'Deliberate Freedom’: Using speculation and imagination in historical biography

In this article, I explore the challenges and opportunities associated with using ‘informed imagination’ to write a speculative biography of an historical figure. In the process, I problematize the notion of the archival gap, which has been recently romanced by numerous writers, including myself. By citing archival gaps as a justification for creative license, we neglect the fact that all archives are inherently idiosyncratic in ways that invite, perhaps even demand, the use of both speculation and imagination. Here, I make a case for what I am calling the archival overlap. A careful examination of the existing sources, however sparse or abundant, is likely to reveal reoccurring clues that can be used to shape how we image and construct our subjects. Before we consider the gaps we should tend to these overlaps, I argue, using a current work-in-progress case study of the colonial artist Adelaide Ironside to explore how speculation and imagination are intrinsic to these stages of the biographical process

Inpatient GHB withdrawal management in an inner-city hospital in Sydney, Australia: a retrospective medical record review

Rationale: Regular consumption of gamma-hydroxybutyrate (GHB) may result in a dependence syndrome that can lead to withdrawal symptoms. There are limited data on medications to manage GHB withdrawal. Objectives: To examine characteristics associated with delirium and discharge against medical advice (DAMA), in the context of implementing a GHB withdrawal management protocol at an inner-city hospital in 2020. Methods: We retrospectively reviewed records (01 January 2017–31 March 2021), and included admissions that were ≥ 18 years of age, admitted for GHB withdrawal, and with documented recent GHB use. Admissions were assessed for demographics, medications administered, features of delirium, ICU admission, and DAMA. Exploratory analyses were conducted to examine factors associated (p < 0.2) with features of delirium and DAMA. Results: We identified 135 admissions amongst 91 patients. Medications administered included diazepam (133 admissions, 98.5%), antipsychotics (olanzapine [70 admissions, 51.9%]), baclofen (114 admissions, 84%), and phenobarbital (8 admissions, 5.9%). Features of delirium were diagnosed in 21 (16%) admissions. Delirium was associated with higher daily GHB consumption prior to admission, while duration of GHB use, time from presentation to first dose of diazepam, and concomitant methamphetamine use were inversely associated with delirium. DAMA occurred amongst 41 (30%) admissions, and was associated with a longer time from presentation to first dose of baclofen, while being female and receiving a loading dose of diazepam were inversely associated. Conclusions: This study adds to the literature in support of the safety and feasibility of diazepam and baclofen for the management of GHB withdrawal. Prospective, randomised trials are required

Comparing two intramedullary devices for treating trochanteric fractures: A prospective study

<p>Abstract</p> <p>Background</p> <p>Intertrochanteric fractures are surgically treated by using different methods and implants. The optional type of surgical stabilization is still under debate. However, between devices with the same philosophy, different design characteristics may substantially influence fracture healing. This is a prospective study comparing the complication and final functional outcome of two intramedullary devices, the intramedullary hip screw (IMHS) and the ENDOVIS nail.</p> <p>Materials and methods</p> <p>Two hundred fifteen patients were randomized on admission in two treatment groups. Epidemiology features and functional status was similar between two treatment groups. Fracture stability was assessed according to the Evan's classification. One hundred ten patients were treated with IMHS and 105 with ENDOVIS nail.</p> <p>Results</p> <p>There were no significant statistical differences between the two groups regarding blood loss, transfusion requirements and mortality rate. In contrast, the number of total complications was significantly higher in the ENDOVIS nail group. Moreover, the overall functional and walking competence was superior in the patients treated with the IMHS nail.</p> <p>Conclusions</p> <p>These results indicate that the choice of the proper implant plays probably an important role in the final outcome of surgical treatment of intertrochanteric fractures. IMHS nail allows for accurate surgical technique, for both static and dynamic compression and high rotational stability. IMHS nail proved more reliable in our study regarding nail insertion and overall uncomplicated outcome.</p

The genetic basis of multiple sclerosis: a model for MS susceptibility

<p>Abstact</p> <p>Background</p> <p>MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.</p> <p>Methods</p> <p>A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.</p> <p>Results</p> <p>For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ≤ 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.</p> <p>Conclusions</p> <p>The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.</p> <p>The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.</p

Congenital bovine spinal dysmyelination is caused by a missense mutation in the SPAST gene

Bovine spinal dysmyelination (BSD) is a recessive congenital neurodegenerative disease in cattle (Bos taurus) characterized by pathological changes of the myelin sheaths in the spinal cord. The occurrence of BSD is a longstanding problem in the American Brown Swiss (ABS) breed and in several European cattle breeds upgraded with ABS. Here, we show that the disease locus on bovine chromosome 11 harbors the SPAST gene that, when mutated, is responsible for the human disorder hereditary spastic paraplegia (HSP). Initially, SPAST encoding Spastin was considered a less likely candidate gene for BSD since the modes of inheritance as well as the time of onset and severity of symptoms differ widely between HSP and BSD. However, sequence analysis of the bovine SPAST gene in affected animals identified a R560Q substitution at a position in the ATPase domain of the Spastin protein that is invariant from insects to mammals. Interestingly, three different mutations in human SPAST gene at the equivalent position are known to cause HSP. To explore this observation further, we genotyped more than 3,100 animals of various cattle breeds and found that the glutamine allele exclusively occurred in breeds upgraded with ABS. Furthermore, all confirmed BSD carriers were heterozygous, while all affected calves were homozygous for the glutamine allele consistent with recessive transmission of the underlying mutation and complete penetrance in the homozygous state. Subsequent analysis of recombinant Spastin in vitro showed that the R560Q substitution severely impaired the ATPase activity, demonstrating a causal relationship between the SPAST mutation and BSD

Sustainability and Long Term-Tenure: Lion Trophy Hunting in Tanzania

It is argued that trophy hunting of large, charismatic mammal species can have considerable conservation benefits but only if undertaken sustainably. Social-ecological theory suggests such sustainability only results from developing governance systems that balance financial and biological requirements. Here we use lion (Panthera leo) trophy hunting data from Tanzania to investigate how resource ownership patterns influence hunting revenue and offtake levels. Tanzania contains up to half of the global population of free-ranging lions and is also the main location for lion trophy hunting in Africa. However, there are concerns that current hunting levels are unsustainable. The lion hunting industry in Tanzania is run by the private sector, although the government leases each hunting block to companies, enforces hunting regulation, and allocates them a species-specific annual quota per block. The length of these leases varies and theories surrounding property rights and tenure suggest hunting levels would be less sustainable in blocks experiencing a high turnover of short-term leases. We explored this issue using lion data collected from 1996 to 2008 in the Selous Game Reserve (SGR), the most important trophy hunting destination in Tanzania. We found that blocks in SGR with the highest lion hunting offtake were also those that experienced the steepest declines in trophy offtake. In addition, we found this high hunting offtake and the resultant offtake decline tended to be in blocks under short-term tenure. In contrast, lion hunting levels in blocks under long-term tenure matched more closely the recommended sustainable offtake of 0.92 lions per 1000 km2. However, annual financial returns were higher from blocks under short-term tenure, providing $133 per km2 of government revenue as compared to$62 per km2 from long-term tenure blocks. Our results provide evidence for the importance of property rights in conservation, and support calls for an overhaul of the system in Tanzania by developing competitive market-based approaches for block allocation based on long-term tenure of ten years

Epigenetic regulation of S100 protein expression

S100 proteins are small, calcium-binding proteins whose genes are localized in a cluster on human chromosome 1. Through their ability to interact with various protein partners in a calcium-dependent manner, the S100 proteins exert their influence on many vital cellular processes such as cell cycle, cytoskeleton activity and cell motility, differentiation, etc. The characteristic feature of S100 proteins is their cell-specific expression, which is frequently up- or downregulated in various pathological states, including cancer. Changes in S100 protein expression are usually characteristic for a given type of cancer and are therefore often considered as markers of a malignant state. Recent results indicate that changes in S100 protein expression may depend on the extent of DNA methylation in the S100 gene regulatory regions. The range of epigenetic changes occurring within the S100 gene cluster has not been defined. This article reviews published data on the involvement of epigenetic factors in the control of S100 protein expression in development and cancer

Epistatic Relationships between sarA and agr in Staphylococcus aureus Biofilm Formation

Background: The accessory gene regulator (agr) and staphylococcal accessory regulator (sarA) play opposing roles in Staphylococcus aureus biofilm formation. There is mounting evidence to suggest that these opposing roles are therapeutically relevant in that mutation of agr results in increased biofilm formation and decreased antibiotic susceptibility while mutation of sarA has the opposite effect. To the extent that induction of agr or inhibition of sarA could potentially be used to limit biofilm formation, this makes it important to understand the epistatic relationships between these two loci. Methodology/Principal Findings: We generated isogenic sarA and agr mutants in clinical isolates of S. aureus and assessed the relative impact on biofilm formation. Mutation of agr resulted in an increased capacity to forma biofilmin the 8325-4 laboratory strain RN6390 but had little impact in clinical isolates S. aureus. In contrast, mutation of sarA resulted in a reduced capacity to form a biofilm in all clinical isolates irrespective of the functional status of agr. This suggests that the regulatory role of sarA in biofilm formation is independent of the interaction between sarA and agr and that sarA is epistatic to agr in this context. This was confirmed by demonstrating that restoration of sarA function restored the ability to form a biofilm even in the corresponding agr mutants. Mutation of sarA in clinical isolates also resulted in increased production of extracellular proteases and extracellular nucleases, both of which contributed to the biofilm-deficient phenotype of sarA mutants. However, studies comparing different strains with and without proteases inhibitors and/or mutation of the nuclease genes demonstrated that the agr-independent, sarA-mediated repression of extracellular proteases plays a primary role in this regard. Conclusions and Significance: The results we report suggest that inhibitors of sarA-mediated regulation could be used to limit biofilm formation in S. aureus and that the efficacy of such inhibitors would not be limited by spontaneous mutation of agr in the human host