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There is a surprising lack of evidence documenting the volumetric symmetry of the bony orbit. This paper establishes reference values for orbital volume (OV) and symmetry in the 25 - 40 year old caucasian population. Secondarily, this paper sets a landmark for the tolerances in OV that can be expected when reconstructing the bony defects which may occur from trauma. A standardised method of quantitative OV measurement was developed using CT sinus examinations acquired for indications unrelated to orbital trauma. Sex, ethnicity, age, right and left OV were recorded. Data for 100 patients was obtained (50 male, 50 female). Mean left OV was 23.1cm

Objectives Prescription drug monitoring programs (PDMPs) are state-maintained databases that providers may reference when deciding to prescribe or dispense controlled substances. As more states begin to mandate PDMP use at the point of care, it is imperative to assess how pharmacists use PDMP information when determining whether to fill a controlled substance prescription (CSP). The objective of this study was to evaluate which factors affected fourth-year student pharmacists’ decision to fill an opioid prescription, their level of confidence in their decision making, and familiarity with the PDMP. Methods We used a 24 factorial design to present a series of text-based vignettes to fourth-year student pharmacists. Each participant received 8 vignettes (5 randomly selected, 3 fixed), representing a hypothetical hydrocodone-acetaminophen combination prescription with varying levels of the following dichotomous factors: doctor shopping, dosage, pharmacy shopping, and concurrent benzodiazepine prescription. Participants were asked to decide whether or not they would fill each of the hypothetical prescriptions they received. A multilevel model was used to measure the association between each of the vignette factors, age, race, sex, experience with PDMP, and the decision to refuse to fill a prescription. Each vignette response served as an independent observation. Results A total of 87 participants yielded 696 vignette responses. Participants were significantly more likely to refuse to fill prescriptions with doctor shopping (adjusted odds ratio [aOR] 19.86 [95% CI 10.78–36.58]), pharmacy shopping (6.78 [4.13–11.12]), dosage (1.83 [1.16–2.90]), or if the student pharmacist was of female sex (1.73 [1.02–2.93]). Concomitant benzodiazepine use was not associated with a no-fill decision (1.45 [0.92–2.27]). Conclusion This study reveals that student pharmacists’ decision to fill a prescription is dependent on both prescription characteristics and a patient’s CSP history. The importance of PDMP history cannot be downplayed and suggests that PDMP use may be effective in informing patient care decisions. Still, the variability in filling decision highlights the need to teach a formulaic approach to CSP dispensing in colleges of pharmacy.

Interest in the role of epigenetic mechanisms in human biology has exponentially increased over the past several decades. The multitude of opposing and context-dependent chromatin-modifying enzymes/coregulator complexes is just beginning to be understood at a molecular level. This science has benefitted tremendously from studies of erythropoiesis, in which a series of β-globin genes are in sequence turned "on" and "off," serving as a fascinating model of coordinated gene expression. We, therefore, describe here epigenetic complexes about which we know most, using erythropoiesis as the context. The biochemical insights lay the foundation for proposing and developing novel treatments for diseases of red cells and of erythropoiesis, identifying for example epigenetic enzymes that can be drugged to manipulate β-globin locus regulation, to favor activation of unmutated fetal hemoglobin over mutated adult β-globin genes to treat sickle cell disease and β-thalassemias. Other potential translational applications are in redirecting hematopoietic commitment decisions, as treatment for bone marrow failure syndromes.

Internationally, diabetes mellitus is recognised as a risk factor for severe COVID-19. The relationship between diabetes mellitus and severe COVID-19 has not been reported in the Australian population.The objective of this study was to determine the prevalence of and outcomes for patients with diabetes admitted to Australian intensive care units (ICUs) with COVID-19.This is a nested cohort study of four ICUs in Melbourne participating in the Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT-SARI) Australia project. All adult patients admitted to the ICU with COVID-19 from 20 February 2020 to 27 February 2021 were included. Blood glucose and glycated haemoglobin (HbA1c) data were retrospectively collected. Diabetes was diagnosed from medical history or an HbA1c ≥6.5% (48 mmol/mol). Hospital mortality was assessed using logistic regression.There were 136 patients with median age 58 years [48-68] and median Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 14 [11-19]. Fifty-eight patients had diabetes (43%), 46 patients had stress-induced hyperglycaemia (34%), and 32 patients had normoglycaemia (23%). Patients with diabetes were older, were with higher APACHE II scores, had greater glycaemic variability than patients with normoglycaemia, and had longer hospital length of stay. Overall hospital mortality was 16% (22/136), including nine patients with diabetes, nine patients with stress-induced hyperglycaemia, and two patients with normoglycaemia.Diabetes is prevalent in patients admitted to Australian ICUs with severe COVID-19, highlighting the need for prevention strategies in this vulnerable population.

Training in UK surgery has changed dramatically since 1995, from a relative lack of structure to time-limited and highly documented programmes. Training in oral and maxillofacial surgery (OMFS) has shared these changes and included some significant changes of its own. Minutes from the OMFS Specialty Advisory Committee (SAC) were reviewed over the last 25 years to record the number and location of newly approved posts. The General Medicine Council's (GMC) OMFS specialist list in 2019 was combined with the records of OMFS specialists' dental qualifications held by the General Dental Council (GDC) and augmented from a database of OMFS trainees and consultants in the UK. Data on demographics, location, and nature of the first medical or dental degree were noted for analysis. A total of 691 OMFS specialists and trainees were identified from GMC, OMFS SAC and consultant databases. Of these, 12 consultants held only dental qualification/registration. First degree data could not be obtained for 12 specialists (all male). A further 20 OMFS specialists, whose training was outside the UK, were also excluded from further analysis. In 1995 there were 95 national training posts, by 2013 there were 150. Over the last quarter of a century, there has been an increase in medicine first trainees, an increase in female trainees and specialists, and a relative decrease in OMFS trainees from the Indian subcontinent. The varied origins of the OMFS workforce has contributed to greater diversity and inclusion within the specialty. In the UK, OMFS appears to have produced the correct number of specialists whilst maintaining a high standard of training. The next change in OMFS training programmes is to deliver The Postgraduate Medical Education and Training Board's (PMETB) recommendations. As we move to achieve this it is imperative that as new doors open, we do not close others.

It is 11 years since Cameron and Westcott published ‘Maxillofacial training is no longer than other surgical specialties’1. This showed that OMFS trainees completed training at ages comparable to their surgical peers. Much has changed in surgical training since then so an updated review was undertaken. Based on published training pathways specialty training in most surgical specialties should be ten years (two years foundation, two years core and six years specialty training). For OMFS specialty training in the UK from either medicine first or dentistry first is 18–21 years depending on the length of second degrees and participation in pre-Certificate of Competition of Training (CCT) fellowships. Information on the age of entry onto the surgical specialist lists between 1997 and 2018 was obtained from the General Medical Council (GMC). The ‘age on entry’ included the ages of specialists from other nations joining the list for the first time and doctors re-joining the lists after a break. The age on joining surgical specialist lists ranged from 27–83 years, with the median of 39 and mean of 41.4 years. In Oral and Maxillofacial Surgery (OMFS), age ranged from 32–67 years, with the median and mean of 41 and 42.7 years respectively. Looking in more detail at the small differences in median and mean, the surgical specialties of vascular and cardiothoracic had age distributions which were statistically similar to OMFS. For other surgical specialties the distribution was wider. The small number of OMFS specialists whose age at joining the OMFS specialist list in their early 30 s had all trained overseas in nations where the second degree was incorporated into specialty training. These data show that there is a small difference between age on entry to the OMFS specialist list and those joining other surgical specialties. Combining integration of second-degree studies into UK specialty training as recommended by the 2008 PMETB Review of OMFS Training with the new competency based OMFS curriculum could reverse this age difference.

In 2013, China launched its ‘Belt and Road Initiative’ (BRI) as a major effort to enhance international trade and economic development. An important feature of the BRI is that it supports free trade regimes and a world economy based upon open regional cooperation. The concept of BRI involves establishing a transport route between China and participating countries to provide more profitable trade and investment corridors. There are few comprehensive studies examining the social and environmental impact on development in recipient countries. To address this gap, this study gathered empirical evidence on railroad projects in three key countries: Indonesia, Ethiopia, and Kenya. The comparative analysis revealed that while political leaders signed agreements that welcomed China’s BRI in support of their national transport development plans, the implementation of these ambitious infrastructure projects faced significant management and operational challenges that had not been foreseen by the Chinese partners. More effective implementation of BRI infrastructure projects in the future will require better understandings of governance, specifically through harmonization with the cultural, institutional and political contexts in partner countries. Social and cultural characteristics of the countries where Chinese firms are working need to be well understood if sustainable and inclusive benefits from the BRI infrastructure projects are to be delivered. Further research on the benefits gained by local people living in the areas affected by the BRI investments is needed.

Sickle cell disease (SCD), an inherited blood disorder caused by a point mutation that renders hemoglobin susceptible to polymerization when deoxygenated, affects millions of people worldwide. Manifestations of SCD include chronic hemolytic anemia, inflammation, painful vaso-occlusive crises, multisystem organ damage, and reduced life expectancy. Part of SCD pathophysiology is the excessive formation of intracellular reactive oxygen species (ROS) in SCD red blood cells (RBCs), which accelerates their hemolysis. Normal RBC precursors eliminate their mitochondria during the terminal differentiation process. Strikingly, we observed an increased percentage of RBCs retaining mitochondria in SCD patient blood samples compared with healthy individuals. In addition, using an experimental SCD mouse model, we demonstrate that excessive levels of ROS in SCD are associated with this abnormal mitochondrial retention. Interestingly, the LSD1 inhibitor, RN-1, and the mitophagy-inducing agent mammalian target of rapamycin (mTOR) inhibitor, sirolimus, increased RBC lifespan and reduced ROS accumulation in parallel with reducing mitochondria-retaining RBCs in the SCD mouse model. Furthermore, gene expression analysis of SCD mice treated with RN-1 showed increased expression of mitophagy genes. Our findings suggest that reduction of mitochondria-retaining RBCs may provide a new therapeutic approach to preventing excessive ROS in SCD.

Highlights: • Indonesia’s annual area of forest degradation is equal to deforestation. • Numerous forest restoration initiatives exist but with varying levels of success. • Government control provides a disincentive to restoration initiatives. • Partnerships across multiple scales can enhance FLR learning opportunities.

The human genome harbors 14,000 duplicated or retroposed pseudogenes. Given their functionality as regulatory RNAs and low conservation, we hypothesized that pseudogenes could shape human-specific phenotypes. To test this, we performed co-expression analyses and found that pseudogene exhibited tissue-specific expression, especially in the bone marrow. By incorporating genetic data, we identified a bone-marrow-specific duplicated pseudogene, HBBP1 (η-globin), which has been implicated in β-thalassemia. Extensive functional assays demonstrated that HBBP1 is essential for erythropoiesis by binding the RNA-binding protein (RBP), HNRNPA1, to upregulate TAL1, a key regulator of erythropoiesis. The HBBP1/TAL1 interaction contributes to a milder symptom in β-thalassemia patients. Comparative studies further indicated that the HBBP1/TAL1 interaction is human-specific. Genome-wide analyses showed that duplicated pseudogenes are often bound by RBPs and less commonly bound by microRNAs compared with retropseudogenes. Taken together, we not only demonstrate that pseudogenes can drive human evolution but also provide insights on their functional landscapes.

Land tenure in Indonesia is regulated by a complex combination of traditional, formal and informal arrangements. Legal ambiguity over land and natural resources has resulted in tenure insecurity, impacting livelihoods and perpetuating conflict. We reviewed land and forest laws in Indonesia and their effect on livelihoods and conflict and studied the impact of land tenure uncertainty in Rempek village on the island of Lombok, Nusa Tenggara Barat. In Rempek, conflict over land tenure and forest boundaries has occurred since 1984. We built a timeline of events from discussions with various stakeholders and obtained legal documents to support our analysis. The major driver of conflict is the disagreement over the forest boundaries between the Ministry of Forestry and the National Land Agency. This disagreement has escalated and introduced uncertainty, which negatively affects livelihoods in the area. Conflict resolution in Rempek requires a multi-stakeholder approach and an agreement between the Ministry of Forestry and the National Land Agency over the forest boundary and an explicit classification of land status in the conflict area. Our case study is relevant to recurrent disputes over land tenure in contemporary Indonesia. Agrarian conflict and tenure insecurity have stimulated political and social justice movements throughout the country. Recent reforms of land and forest tenure in Indonesia are opening up new pathways for local forest tenure arrangements in situations such as Rempek. Integrated landscape approaches are emerging in Indonesia and have elements that may contribute to resolving land tenure uncertainty. As land tenure security underpins livelihoods for most Indonesians, land authorities must demonstrate stronger coordination and pay more attention to realities on the ground to achieve political and legal progress on land tenure arrangements.

The anatomy of differentiation in the BM is poorly understood due to a lack of markers to image stepwise HSPC differentiation. We immunophenotyped all types of multipotent and lineage committed HSPC and identified 56 cell surface markers that can be “mixed and matched” to prospectively image HSPC. We used this data to develop a pipeline to map erythropoiesis in whole-mounted sternum. Pre-Meg-E are ESAM-Ly6C-CD117+CD150+CD71-, Pre-CFU-E are Ly6C-CD117+CD150+CD71+ and CFU-E are Ly6C-CD117+CD150-CD71+ cells. We found that all three types of erythroid progenitors show no specific association with LT-HSC/MPP2/MkP, indicating that Pre-Meg-E or more primitive progenitors leave the HSC niche after differentiation. Both Pre-Meg-E and Pre-CFU-E are found as single cells through the central BM space and do not specifically associate with other progenitors, or components of the microenvironment. In contrast almost all CFU-E locate to strings (28 strings per sternum) containing 6±0.28 CD117brightCD71dim CFU-E that are selectively recruited to sinusoids (mean CFU-E to sinusoid distance=2.2µm). As soon as CFU-E detach from sinusoids they show sharp reductions in CD117 and upregulation of CD71 giving rise to a cluster of early erythroblasts that buds from the vessel. These progressively upregulate Ter119 to generate large clusters of late erythroblasts that in turn differentiate into clusters of reticulocytes and erythrocytes. To understand how the architecture of erythropoiesis changes in response to stress we performed phlebotomy. Two days later we found Pre-Meg-E and Pre-CFU-E numbers and locations was unaltered. The number of CFU-E strings remained constant (30 CFUE strings/sternum) but all strings contained more CFU-E (2-fold) that then differentiated as above. Our imaging pipeline can be quickly adapted to image all other HSPC during normal, stress, and diseased hematopoiesis.

Mounting evidence indicates that lineage decisions are controlled by local structures that support differentiation in distinct regions of the bone marrow. Our ability to manipulate hematopoiesis to treat disease has been hampered by our lack of understanding of these anatomical cues. Here we described the development of pipelines to simultaneously image myeloid progenitors together with their offspring, HSC, and endosteal and vascular niches. We found that myeloid progenitors move away from HSC during differentiation. Myeloid progenitors do not localize with each other, instead they localize to different sinusoids where they give rise to clusters of immature cells. Granulocyte, monocyte, and dendritic cell production takes place in different sinusoids suggesting the existence of specialized microenvironments that organize myelopoieis. Indeed, MDP selectively cluster with Ly6Clo monocytes and conventional dendritic cells; and localize to a unique subset of CSF1-expressing sinusoids (8% of all sinusoids), Csf1 deletion in the vasculature disrupted the MDP clusters and their interaction with sinusoids, leading to reduced MDP numbers and differentiation ability, with subsequent loss of Ly6Clo monocytes and dendritic cells. These indicate that there is a specific spatial organization of definitive hematopoiesis and that local cues produced by distinct vascular niches are responsible for this organization.

We assess the opportunities and threats posed by small and large-scale mining in Eastern Indonesia. Here, both activities coexist in one landscape: in the Bitung and North Minahasa Districts of North Sulawesi. Each is associated with different development pathways. Both scales of mining have been controversial and are criticized for their environmental and socio-economic impacts. Small-scale mining contributes more to the local economy encouraging local entrepreneurship but yields a lower total financial return. Large-scale mining provides better job security and safer working conditions for employees, but any benefits of capital transformation do not accrue locally. Policy should focus on the formalization of small-scale mining and pay closer attention to the impact of large-scale mining on local communities. The governance of both scales of mining would benefit from a ‘landscapes approach’ to negotiating conservation and development trade-offs.

A landscape provides key livelihood resources for people such as agriculture, forestry, fisheries, extractive industries, and other productive land uses. It is the space in which dynamic and evolving nature-human interactions occur. Hence, understanding different functions and processes in a landscape becomes vital for poverty alleviation as well as sustainable management of natural resources. In our study to understand the landscape changes of North Sulawesi, the second richest province in Indonesia, we use a landscape approach to understand the connections between human livelihoods and environment. We studied five villages using Participatory Rural Assessments tools, consolidated questionnaires, formal and informal interviews of various stakeholders, GIS-based participatory mapping and in-the-field observations as well as secondary sources. We find natural hazards, climate variability, accessibility, extractive industries, food security and water scarcity are interlinked as big drivers of change in the landscape. Decision makers must consider them together to ensure community prosperity.

SummaryChromosomal inversion between 3q21 and 3q26 results in high-risk acute myeloid leukemia (AML). In this study, we identified a mechanism whereby a GATA2 distal hematopoietic enhancer (G2DHE or −77-kb enhancer) is brought into close proximity to the EVI1 gene in inv(3)(q21;q26) inversions, leading to leukemogenesis. We examined the contribution of G2DHE to leukemogenesis by creating a bacterial artificial chromosome (BAC) transgenic model that recapitulates the inv(3)(q21;q26) allele. Transgenic mice harboring a linked BAC developed leukemia accompanied by EVI1 overexpression—neoplasia that was not detected in mice bearing the same transgene but that was missing the GATA2 enhancer. These results establish the mechanistic basis underlying the pathogenesis of a severe form of leukemia through aberrant expression of the EVI1 proto-oncogene.

Objectifs Il persiste un besoin majeur de biomarqueurs predictifs de reponse a un traitement par chimiotherapie neoadjuvante (cna) pour les tumeurs de vessie infiltrant le muscle (tvim) afin proceder a une chirurgie immediate chez les patients non repondeurs. L’objectif de ce travail est d’evaluer l’impact des mutations des genes impliques dans la reparation de l’adn (gra) dans une cohorte multicentrique. Methodes Un sequencage de l’exome entier a ete realise sur des echantillons de resection transuretrale de la vessie (rtuv) avant la chimiotherapie neoadjuvante chez les patients ayant une tvim. Toute mutation de rb1, atm, ercc2 ou fancc avec un impact fonctionnel predit comme deletere (non sens, decalage du cadre ou affectant un site d’epissage et certaines mutations faux-sens apres revision manuelle) etait retenue. La reponse a la chimiotherapie neoadjuvante a ete definie comme l’absence de tvim sur la piece de cystectomie. La survie globale (sg) a ete analysee par l’estimation de Kaplan–Meier. Une regression logistique a ete realisee pour estimer l’impact sur la reponse pathologique. Resultats Nous avons inclus 109 patients avec tvim traites par chimiotherapie neoadjuvante suivi d’une cystectomie avec un suivi median de 2,7 ans [0,86–4,45]. Trente-six (33 %) patients ont une mutation des gra. La survie globale a 3 ans etait de 84,2 % [ic 95 % 72,4–98] pour les patients avec une mutation des gra et 52,5 % [95 % 41,8–66] pour les patients sans mutations (p = 0,0023). Hr de la mutation des gra est de 0,30 (p = 0,004). De plus, la presence de la mutation des gra etait correlee a une reponse histologique (or 5,6, p Figure 1 , Figure 2 , Figure 3 ). Conclusion Avoir une mutation dans les genes impliques dans la reparation de l’ADN (ercc2, fancc, rb1 et atm) est associee a une meilleure survie globale ainsi qu’a une meilleure reponse histologique pour les patients traites pour une tvim par chimiotherapie neoadjuvante suivi de cystectomie radicale.