A retrospective study of tuberculosis outcomes in Gulf Province, Papua New Guinea.

SETTING: Gulf Province, a rural area of mainland Papua New Guinea, is known to have one of the highest burdens of tuberculosis (TB) in the country. OBJECTIVES: To describe the characteristics and outcomes of TB patients registered for first-line treatment in Kerema General Hospital in Gulf Province between January and December 2016. DESIGN: This was a retrospective cohort study using routinely collected programme data. RESULTS: Of 347 cases with a recorded TB site, 54% were male and 32% were aged <15 years. No human immunodeficiency virus (HIV) status was recorded for 51% of cases. TB was bacteriologically confirmed in 23% of cases. Among the cohort, there were 145 extrapulmonary TB cases (42%); the site of disease was unknown in 56% of these cases. Of the 297 cases with treatment outcome evaluated, 56% had a favourable outcome and 26% were lost to follow-up. On multivariable analysis, extrapulmonary TB (adjusted OR [aOR] 0.51, 95%CI 0.30-0.88, P = 0.02) and bacteriologically confirmed TB (aOR 0.40, 95%CI 0.21-0.77, P < 0.01) were associated with decreased odds of an unfavourable treatment outcome. CONCLUSION: The study findings highlight the need to improve TB diagnosis, access to HIV testing, treatment adherence, patient support and the quality of TB programme data in Gulf Province.

Catastrophic drug errors involving tranexamic acid administered during spinal anaesthesia.

We have reviewed accidental spinal administration of tranexamic acid. We performed a MEDLINE search of cases of administration of tranexamic acid during epidural or spinal anaesthesia between 1960 and 2018. No reports of epidural administration were identified. We identified 21 cases of spinal tranexamic acid administration. Life-threatening neurological and/or cardiac complications, requiring resuscitation and/or intensive care, occurred in 20 patients; 10 patients died. We used a Human Factors Analysis Classification System model to analyse any contributing factors, and the reports were also assessed using four published recommendations for the reduction in neuraxial drug error. In 20 cases, ampoule error was the cause; in the last case a spinal catheter was mistaken for an intravenous catheter. All were classified as skill-based errors. Several human factors related to organisational policy; dispensing and storage of drugs and preparation for spinal anaesthesia tasks were present. All errors could have been prevented by implementing the four published recommendations.

Demographic histories and genetic diversity across pinnipeds are shaped by human exploitation, ecology and life-history.

A central paradigm in conservation biology is that population bottlenecks reduce genetic diversity and population viability. In an era of biodiversity loss and climate change, understanding the determinants and consequences of bottlenecks is therefore an important challenge. However, as most studies focus on single species, the multitude of potential drivers and the consequences of bottlenecks remain elusive. Here, we combined genetic data from over 11,000 individuals of 30 pinniped species with demographic, ecological and life history data to evaluate the consequences of commercial exploitation by 18th and 19th century sealers. We show that around one third of these species exhibit strong signatures of recent population declines. Bottleneck strength is associated with breeding habitat and mating system variation, and together with global abundance explains much of the variation in genetic diversity across species. Overall, bottleneck intensity is unrelated to IUCN status, although the three most heavily bottlenecked species are endangered. Our study reveals an unforeseen interplay between human exploitation, animal biology, demographic declines and genetic diversity.

Requiem for Nigro or is anal squamous carcinoma still a surgical problem: Abdominoperineal excision rather than a defunctioning stoma?

BACKGROUND: Combined multimodal treatment (CMT) is the preferred treatment for anal squamous carcinoma with radical surgery reserved for treatment failure. Some patients require a defunctioning stoma prior to CMT. Successful closure of such a stoma is unlikely. Abdominoperineal excision (APE) may be suitable as primary treatment in these patients. METHOD: A retrospective review of all patients with anal squamous carcinoma was undertaken. Patients who required defunctioning colostomies prior to CMT were analysed for potential resectability of tumour prior to CMT and rate of permanent stoma. OBJECTIVE: To evaluate organ preservation in the treatment of anal squamous cancer and the closure rate of pre-treatment, temporary diverting colostomy, thereby assessing whether APE could be offered as primary treatment in those requiring a pre-treatment colostomy. RESULTS: One hundred and twenty-five patients were included of which 58 were males. The mean age was 56 years. 107 were treated with curative intent. Six received primary APE and 12 salvage APE. Thirty (22 males) required pretreatment diverting colostomies. Three (10%) stomas were successfully reversed. Forty-eight (38%) of the 125 completed treatment with a permanent colostomy. Six patients who needed a stoma prior to CMT were deemed resectable. CONCLUSION: Organ preservation was not possible in about a third of patients. Defunctioning stomas prior to CMT were likely to be permanent. We propose that APE could be considered as an alternative in selective cases where the tumour is resectable with low morbidity and a stoma is indicated.

Uncovering the structure of the mouse gait controller: Mice respond to substrate perturbations with adaptations in gait on a continuum between trot and bound.

Animals, including humans, have been shown to maintain a gait during locomotion that minimizes the risk of injury and energetic cost. Despite the importance of understanding the mechanisms of gait regulation, ethical and experimental challenges have prevented full exploration of these. Here we present data on the gait response of mice to rapid, precisely timed, spatially confined mechanical perturbations. Our data elucidate that after the mechanical perturbation, the mouse gait response is anisotropic, preferring deviations away from the trot towards bounding, over those towards other gaits, such as walk or pace. We quantified this shift by projecting the observed gait onto the line between trot and bound, in the space of quadrupedal gaits. We call this projection λ. For λ=0, the gait is the ideal trot; for λ=±π, it is the ideal bound. We found that the substrate perturbation caused a significant shift in λ towards bound during the stride in which the perturbation occurred and the following stride (linear mixed effects model: Δλ=0.26±0.07 and Δλ=0.21±0.07, respectively; random effect for animal, p < 0.05 for both strides, n = 8 mice). We hypothesize that this is because the bounding gait is better suited to rapid acceleration or deceleration, and an exploratory analysis of jerk showed that it was significantly correlated with λ (p < 0.05). Understanding how gait is controlled under perturbations can aid in diagnosing gait pathologies and in the design of more agile robots.

Sex-related differences in the thanatomicrobiome in postmortem heart samples using bacterial gene regions V1-2 and V4.

Recent studies have revealed distinct thanatomicrobiome (microbiome of death) signatures in human body sites after death. Thanatomicrobiome studies suggest that microbial succession after death may have the potential to reveal important postmortem biomarkers for the identification of time of death. We surveyed the postmortem microbiomes of cardiac tissues from 10 corpses with varying times of death (6-58 h) using amplicon-based sequencing of the 16S rRNA gene' V1-2 and V4 hypervariable regions. The results demonstrated that amplicons had statistically significant (P < 0·05) sex-dependent changes. Clostridium sp., Pseudomonas sp., Pantoea sp. and Streptococcus sp. had the highest enrichment for both V1-2 and V4 regions. Interestingly, the results also show that V4 amplicons had higher abundance of Clostridium sp. and Pseudomonas sp. in female hearts compared to males. In addition, Streptococcus sp. was solely found in male heart samples. The distinction between sexes was further supported by principle coordinate analysis, which revealed microbes in female hearts formed a distinctive cluster separate from male cadavers for both hypervariable regions. This study provides data that demonstrates that two hypervariable regions show discriminatory power for sex differences in postmortem heart samples. SIGNIFICANCE AND IMPACT OF THE STUDY: The findings represent preliminary data of the first thanatomicrobiome investigation of a comparison between 16S rRNA gene V1-2 and V4 amplicon signatures in corpse heart tissues. The results demonstrated that V4 hypervariable region amplicons had statistically significant (P < 0·05) sex-dependent microbial diversity. For example, Streptococcus sp. was solely found in male postmortem heart tissues. Interestingly, the results also show that V4 amplicons had higher abundance of Clostridium sp. and Pseudomonas sp. in female heart tissues compared to males. The finding of Clostridium sp. supports the postmortem clostridium effect in corpse heart tissues.

Nodal disease predicts recurrence whereas other traditional factors affect survival in a cohort of South African patients with differentiated thyroid carcinoma.

BACKGROUND AND AIM: Information on patients with differentiated thyroid carcinoma in South Africa is limited. The objective of this study was to review demographics and tumour characteristics in a cohort of patients with differentiated thyroid carcinoma, presenting to Groote Schuur Hospital and evaluate risk factors for recurrence and survival. PATIENTS AND METHODOLOGY: Retrospective demographic and clinical data were collected on all patients referred between January 2003 and December 2013. Prognostic factors for recurrence free survival and cancer specific survival were assessed using univariate and multivariate analyses. RESULTS: The total number of patients was 231.The median age at presentation was 44 years and 82% were female patients. The pathological sub-types were papillary (60.6%), follicular (38.9%) and poorly differentiated (0.5%). Total thyroidectomy was performed in 191 patients and 30 patients required neck dissections. A total of 171 (74%) patients received 131Iodine. The recurrence free and cause specific survival rates at 10 years were 83 and 91%, respectively. Nodal disease at presentation was the only significant risk factor for recurrence (p <  0.001) on multivariate analysis. Significant risk factors for cause specific mortality were age ≥ 45 years (p = 0.006), follicular pathology (p = 0.004), extra-thyroid extension (p = 0.013) and residual tumour (p = 0.004). CONCLUSIONS: Consistent with international trends, patients with differentiated thyroid carcinoma treated at Groote Schuur Hospital had a favourable prognosis. The known risk factors associated with recurrence and survival in this South African cohort were consistent with those reported in developed countries.

Requiem for Nigro or is anal squamous carcinoma still a surgical problem: abdominoperineal excision rather than a defunctioning stoma?

Background: Combined multimodal treatment (CMT) is the preferred treatment for anal squamous carcinoma with radical surgery reserved for treatment failure. Some patients require a defunctioning stoma prior to CMT. Successful closure of such a stoma is unlikely. Abdominoperineal excision (APE) may be suitable as primary treatment in these patients.Objectives: To evaluate organ preservation in the treatment of anal squamous cancer and the closure rate of pre-treatment, temporary diverting colostomy, thereby assessing whether APE could be offered as primary treatment in those requiring a pre-treatment colostomy.Methods: A retrospective review of all patients with anal squamous carcinoma was undertaken. Patients who required defunctioning colostomies prior to CMT were analysed for potential resectability of tumour prior to CMT and rate of permanent stoma.Results: One hundred and twenty-five patients were included of which 58 were males. The mean age was 56 years. 107 were treated with curative intent. Six received primary APE and 12 salvage APE. Thirty (22 males) required pre-treatment diverting colostomies. Three (10%) stomas were successfully reversed. Forty-eight (38%) of the 125 completed treatment with a permanent colostomy. Six patients who needed a stoma prior to CMT were deemed resectable.Conclusion: Organ preservation was not possible in about a third of patients. Defunctioning stomas prior to CMT were likely to be permanent. We propose that APE could be considered as an alternative in selective cases where the tumour is resectable with low morbidity and a stoma is indicated

Microbial Signatures of Cadaver Gravesoil During Decomposition.

Genomic studies have estimated there are approximately 10(3)-10(6) bacterial species per gram of soil. The microbial species found in soil associated with decomposing human remains (gravesoil) have been investigated and recognized as potential molecular determinants for estimates of time since death. The nascent era of high-throughput amplicon sequencing of the conserved 16S ribosomal RNA (rRNA) gene region of gravesoil microbes is allowing research to expand beyond more subjective empirical methods used in forensic microbiology. The goal of the present study was to evaluate microbial communities and identify taxonomic signatures associated with the gravesoil human cadavers. Using 16S rRNA gene amplicon-based sequencing, soil microbial communities were surveyed from 18 cadavers placed on the surface or buried that were allowed to decompose over a range of decomposition time periods (3-303 days). Surface soil microbial communities showed a decreasing trend in taxon richness, diversity, and evenness over decomposition, while buried cadaver-soil microbial communities demonstrated increasing taxon richness, consistent diversity, and decreasing evenness. The results show that ubiquitous Proteobacteria was confirmed as the most abundant phylum in all gravesoil samples. Surface cadaver-soil communities demonstrated a decrease in Acidobacteria and an increase in Firmicutes relative abundance over decomposition, while buried soil communities were consistent in their community composition throughout decomposition. Better understanding of microbial community structure and its shifts over time may be important for advancing general knowledge of decomposition soil ecology and its potential use during forensic investigations.

Population differentiation and behavioural association of the two 'personality' genes DRD4 and SERT in dunnocks (Prunella modularis).

Quantifying the variation in behaviour-related genes within and between populations provides insight into how evolutionary processes shape consistent behavioural traits (i.e. personality). Deliberate introductions of non-native species offer opportunities to investigate how such genes differ between native and introduced populations and how polymorphisms in the genes are related to variation in behaviour. Here, we compared the genetic variation of the two 'personality' genes, DRD4 and SERT, between a native (United Kingdom, UK) and an introduced (New Zealand, NZ) population of dunnocks, Prunella modularis. The NZ population showed a significantly lower number of single nucleotide polymorphisms (SNPs) compared to the UK population. Standardized F'st estimates of the personality genes and neutral microsatellites indicate that selection (anthropogenic and natural) probably occurred during and post the introduction event. Notably, the largest genetic differentiation was found in the intronic regions of the genes. In the NZ population, we also examined the association between polymorphisms in DRD4 and SERT and two highly repeatable behavioural traits: flight-initiation distance and mating status (promiscuous females and cobreeding males). We found 38 significant associations (for different allele effect models) between the two behavioural traits and the studied genes. Further, 22 of the tested associations showed antagonistic allele effects for males and females. Our findings illustrate how introduction events and accompanying ecological changes could influence the genetic diversity of behaviour-related genes.

Population structure within an alpine archipelago: strong signature of past climate change in the New Zealand rock wren (Xenicus gilviventris).

Naturally subdivided populations such as those occupying high-altitude habitat patches of the 'alpine archipelago' can provide significant insight into past biogeographical change and serve as useful models for predicting future responses to anthropogenic climate change. Among New Zealand's alpine taxa, phylogenetic studies support two major radiations: the first correlating with geological forces (Pliocene uplift) and the second with climatic processes (Pleistocene glaciations). The rock wren (Xenicus gilviventris) is a threatened alpine passerine belonging to the endemic New Zealand wren family (Acanthisittidae). Rock wren constitute a widespread, naturally fragmented population, occurring in patches of suitable habitat over c. 900 m in altitude throughout the length of the South Island, New Zealand. We investigated the relative role of historical geological versus climatic processes in shaping the genetic structure of rock wren (N = 134) throughout their range. Using microsatellites combined with nuclear and mtDNA sequence data, we identify a deep north-south divergence in rock wren (3.7 ± 0.5% at cytochrome b) consistent with the glacial refugia hypothesis whereby populations were restricted in isolated refugia during the Pleistocene c. 2 Ma. This is the first study of an alpine vertebrate to test and provide strong evidence for the glacial refugia hypothesis as an explanation for the low endemicity central zone known as the biotic 'gap' in the South Island of New Zealand.

Putting memory in context: dissociating memories by distinguishing the nature of context.

In recent years, spontaneous recognition tasks have become commonplace methods of assessing memory in animals. Adaptations of these tasks allow us to look at the role of objects, contexts and spatial locations in memory. Recent findings have highlighted that not all types of contexts in these tasks rely on the same neural systems. Similarly, asking different questions about the same types of context can allow the dissociation of neural systems underlying these memories. Here we review the current position in how context is used in such tasks, and we consider the fundamental importance of clearly defining both the nature of the context being used, and the questions asked of it in order to fully appreciate the neural and cognitive mechanisms being studied in such tasks.

Pleomorphic adenomas: post-operative radiotherapy is unnecessary following primary incomplete excision: a retrospective review.

BACKGROUND: Current standard treatment of Pleomorphic Salivary Adenoma (PSA) of the Parotid Gland is by surgical excision. The management of incomplete excision remains undecided with post-operative radiotherapy advocated by some and observation by others. METHODS: 190 patients who underwent resection of PSA of the parotid gland within the West of Scotland region from 1981 to 2008 were identified and data collected. RESULTS: 78/190 patients had a primary incomplete excision. 25/78 received post-operative radiotherapy and 53 were observed. Recurrences occurred in 11/53 in those observed and in 1/25 of those who received radiotherapy. 21/25 complained of significant side effects from the radiotherapy. 38 surgeons performed 190 procedures, with a range of experience from 1 to28 procedures. CONCLUSIONS: Radiotherapy does appear to reduce recurrence with incomplete excision, however it is associated with significant side effects. We therefore feel radiotherapy should not be routinely recommended. Subspecialisation should be adopted to increase the operating surgeon's experience.

Postglacial expansion and not human influence best explains the population structure in the endangered kea (Nestor notabilis).

Inferring past demography is a central question in evolutionary and conservation biology. It is, however, sometimes challenging to infer the processes that shaped the current patterns of genetic variation in endangered species. Population substructuring can occur as a result of survival in several isolated refugia and subsequent recolonization processes or via genetic drift following a population decline. The kea (Nestor notabilis) is an endemic parrot widely distributed in the mountains of the South Island of New Zealand that has gone through a major human-induced population decline during the 1860s-1970s. The aims of this study were to understand the glacial and postglacial history of kea and to determine whether the recent population decline played a role in the shaping of the current genetic variation. We examined the distribution of genetic variation, differentiation and admixture in kea using 17 microsatellites and the mitochondrial control region. Mitochondrial data showed a shallow phylogeny and a genetic distinction between the North and South of the range consistent with the three genetic clusters identified with microsatellite data. Both marker types indicated an increase in genetic isolation by geographic distance. Approximate Bayesian Computation supported a scenario of postglacial divergence from a single ancestral glacial refugium, suggesting that the contemporary genetic structure has resulted from recolonization processes rather than from a recent population decline. The recent evolutionary origin of this genetic structure suggests that each genetic cluster does not need to be considered as independent conservation units.

Control of glutamine metabolism by the tumor suppressor Rb.

Retinoblastoma (Rb) protein is a tumor suppressor that is dysregulated in a majority of human cancers. Rb functions to inhibit cell cycle progression in part by directly disabling the E2F family of cell cycle-promoting transcription factors. Because the de novo synthesis of multiple glutamine-derived anabolic precursors is required for cell cycle progression, we hypothesized that Rb also may directly regulate proteins involved in glutamine metabolism. We examined glutamine metabolism in mouse embryonic fibroblasts (MEFs) isolated from mice that have triple knock-outs (TKO) of all three Rb family members (Rb-1, Rbl1 and Rbl2) and found that loss of global Rb function caused a marked increase in (13)C-glutamine uptake and incorporation into glutamate and tricarboxylic acid cycle (TCA) intermediates in part via upregulated expression of the glutamine transporter ASCT2 and the activity of glutaminase 1 (GLS1). The Rb-controlled transcription factor E2F-3 altered glutamine uptake by direct regulation of ASCT2 mRNA and protein expression, and E2F-3 was observed to associate with the ASCT2 promoter. We next examined the functional consequences of the observed increase in glutamine uptake and utilization and found that glutamine exposure potently increased oxygen consumption, whereas glutamine deprivation selectively decreased ATP concentration in the Rb TKO MEFs but not the wild-type (WT) MEFs. In addition, TKO MEFs exhibited elevated production of glutathione from exogenous glutamine and had increased expression of gamma-glutamylcysteine ligase relative to WT MEFs. Importantly, this metabolic shift towards glutamine utilization was required for the proliferation of Rb TKO MEFs but not for the proliferation of the WT MEFs. Last, addition of the TCA cycle intermediate α-ketoglutarate to the Rb TKO MEFs reversed the inhibitory effects of glutamine deprivation on ATP, GSH levels and viability. Taken together, these studies demonstrate that the Rb/E2F cascade directly regulates a major energetic and anabolic pathway that is required for neoplastic growth.

BAS: balanced acceptance sampling of natural resources.

To design an efficient survey or monitoring program for a natural resource it is important to consider the spatial distribution of the resource. Generally, sample designs that are spatially balanced are more efficient than designs which are not. A spatially balanced design selects a sample that is evenly distributed over the extent of the resource. In this article we present a new spatially balanced design that can be used to select a sample from discrete and continuous populations in multi-dimensional space. The design, which we call balanced acceptance sampling, utilizes the Halton sequence to assure spatial diversity of selected locations. Targeted inclusion probabilities are achieved by acceptance sampling. The BAS design is conceptually simpler than competing spatially balanced designs, executes faster, and achieves better spatial balance as measured by a number of quantities. The algorithm has been programed in an R package freely available for download.

Measuring communicative participation using the FOCUS©: Focus on the Outcomes of Communication Under Six.

BACKGROUND: The FOCUS© is a new outcome tool for use by both parents and clinicians that measures changes in the communicative participation skills of preschool children. Changes in communicative participation skills as measured by the FOCUS were compared across three groups of children: those with speech impairments only (SI), those with language impairments only (LI) and those with both speech and language impairments (S/LI). METHODS: Participating families (n = 112, 75 male children) were recruited through 13 Canadian organizations. Children ranged from 10 months to 6 years 0 months (mean = 2.11 years; SD = 1.18 years) and attended speech-language intervention. Parents completed the FOCUS at the start and end of treatment. There were 23 children in the SI group, 62 children in the LI group and 27 children in the S/LI group. The average amount of the children's therapy varied from 7 to 10 h. RESULTS: The FOCUS captures changes in communicative participation for children with a range of communication disorder types and severities. All three groups of children made clinically important improvements according to their FOCUS scores (MCID ≥ 16 points). The FOCUS captured improvements in intelligibility, independent communication, play and socialization. CONCLUSIONS: The FOCUS measured positive changes in communicative participation skills for all three groups of children after 7-10 h of speech-language therapy. An outcome measure that targets only specific speech and language skills would miss many of the important social function changes associated with speech-language treatment.