the true covariate of interest. For each CSS design, we develop efficient estimation of treatment efficacy under binary outcome and all-or-none observed compliance. Then we derive a minimal cost CSS design that achieves a required precision for estimating treatment efficacy. We compare the properties of the CSS design to those of conventional protocols in a study of patient choices for medical care at the end of life.

Yersinia pestis pFra shows biovar-specific differences and recent common ancestry with a Salmonella enterica serovar Typhi plasmid.

Population genetic studies suggest that Yersinia pestis, the cause of plague, is a clonal pathogen that has recently emerged from Yersinia pseudotuberculosis. Plasmid acquisition is likely to have been a key element in this evolutionary leap from an enteric to a flea-transmitted systemic pathogen. However, the origin of Y. pestis-specific plasmids remains obscure. We demonstrate specific plasmid rearrangements in different Y. pestis strains which distinguish Y. pestis bv. Orientalis strains from other biovars. We also present evidence for plasmid-associated DNA exchange between Y. pestis and the exclusively human pathogen Salmonella enterica serovar Typhi.

Rethinking historical controls.

Inference from traditional historical controls, i.e. comparing a new treatment in a current series of patients with an old treatment in a previous series of patients, may be subject to a strong selection bias. To avoid this bias, Baker and Lindeman (1994) proposed the paired availability design. By applying this methodology to estimate the effect of epidural analgesia on the probability of Cesarean section, we made two important contributions with the current study. First, we generalized the methodology to include different types of availability and multiple time periods. Second, we investigated how well the paired availability design reduced selection bias by comparing results to those from a meta-analysis of randomized trials and a multivariate analysis of concurrent controls. The confidence interval from the paired availability approach differed considerably from that of the multivariate analysis of concurrent controls but was similar to that from the meta-analysis of randomized trials. Because we believe the multivariate analysis of concurrent controls omitted an important predictor and the meta-analysis of randomized trials was the gold standard for inference, we concluded that the paired availability design did, in fact, reduce selection bias.

Identifying combinations of cancer markers for further study as triggers of early intervention.

In many long-term clinical trials or cohort studies, investigators repeatedly collect and store tissue or serum specimens and later test specimens from cancer cases and a random sample of controls for potential markers for cancer. An important question is what combination, if any, of the molecular markers should be studied in a future trial as a trigger for early intervention. To answer this question, we summarized the performance of various combinations using Receiver Operating Characteristic (ROC) curves, which plot true versus false positive rates. To construct the ROC curves, we proposed a new class of nonparametric algorithms which extends the ROC paradigm to multiple tests. We fit various combinations of markers to a training sample and evaluated the performance in a test sample using a target region based on a utility function. We applied the methodology to the following markers for prostate cancer, the last value of total prostate-specific antigen (PSA), the last ratio of total to free PSA, the last slope of total PSA, and the last slope of the ratio. In the test sample, the ROC curve for last total PSA was slightly closer to the target region than the ROC curve for a combination of four markers. In a separate validation sample, the ROC curve for last total PSA intersected the target region in 77% of bootstrap replications, indicating some promise for further study. We also discussed sample size calculations.

A method for identifying abrupt changes in U.S. cancer mortality trends.

BACKGROUND: Summaries of trends in cancer rates evaluated over a fixed, short period are informative, but methods that evaluate trends over a longer time period, identifying when changes occur as well as the magnitude of the changes, can provide additional information. METHODS: Cancer mortality trends from 1973-1995 were determined for more than 15 anatomic sites for white and black males and females using weighted piecewise linear regression analysis with a stepwise selection procedure. The dependent variable was the natural logarithm of the annual mortality rate, and the weight was the annual number of cancer deaths. The variability of estimated change points was examined by bootstrapping the residuals from the resulting models. RESULTS: For black males, cancer mortality rates declined in the 1990s due to decreases in lung, esophageal, oral cavity, and prostate cancer rates. However, there was no significant decline for cancer of the colon and rectum. For white males, cancer mortality rates declined in the 1990s due to declines in cancer of the lung and colon/rectum since the mid-1980s and declines in prostate cancer in the 1990s. For black females and white females, total cancer mortality rates declined, but not significantly. Cancer rates for all sites except the lung declined significantly in the 1990s for white, but not black, females due to declining trends for carcinoma of the colon and rectum since the mid-1980s and for breast cancer in the 1990s. CONCLUSIONS: A method for identifying major changes in cancer trends has been developed. Trends for cancer of the breast and colon/rectum indicate that gaps between rates for blacks and whites are widening.

The partial testing design: a less costly way to test equivalence for sensitivity and specificity.

We propose a new, less costly, design to test the equivalence of digital versus analogue mammography in terms of sensitivity and specificity. Because breast cancer is a rare event among asymptomatic women, the sample size for testing equivalence of sensitivity is larger than that for testing equivalence of specificity. Hence calculations of sample size are based on sensitivity. With the proposed design it is possible to achieve the same power as a completely paired design by increasing the number of less costly analogue mammograms and not giving the more expensive digital mammograms to some randomly selected subjects who are negative on the analogue mammogram. The key idea is that subjects who are negative on the analogue mammogram are unlikely to have cancer and hence contribute less information for estimating sensitivity than subjects who are positive on the analogue mammogram. To ascertain disease state among subjects not biopsied, we propose another analogue mammogram at a later time determined by a natural history model. The design differs from a double sampling design because it compares two imperfect tests instead of combining information from a perfect and imperfect test.

Evaluating the age to begin periodic breast cancer screening using data from a few regularly scheduled screenings.

To evaluate various ages to begin periodic breast cancer screening, we propose a method of analysis that can be applied to either a nonrandomized or a randomized study involving only a few screenings at regular intervals. For the analysis of data from a nonrandomized study, we assume (i) once breast cancer can be detected on screening and confirmed by biopsy, it will stay that way; (ii) given age, the probability of breast cancer detection does not depend on year of birth; and (iii) subjects who refuse screening have the same rates of breast cancer mortality following diagnosis as screened subjects had they not received screening. The key idea is that older screened subjects are controls for younger screened subjects. For the analysis of data from a randomized study, we relax assumption (iii). Based on the HIP randomized trial and assumptions (i) and (ii), we estimate that starting periodic breast cancer screening with mammography and physical examination at age 40 instead of age 50 reduces breast cancer mortality by 14 per 10,000 with a 95% confidence interval of (-4/10,000, 32/10,000). This must be weighted against an estimated increase in the number of biopsies that do not detect cancer of 580 per 10,000 with a 95% confidence interval of (520/10,000, 650/10,000).

Cytologic detection of esophageal squamous cell carcinoma and precursor lesions using balloon and sponge samplers in asymptomatic adults in Linxian, China.

BACKGROUND: The principal reason for the poor prognosis of esophageal carcinoma is that most tumors are asymptomatic and go undetected until they are unresectable. Previous studies have shown that cytologic screening of asymptomatic high risk individuals can detect curable esophageal carcinomas and precursor lesions, but the sensitivity of such screening is not well documented. The current study evaluated the sensitivity and specificity of currently available balloon and sponge cytologic samplers for detecting biopsy-proven squamous dysplasia and carcinoma in asymptomatic individuals from a high risk population in Linxian, China. METHODS: Asymptomatic adults were examined with both balloon and sponge samplers, in random order, followed by endoscopy with mucosal iodine staining and biopsy of all unstained lesions. The cytology slides were interpreted using the criteria of the Bethesda System. The balloon and sponge cytologic diagnoses (test) were compared with the biopsy diagnosis (truth) in each patient to estimate the sensitivity and specificity of each sampler. RESULTS: Of the 439 patients with adequate biopsies, 123 (28%) had histologic squamous dysplasia and 16 (4%) had an invasive squamous carcinoma. The sensitivities/specificities of the balloon and sponge were 44%/99% and 18%/100%, respectively, for detecting biopsy-proven squamous cell carcinoma, and 47%/81% and 24%/92%, respectively, for identifying squamous dysplasia or carcinoma. CONCLUSIONS: In this study, the balloon sampler was more sensitive than the sponge sampler for detecting esophageal squamous disease, but both techniques were less than optimal. Improved samplers and/or cytologic criteria should increase the sensitivities observed in this baseline study.

Brief communication: prehistoric dentistry in the American southwest: a drilled canine from Sky Aerie, Colorado.

A prehistoric Native American mandible from a Fremont site (circa AD 1025) in Colorado has a conical pit in the worn occlusal surface of the lower right canine. Natural causes for this modification are ruled out by the presence of internal striae, a finding confirmed by experimental replication. The canine was artificially drilled before the individual's death and is associated with a periapical abscess. This is one of a very few examples of prehistoric dentistry in the world, and the first from the American Southwest.

The "amnesty" aftermath: current policy issues stemming from the legalization programs of the 1986 Immigration Reform and Control Act.

"The 1986 Immigration Reform and Control Act (IRCA) created two one-time only legalization programs affecting nearly 3 million undocumented immigrants. Legalization has produced important changes among immigrants and in immigration policy. These changes include new patterns of immigrant social and economic adaptation to the United States and new immigrant flows through family ties to IRCA-legalized aliens.... This article combines data from a longitudinal survey of the IRCA-legalized population with qualitative field data on current immigration issues from key informants in eight high-immigration metropolitan areas. It reviews the political evolution and early implementation of legalization, the current socioeconomic position of legalized aliens, and changes in the immigration ¿policy space' resulting from legalization."

The analysis of categorical case-control data subject to nonignorable nonresponse.

In analyzing partially observed categorical case-control data, Williamson and Haber (1994, Biometrics 50, 194-203) assumed ignorable nonresponse. We reanalyzed the data allowing for nonignorable nonresponse while explicitly incorporating case-control sampling.