The extinct, giant giraffid Sivatherium giganteum – skeletal reconstruction and body mass estimation

Sivatherium giganteum is an extinct giraffid from the Plio–Pleistocene boundary of the Himalayan foothills. To date, there has been no rigorous skeletal reconstruction of this unusual mammal. Historical and contemporary accounts anecdotally state that Sivatherium rivalled the African elephant in terms of its body mass, but this statement has never been tested. Here, we present a three-dimensional composite skeletal reconstruction and calculate a representative body mass estimate for this species using a volumetric method. We find that the estimated adult body mass of 1246 kg (857—1812 kg range) does not approach that of an African elephant, but confirms that Sivatherium was certainly a large giraffid, and may have been the largest ruminant mammal that has ever existed. We contrast this volumetric estimate with a bivariate scaling estimate derived from Sivatherium's humeral circumference and find that there is a discrepancy between the two. The difference implies that the humeral circumference of Sivatherium is greater than expected for an animal of this size, and we speculate this may be linked to a cranial shift in centre of mass

Temporal and phylogenetic evolution of the sauropod dinosaur body plan

The colossal size and body plan of sauropod dinosaurs are unparalleled in terrestrial vertebrates. However, to date, there have been only limited attempts to examine temporal and phylogenetic patterns in the sauropod bauplan. Here, we combine three-dimensional computational models with phylogenetic reconstructions to quantify the evolution of whole-body shape and body segment properties across the sauropod radiation. Limitations associated with the absence of soft tissue preservation in fossils result in large error bars about mean absolute body shape predictions. However, applying any consistent skeleton : body volume ratio to all taxa does yield changes in body shape that appear concurrent with major macroevolutionary events in sauropod history. A caudad shift in centre-of-mass (CoM) in Middle Triassic Saurischia, associated with the evolution of bipedalism in various dinosaur lineages, was reversed in Late Triassic sauropodomorphs. A craniad CoM shift coincided with the evolution of quadrupedalism in the Late Triassic, followed by a more striking craniad shift in Late Jurassic–Cretaceous titanosauriforms, which included the largest sauropods. These craniad CoM shifts are strongly correlated with neck enlargement, a key innovation in sauropod evolution and pivotal to their gigantism. By creating a much larger feeding envelope, neck elongation is thought to have increased feeding efficiency and opened up trophic niches that were inaccessible to other herbivores. However, we find that relative neck size and CoM position are not strongly correlated with inferred feeding habits. Instead the craniad CoM positions of titanosauriforms appear closely linked with locomotion and environmental distributions, potentially contributing to the continued success of this group until the end-Cretaceous, with all other sauropods having gone extinct by the early Late Cretaceous

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

Purpose The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. Methods A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. Results Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. Conclusion Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies

A New Encoding Algorithm for a Multidimensional Version of the Montgomery Ladder

We propose a new encoding algorithm for the simultaneous differential multidimensional scalar point multiplication algorithm $d$-MUL. Previous encoding algorithms are known to have major drawbacks in their efficient and secure implementation. Some of these drawbacks have been avoided in a recent paper in 2018 at a cost of losing the general functionality of the point multiplication algorithm. In this paper, we address these issues. Our new encoding algorithm takes the binary representations of scalars as input, and constructs a compact binary sequence and a permutation, which explicitly determines a regular sequence of group operations to be performed in $d$-MUL. Our algorithm simply slides windows of size two over the scalars and it is very efficient. As a result, while preserving the full generality of $d$-MUL, we successfully eliminate the recursive integer matrix computations in the originally proposed encoding algorithms. We also expect that our new encoding algorithm will make it easier to implement $d$-MUL in constant time. Our results can be seen as the efficient and full generalization of the one dimensional Montgomery ladder to arbitrary dimension

Temporal and phylogenetic evolution of the sauropod dinosaur body plan

The colossal size and body plan of sauropod dinosaurs are unparalleled in terrestrial vertebrates. However, to-date there have been only limited attempts to examine temporal and phylogenetic patterns in the sauropod bauplan. Here we combine three-dimensional computational models with phylogenetic reconstructions to quantify the evolution of whole-body shape and body segment properties across the sauropod radiation. Limitations associated with the absence of soft tissue preservation in fossils result in large error bars about mean absolute body shape predictions. However, applying any consistent skeleton:body volume ratio to all taxa does yield changes in body shape that appear concurrent with major macroevolutionary events in sauropod history. A caudad shift in centre-of-mass in Middle Triassic Saurischia, associated with the evolution of bipedalism in various dinosaur lineages, was reversed in Late Triassic sauropodomorphs. A craniad centre-of-mass shift coincided with the evolution of quadrupedalism in the Late Triassic, followed by a more striking craniad shift in Late Jurassic–Cretaceous titanosauriforms, which included the largest sauropods. These craniad CoM shifts are strongly correlated with neck enlargement, a key innovation in sauropod evolution and pivotal to their gigantism. By creating a much larger feeding envelope, neck elongation is thought to have increased feeding efficiency and opened up trophic niches that were inaccessible to other herbivores. However, we find that relative neck size and center-of-mass position are not strongly correlated with inferred feeding habits. Instead the craniad center-of-mass positions of titanosauriforms appear closely linked with locomotion and environmental distributions, potentially contributing to the continued success of this group until the end-Cretaceous, with all other sauropods having gone extinct by the early Late Cretaceous

Low specificity of determine HIV1/2 RDT using whole blood in south west Tanzania

Objective: To evaluate the diagnostic performance of two rapid detection tests (RDTs) for HIV 1/2 in plasma and in whole blood samples. Methods: More than 15,000 study subjects above the age of two years participated in two rounds of a cohort study to determine the prevalence of HIV. HIV testing was performed using the Determine HIV 1/2 test (Abbott) in the first (2006/2007) and the HIV 1/2 STAT-PAK Dipstick Assay (Chembio) in the second round (2007/2008) of the survey. Positive results were classified into faint and strong bands depending on the visual appearance of the test strip and confirmed by ELISA and Western blot. Results: The sensitivity and specificity of the Determine RDT were 100% (95% confidence interval = 86.8 to 100%) and 96.8% (95.9 to 97.6%) in whole blood and 100% (99.7 to 100%) and 97.9% (97.6 to 98.1%) in plasma respectively. Specificity was highly dependent on the tested sample type: when using whole blood, 67.1% of positive results were false positive, as opposed to 17.4% in plasma. Test strips with only faint positive bands were more often false positive than strips showing strong bands and were more common in whole blood than in plasma. Evaluation of the STAT-PAK RDT in plasma during the second year resulted in a sensitivity of 99.7% (99.1 to 99.9%) and a specificity of 99.3% (99.1 to 99.4%) with 6.9% of the positive results being false. Conclusions: Our study shows that the Determine HIV 1/2 strip test with its high sensitivity is an excellent tool to screen for HIV infection, but that – at least in our setting – it can not be recommended as a confirmatory test in VCT campaigns where whole blood is used

Religion and HIV in Tanzania: Influence of Religious Beliefs on HIV stigma, Disclosure, and Treatment Attitudes.

Religion shapes everyday beliefs and activities, but few studies have examined its associations with attitudes about HIV. This exploratory study in Tanzania probed associations between religious beliefs and HIV stigma, disclosure, and attitudes toward antiretroviral (ARV) treatment. A self-administered survey was distributed to a convenience sample of parishioners (n = 438) attending Catholic, Lutheran, and Pentecostal churches in both urban and rural areas. The survey included questions about religious beliefs, opinions about HIV, and knowledge and attitudes about ARVs. Multivariate logistic regression analysis was performed to assess how religion was associated with perceptions about HIV, HIV treatment, and people living with HIV/AIDS. Results indicate that shame-related HIV stigma is strongly associated with religious beliefs such as the belief that HIV is a punishment from God (p < 0.01) or that people living with HIV/AIDS (PLWHA) have not followed the Word of God (p < 0.001). Most participants (84.2%) said that they would disclose their HIV status to their pastor or congregation if they became infected. Although the majority of respondents (80.8%) believed that prayer could cure HIV, almost all (93.7%) said that they would begin ARV treatment if they became HIV-infected. The multivariate analysis found that respondents' hypothetical willingness to begin ARV treatme was not significantly associated with the belief that prayer could cure HIV or with other religious factors. Refusal of ARV treatment was instead correlated with lack of secondary schooling and lack of knowledge about ARVs. The decision to start ARVs hinged primarily on education-level and knowledge about ARVs rather than on religious factors. Research results highlight the influence of religious beliefs on HIV-related stigma and willingness to disclose, and should help to inform HIV-education outreach for religious groups

Health Diplomacy the Adaptation of Global Health Interventions to Local Needs in sub-Saharan Africa and Thailand: Evaluating Findings from Project Accept (HPTN 043).

Study-based global health interventions, especially those that are conducted on an international or multi-site basis, frequently require site-specific adaptations in order to (1) respond to socio-cultural differences in risk determinants, (2) to make interventions more relevant to target population needs, and (3) in recognition of 'global health diplomacy' issues. We report on the adaptations development, approval and implementation process from the Project Accept voluntary counseling and testing, community mobilization and post-test support services intervention. We reviewed all relevant documentation collected during the study intervention period (e.g. monthly progress reports; bi-annual steering committee presentations) and conducted a series of semi-structured interviews with project directors and between 12 and 23 field staff at each study site in South Africa, Zimbabwe, Thailand and Tanzania during 2009. Respondents were asked to describe (1) the adaptations development and approval process and (2) the most successful site-specific adaptations from the perspective of facilitating intervention implementation. Across sites, proposed adaptations were identified by field staff and submitted to project directors for review on a formally planned basis. The cross-site intervention sub-committee then ensured fidelity to the study protocol before approval. Successfully-implemented adaptations included: intervention delivery adaptations (e.g. development of tailored counseling messages for immigrant labour groups in South Africa) political, environmental and infrastructural adaptations (e.g. use of local community centers as VCT venues in Zimbabwe); religious adaptations (e.g. dividing clients by gender in Muslim areas of Tanzania); economic adaptations (e.g. co-provision of income generating skills classes in Zimbabwe); epidemiological adaptations (e.g. provision of 'youth-friendly' services in South Africa, Zimbabwe and Tanzania), and social adaptations (e.g. modification of terminology to local dialects in Thailand: and adjustment of service delivery schedules to suit seasonal and daily work schedules across sites). Adaptation selection, development and approval during multi-site global health research studies should be a planned process that maintains fidelity to the study protocol. The successful implementation of appropriate site-specific adaptations may have important implications for intervention implementation, from both a service uptake and a global health diplomacy perspective

Diagnosis of alpha-1-antitrypsin deficiency in bleeding disorder-related neonatal death

Alpha-1-antitrypsin (AAT) deficiency is a rare genetic disorder characterized by hepatitis in neonates, childhood and adulthood (protease inhibitor (PI)*ZZ) and emphysema with or without hepatitis (PI*ZZ)/(PI*SS,SZ or null) in adulthood. We report the case of a female neonate born at 40 weeks of gestation who presented with vitamin K deficiency-related intracranial bleeding and cholestasis of which she died at 28 days of age. At autopsy, the infant was found to have intracranial bleeding, hepatomegaly, and cholestasis with paucity of bile ducts in the liver. Small periodic acid-Schiff diastase positive intrahepatic granules and positive staining with antibodies against AAT protein suggested an AAT deficiency. AAT is a glycoprotein that has a protease inhibitor function. Its deficiency can be the result of various point mutations in Serpin 1 located on chromosome 14. The diagnosis AAT deficiency was confirmed by mutation analysis showing the PI*ZZ genotype in the neonate. In conclusion, AAT deficiency is a rare genetic disorder that can lead to a serious bleeding disorder in the neonatal period if not recognised on time. Pathological diagnosis together with verifying molecular analysis can be used to identify index patients

Availability of supplies and motivations for accessing voluntary HIV counseling and testing services in Blantyre, Malawi

<p>Abstract</p> <p>Background</p> <p>HIV counseling and testing is an important intervention in the prevention, control and management of the human immunodeficiency virus (HIV). Counseling and testing can be an entry point for prevention, care and support. Knowledge of the quality of services and motivations for testing by individuals is important for effective understanding of the testing environment.</p> <p>Methods</p> <p>A cross sectional explorative study of clients accessing HIV voluntary counseling and testing (VCT) and counselors was conducted in 6 government health centers in Blantyre City, Malawi. We aimed to assess the availability of critical clinic supplies and identify the motivations of clients seeking counseling and testing services. We also aimed to identify the health professional cadres that were providing VCT in Blantyre city.</p> <p>Results</p> <p>102 VCT clients and 26 VCT counselors were interviewed. Among the VCT clients, 74% were <=29 years, 58.8% were females and only 7% reported no formal education. 42.2% were single, 45.1% married, 8.8% widowed and 3.9% divorced or separated. The primary reasons for seeking HIV counseling and testing were: recent knowledge about HIV (31.4%), current illness (22.5%), self-assessment of own behavior as risky (15.5%), suspecting sexual partner's infidelity (13.7%) and seeking HIV confirmatory test (9.8%) and other reasons (6.9%). Of the 26 VCT counselors, 14 were lay volunteers, 7 health surveillance assistants and 5 nurses. All except one had been trained specifically for HIV counseling and testing. All 6 facilities were conducting rapid HIV testing with same day test results provided to clients. Most of the supplies were considered adequate for testing.</p> <p>Conclusion</p> <p>HIV counseling and testing facilities were available in Blantyre city in all the six public health facilities assessed. The majority of counseling and testing clients were motivated by perceptions of being at risk of HIV infection. In a country with 12% of individuals 15 to 49 years infected, there is need to encourage testing among population groups that may not perceive themselves to be at risk of infection.</p