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The determination of the variability of critical dosage form attributes has been a challenge in establishing the quality of pharmaceutical products. During the development process knowledge is minimal. Consequently, ad hoc statistical tools such as hypothesis or significance tests, with calibrated decision error rates are often used in an effort to vet CQAs (Critical Quality Attributes) and keep their levels "between the curbs". As progress moves towards product launch, process and mechanistic understanding grows considerably and there are opportunities to leverage that knowledge for predictive modeling. Bayesian models offer a coherent strategy for integrating prior knowledge into both experimental design as well as predictive analysis for optimal risk-based decision making. This is because the Bayesian paradigm, unlike the frequentist paradigm, can assign probabilities to underlying states of nature that directly impact safety and efficacy such as the population distribution of tablet potencies or dissolution profiles in a batch. However, there are challenges and reluctance in switching to a predictive modeling quality framework once regulatory approval has been attained. This paper offers encouragement to make this switch. In this paper, we review a joint Long Island University - Purdue University (LIU-PU) FDA funded project whose purpose was to further integrate the concepts of this adaptive approach to lot release with the rationale and methods for data generation and curation and to extend the testing of this approach. We discuss the utility of the approach in product development. We consider the regulatory compliance implications, with examples, and establish a potential way forward toward implementation of this approach for both industry and regulatory stake-holders.

IMPORTANCE: Transient global amnesia (TGA) is usually considered a benign event with a low recurrence rate. However, recurrence rates vary considerably among studies and there are no known risk factors for TGA. OBJECTIVE: To examine risk factors for the recurrence of TGA. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study involved medical record review of patients with isolated or recurrent TGA presenting to the Mayo Clinic in Rochester, Minnesota, between August 1, 1992, and February 28, 2018. A total of 1491 cases were reviewed and 1044 met diagnostic inclusion criteria for TGA, with the remainder excluded owing to indeterminate or alternate diagnoses or limited information available in the medical record. EXPOSURES: Single vs recurrent episodes of TGA. MAIN OUTCOMES AND MEASURES: Demographics, precipitating factors, migraine history, imaging and electrodiagnostic findings, and family history of TGA were collected. The main outcome measure was TGA recurrence. RESULTS: Of 1044 included patients, 575 (55.1%) were male, and the mean (SD) age at inclusion was 75.0 (11.5) years. A total of 901 patients (86.3%) had a single episode of TGA and 143 (13.7%) had recurrent episodes of TGA. The 2 groups were similar in age at inclusion, sex, identifiable triggers, and duration of anterograde amnesia. The number of recurrences ranged from 1 to 9, with 137 individuals (95.8%) having 3 or fewer recurrences. The mean (SD) age at first episode of TGA was 65.2 (10.0) years for individuals with a single episode vs 58.8 (10.3) years for those with recurrent episodes (P

Objective: To characterize the clinical, EEG, and neuroimaging profiles of transient epileptic amnesia (TEA). Methods: We performed a retrospective analysis of patients diagnosed with TEA at the Mayo Clinic Minnesota from January 1, 1998 to September 21, 2017. Diagnostic criteria included the presence of recurrent episodes of transient amnesia with preservation of other cognitive functions and evidence for epilepsy [epileptiform abnormalities on EEG, clinical features of seizures, or symptomatic response to anti-seizure medications (ASMs)]. Results: Nineteen patients were identified (14 men, 5 women) with median onset age 66 years and median time to diagnosis 2 years. Thirteen patients (68%) reported persistent cognitive/behavioral symptoms, including 4 (21%) for whom these were the chief presenting complaints. EEG revealed epileptiform abnormalities involving the frontal and/or temporal regions in 12/19 individuals (63%), including activation during sleep in all of these cases. In numerous cases, sleep and prolonged EEG evaluations identified abnormalities not previously seen on shorter or awake-state studies. Brain MRI revealed focal abnormalities in only 4/19 cases (21%). FDG-PET identified focal hypometabolism in 2/8 cases where it was performed, both involving the frontal and/or temporal regions. Anti-seizure therapy, most often with a single agent, resulted in improvement (reduction in spell frequency and/or subjective improvement in interictal cognitive/behavioral complaints) in all 17 cases with available follow-up. Conclusions: TEA is a treatable cause of amnestic spells in older adults. This syndrome is frequently associated with persistent interictal cognitive/behavioral symptoms and thus can be mistaken for common mimics. In the appropriate clinical context, our findings support the use of early prolonged EEG with emphasis on sleep monitoring as a key diagnostic tool. FDG-PET may also complement MRI in distinguishing TEA from neurodegenerative disease when suspected.

We deal with the following question: Can the consumption of contaminated bush meat, the funeral practices and the environmental contamination explain the recurrence and persistence of Ebola virus disease outbreaks in Africa? We develop an SIR-type model which, incorporates both the direct and indirect transmissions in such a manner that there is a provision of Ebola viruses. We prove that the full model has one (endemic) equilibrium which is locally asymptotically stable whereas, it is globally asymptotically stable in the absence of the Ebola virus shedding in the environment. For the sub-model without the provision of Ebola viruses, the disease dies out or stabilizes globally at an endemic equilibrium. At the endemic level, the number of infectious is larger for the full model than for the sub-model without provision of Ebola viruses. We design a nonstandard finite difference scheme, which preserves the dynamics of the model. Numerical simulations are provided.

Objectives: This study determined the value of whole body computerized tomography with 3D reconstruction and volume rendering in the forensic investigation of five fatal lightning strike cases. Materials and methods: We conducted a prospective study on all lightning deaths presenting to the Pretoria Medico-Legal Laboratory from 1st June 2013 to 1st June 2016. Five fatal lightning strike cases were submitted for forensic medical examination and had whole body computerized tomography with 3D reconstruction and volume rendering prior to medicolegal autopsy examination. All data were treated confidentially. Results: CT detected additional abnormalities in the brain, neck, gastrointestinal and genitourinary tracts, including underlying pre-existing disease compared to standard autopsy. Conclusion: CT with 3D reconstruction and volume rendering in lightning-related deaths, in conjunction with conventional autopsy yielded more significant and relevant findings than CT or autopsy alone. Spinal injuries (C1/C2) and a far more widespread documentation of barotrauma, especially of the lungs may be seen as a refinement of current knowledge. In general, with lightning-related deaths, where there are medicolegal implications, CT and standard autopsy should be performed together for optimal information.

Summary Background Few studies have examined the efficacy of drug-eluting stents (DES) for reducing aortocoronary saphenous vein bypass graft (SVG) failure compared with bare-metal stents (BMS) in patients undergoing stenting of de-novo SVG lesions. We assessed the risks and benefits of the use of DES versus BMS in de-novo SVG lesions. Methods Patients were recruited to our double-blind, randomised controlled trial from 25 US Department of Veterans Affairs centres. Eligible participants were aged at least 18 years and had at least one significant de-novo SVG lesion (50–99% stenosis of a 2·25–4·5 mm diameter SVG) requiring percutaneous coronary intervention with intent to use embolic protection devices. Enrolled patients were randomly assigned, in a 1:1 ratio, by phone randomisation system to receive a DES or BMS. Randomisation was stratified by presence or absence of diabetes and number of target SVG lesions requiring percutaneous coronary intervention (one or two or more) within each participating site by use of an adaptive scheme intended to balance the two stent type groups on marginal totals for the stratification factors. Patients, referring physicians, study coordinators, and outcome assessors were masked to group allocation. The primary endpoint was the 12-month incidence of target vessel failure, defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularisation. The DIVA trial is registered with ClinicalTrials.gov, number NCT01121224. Findings Between Jan 1, 2012, and Dec 31, 2015, 599 patients were randomly assigned to the stent groups, and the data for 597 patients were used. The patients' mean age was 68·6 (SD 7·6) years, and 595 (>99%) patients were men. The two stent groups were similar for most baseline characteristics. At 12 months, the incidence of target vessel failure was 17% (51 of 292) in the DES group versus 19% (58 of 305) in the BMS group (adjusted hazard ratio 0·92, 95% CI 0·63–1·34, p=0·70). Between-group differences in the components of the primary endpoint, serious adverse events, or stent thrombosis were not significant. Enrolment was stopped before the revised target sample size of 762 patients was reached. Interpretation In patients undergoing stenting of de-novo SVG lesions, no significant differences in outcomes between those receiving DES and BMS during 12 months of follow-up were found. The study results have important economic implications in countries with high DES prices such as the USA, because they suggest that the lower-cost BMS can be used in SVG lesions without compromising either safety or efficacy. Funding US Department of Veterans Affairs Cooperative Studies Program.

This chapter discusses assessment and evaluation of multicultural initiatives by exploring two efforts implemented at a small, liberal arts college.

Background. Registrars play a vital role in teaching undergraduate (UG) medical students. Previous studies indicate that registrars contribute as much as 30% of medical students’ knowledge and that up to 20% of a registrar’s time is spent on teaching UG medical students. The Association for Medical Education in Europe (AMEE) Guide No. 20 defines 12 roles of a teacher, including an on-the-job role-model.Objective. To evaluate the perception and attitudes of registrars with regard to their role as teachers of UG medical students.Methods. A questionnaire-based study with qualitative and quantitative aspects was conducted at the Faculty of Health Sciences, University of Pretoria,South Africa.Results. Despite numerous attempts, the response rate to the study was very poor, with only 25 registrars participating. This pilot study indicated thatregistrars were mostly involved with on-the-job training, followed by ward rounds and practical sessions. The attitudes towards teaching included that registrars deemed teaching as beneficial, with only three indicating that it should not be done by registrars. Advantages of teaching included own learning opportunities and gaining confidence in teaching. Registrars’ own workload and lack of time hampered teaching. The majority of registrars indicated that receiving training with regard to teaching would be useful.Conclusion. Our pilot study concurs with international studies, indicating that the benefits of teaching medical students include knowledge acquired by registrars. Studies showed that the knowledge obtained in this manner outweighed that obtained by self-study/attendance of lectures. The on-the-job role-model as part of teaching is applicable to registrars. The international literature indicates that until recently registrars were not offered a formal teaching programme. Our study echoed this, with only one student indicating that it is not necessary, as registrars should not be expected to teach.

Purpose: To determine the prevalence of HIV in the sudden, unexplained and unexpected (SUU) death population admitted to the Pretoria Medico-Legal Laboratory.Methods: This study was conducted at the Pretoria Medico-Legal Laboratory. Blood samples were obtained from decedents who died suddenly and/or unexpectedly, during autopsy, by a forensic pathologist. Sample collection continued until 100 valid samples were analysed for HIV antibodies. The data collected included demographic details and case-related information.Results and Conclusion: SUU deaths accounted for 14% of all cases admitted to the Pretoria Medico-Legal Laboratory. The HIV prevalence in the SUU deaths was 43%, which is 17% higher than the general mortuary population in Pretoria ( p = 0.0045). The majority of these deaths were due to respiratory disease processes, with 12 cases having HIV/TB co-infection.Keywords: Sudden; Unexplained and unexpected death; Post mortem; HIV; Mortuary; Pretoria; South Africa

Drowning is classified as the 3rd leading cause of accidental deaths worldwide and is deemed to be a preventable cause of death. Bodies retrieved from a water medium pose several challenges to the forensic pathologist with the diagnosis of drowning being primarily one of exclusion. The aim of this study was to do a retrospective descriptive case audit of bodies retrieved from water and immersion related deaths, which were investigated at the Pretoria Medico-Legal Laboratory (PMLL) over a 10 year period (January 2002 through December 2011). A total of 346 cases were identified for inclusion into this study. In 6% (20) of these cases, the death was not related to drowning; in 14% (48) no clear cause of death could be ascertained and in 278 cases (80%) the cause of death was considered to have been due to drowning. Infants (under 1 year, of age) constituted 41 (15%) of the cases; toddlers (aged 1-2 years) comprised 52 (19%) cases; children (aged 2-13 years) 49 (18%) cases; adolescents (aged 13-18 years) comprised 10 (3%) cases; adults (above 18, years) made up 126 (45%) of the cases. The majority of the drownings, occurred in swimming pools [125 cases (38%)]. In infants 23 (56%) of, drownings occurred in swimming pools followed by buckets [7 cases (17%)]. Sixty-nine per cent of toddler drownings (36 cases) occurred in swimming, pools. In the adult population, 40 (32%) of cases occurred in pools and 35 cases (28%) in rivers. Positive blood alcohol results were recorded in 48, (42%) out of 113 cases where the test was requested, 40 (35%) of these, cases higher than 0.05 g per 100 ml. This study suggests that many drowning deaths in Pretoria may be preventable by introducing greater public awareness of the risks and instituting relatively simple, protective measures.

BACKGROUND. The World Health Organization has declared suicide a global health crisis, predicting that ~1.53 million people will commit suicide annually by 2020. OBJECTIVE. A study from South Africa reviewed 1 018 suicide cases in Pretoria over 4 years (1997 - 2000). Our study was undertaken to establish whether there have been substantial changes in the profile of suicide victims who died in Pretoria a decade later. METHODS. Case records at the Pretoria Medico-Legal Laboratory were reviewed retrospectively from 2007 to 2010. RESULTS. A total of 957 suicide cases were identified. Hanging was the most common method of suicide, followed by self-inflicted firearm injury. The true incidence of suicidal intake of prescription drugs/medication was difficult to determine, because of a backlog at the state toxicology laboratories. White males and females appeared to be over-represented among suicide victims, but there has been an increase in suicide among blacks. There seems to have been a substantial decrease in the use of firearms to commit suicide - possibly reflecting a positive outcome of gun control legislation that has been introduced in the interim. CONCLUSION. Suicide continues to constitute almost 10% of all fatalities admitted to the Pretoria Medico-Legal Laboratory, confirming suicide as a major cause of mortality in our society. Further research is needed to clarify the profile of suicidal deaths, with a view to informing resource allocation and to improve preventive strategies.

A 41-year old male sustained a fatal gunshot wound during a house robbery. Police enquiries and scene investigation revealed that a single shot had been fired and that one spent 9 mm cartridge case was retrieved from the scene. At autopsy the beige short sleeved jacket and printed white T-shirt worn by the deceased each displayed a single perforating defect on the right front aspect (approximately overlying the pectoral region), with associated blood staining (Fig. 1). Two penetrating wounds were present on the skin of the anterior aspect of the right pectoral region, one above the other and in close proximity to each other, located approximately 6 cm medial to the right nipple (Fig. 2). The uppermost wound was round in shape, measuring 0.9 cm in diameter with a distinct but irregular concentric peripheral collar of abrasion. The lowermost wound was oval in shape, measuring 2 9 1 cm in size and with a relatively ‘‘clean cut’’ appearance of the edges, except in the 9 o’clock to 1 o’clock position, where there was irregular superficial abrasion of the adjacent skin. Neither of the wounds displayed features of associated heat injury, soot deposition or powder tattooing. Upon palpation and superficial dissection of the back, at a point 25 cm below the level of the shoulder and 5 cm medial to the midline on the left, a somewhat misshapen 7.65 mm projectile was recovered. Transillumination (C-arm fluoroscopy) revealed the presence of two further foreign metal objects in the chest region; one had the typical appearance of a heavy caliber handgun projectile (left posterior chest wall), while the other had the appearance of a spent (misshapen) cartridge case, in the right chest cavity (Fig. 3). Upon opening of the chest, a free-lying deformed 7.65 mm cartridge case was recovered from the right pleural cavity, with bilateral hemothoraces. There were two penetrating wound tracts traversing the right anterior chest wall between the third and fourth ribs parasternally (with some fragmentation of the adjacent sternum) and with two slightly divergent wound tracts subsequently perforating the chest cavity from front to back and from right to left. One tract tangentially involved (inter alia) the anteromedial portion of the upper lobe of the right lung, the proximal ascending aorta and the posteromedial portion of the lower lobe of the left lung, culminating where the spent 7.65 mm caliber projectile had been removed from the superficial subcutaneous tissues of the back (as described above). The second wound tract traversed the anterior pericardial sac, the right and left atria of the heart and the posteromedial portion of the lower lobe of the left lung, culminating in the eighth intercostal space (posterior), where a spent 9 mm caliber projectile was found. Interestingly, the front end of the latter projectile had a clearly visible indentation, being a mirror imprint which corresponded to the base of the cartridge case of the 7.65 mm projectile (Figs. 4, 5). Based on the overall findings, we postulate that the intact 7.65 mm round had previously lodged within the barrel of the firearm, where it was subsequently impacted from behind by the fired 9 mm round and with all the projectiles then entering the chest of the deceased. The approximate configuration of the projectiles would then have been as displayed in the reconstructed sequence shown in Fig. 6. It is not certain which of the wounds was caused by which of the projectiles, but it seems likely that the larger, ovoid wound may have been caused by the 7.65 mm cartridge and/or projectile, with the 9 mm L. du Toit-Prinsloo (&) N. K. Morris G. Saayman Department of Forensic Medicine, University of Pretoria, Private Bag X323, Arcadia 0007, South Africa e-mail: lorraine.dutoit@up.ac.za

BACKGROUND: Malaria case numbers reported in South Africa have reduced considerably over the last decade, necessitating a revision of the national risk map to guide malaria prevention, including the use of chemoprophylaxis. OBJECTIVES: To update the national malaria risk map based on recent case data and to consider the implications of the new transmission profile for guiding prophylaxis. METHODS: The geographical distribution of confirmed malaria cases detected both passively and actively over the last six malaria seasons was used to redefine the geographical distribution and intensity of malaria transmission in the country. RESULTS: The national risk map was revised to reflect zones of transmission reduced both in their extent and their intensity. Most notably, the area of risk has been reduced in the north-western parts of Limpopo Province and is limited to the extreme northern reaches of KwaZulu-Natal Province. Areas previously considered to be of high risk are now regarded to be of moderate risk. CONCLUSION: Chemoprophylaxis is now only recommended from September to May in the north-eastern areas of Limpopo and Mpumalanga Provinces. The recommended options for chemoprophylaxis have not changed from mefloquine, doxycycline or atovaquone-proguanil.

Hairiness in women is a deeply embarrassing topic. Our culture dictates that a female body is only beautiful when it is silky smooth and hair-free. Hair that is normally not noticeable is called vellus hair. It is fine, unpigmented, without a medulla, and is found all over the body’s surface with the exception of the palms of the hands and the soles of the feet. Visible hair is known as terminal hair. It is thicker than vellus hair, pigmented, and medullated. Terminal hair is found, for example, on the scalp, eyelashes, eyebrows, and axilla (armpits), and particularly in males, on the upper lip, chin, chest, arms and legs.

Networking large numbers of simulators over long distances is a very promising concept that has been demonstrated recently with SIMNET. This concept seems to work well with tanks and other slow moving vehicles. However, a question exists whether or not it will work with fast moving highly maneuverable fighter aircraft. Distributed lnteractive Simulation (DIS) has taken on the task of making this happen. A technique, used in SIMNET and to be expanded in DIS, called dead reckoning, reduces the number of network updates required of each participant. This makes better use of the available bandwidth. This paper discusses the implementation and evaluation of a number of extrapolation algorithms. Comparisons are made between first and second order extrapolation and various methods of performing second order extrapolation delays caused by the large distances involved are compensated and the effect is studied. The large jumps caused by low frequency updating are smoothed by several algorithms and the results compared. Overall, very good results were obtained using second order extrapolation by simple Euler algorithms and smoothing the results.

Many archaeologists have ignored the complexities of preservation treatments and have proceeded alone, often with unsatisfactory results. Now that new legislation can provide conservation funding, archaeologists involved in federally funded research should have little reason to ignore professional standards in the areas of conservation, preservation, and collection interpretation and maintenance. Specific advantages of professional conservation input for the archaeologist are cited with reference to a case study in Maine. Archaeology can be defined as the study of human culture as revealed by its material remains.

The conservation of archaeological materials should be considered part of any archaeological recovery analysis or storage operation. In the past two decades, conservation has begun to emerge as a profession. With this advent should come an increased awareness on the part of archaeologists that specialized techniques and practices used by conservators can prolong the life and usefulness of irreplaceable data base collections. With a few notable exceptions, professional conservation for collections has been ignored in the past. The result of neglect has been lost or badly damaged artifacts. This situation can and should be rectified.