Morphometric Analysis of the Calcaneus in a Southeast Asian Population.

Introduction The calcaneus is the most commonly fractured tarsal bone, accounting for up to 60% of tarsal bone fractures and 2% of all fractures in the body. With the calcaneus playing an important role in maintaining a stable and efficient bipedal gait, the sequelae of these injuries have also been associated with potential long-term disability or discomfort, especially if improperly managed. Incorrectly sized implants similarly cause their own set of complications, such as poor fixation, impingement, or implant prominence. This potentially increases the need for revision surgery or implant removal, with increased morbidity for the patient. As such, a thorough understanding of calcaneal morphology is vital to ensure optimal conservative and surgical management of calcaneal pathology. CT imaging has become an indispensable tool in the evaluation of such a complex three-dimensional structure and allows us to accurately map out calcaneal morphology. This study aims to evaluate calcaneal morphology in the Southeast Asian population using CT imaging and to determine if morphological differences exist between male and female patients. Methods Calcaneus measurements were taken from CT scans of 100 patients with intact calcanei, consisting of 34 female and 66 male patients. Patients who have had fractures or previous calcaneus surgery were excluded. IBM SPSS Statistics for Windows, Version 28.0 (Released 2021; IBM Corp., Armonk, NY, USA) was used for statistical calculations. Mean values were calculated, and t-tests were performed to establish any significant differences between measurements taken from male and female patients. Results were deemed to have a significant difference if the p-value was less than 0.05. Results Males had larger calcanei measurements than females in all parameters included. Calcaneal length in females measured on CT axial views was 66.2 mm, compared to 75.2 mm in males (p < 0.001). Calcaneal height, measured at the medial wall, was 28.2 mm in females and 33.9 mm in males (p < 0.001). Calcaneal height measured at the lateral wall was 33.3 mm and 38.1 mm in females and males, respectively (p > 0.001). Calcaneal width was 33.0 mm in females and 36.9 mm in males (p < 0.001). The mean dimensions measured in the total sample were an axial length of 72.1 mm, a medial wall height of 32.0 mm, a lateral wall height of 36.4 mm, and a width of 35.6 mm. Conclusion There is a significant difference in calcaneal morphology on CT imaging between male and female patients in the Southeast Asian population, which is an important consideration for surgical planning and the selection of appropriately sized implants.

The effects of anti-TNF-α biologics on insulin resistance and insulin sensitivity in patients with rheumatoid arthritis: An update systematic review and meta-analysis.

BACKGROUND AND AIM: Increasing evidence demonstrates a link between the chronic inflammatory state in patients with rheumatoid arthritis (RA) and the development of insulin resistance. It is thought that anti-TNF-α biologic therapy may improve insulin sensitivity and ameliorate insulin resistance by the downregulation of inflammatory cytokines, however, pre-clinical and clinical studies have yielded conflicting results. A meta-analysis on this topic is necessary to summarize current evidence and generate hypotheses for future research. METHODS: Literature search was performed in four databases, namely PubMed, EMBASE, Scopus, and The Cochrane Library, from inception till April 9, 2023, querying studies reporting peripheral insulin resistance with and without anti-TNF-α use in patients with RA. Peripheral insulin resistance or sensitivity was quantified by the Homeostasis Model Assessment of Insulin Resistance (HOMA) index or the Quantitative Insulin Sensitivity Check Index (QUICKI) respectively. The difference in insulin resistance or sensitivity between the treatment and control group was calculated using standardized mean difference (SMD) for the purposes of the meta-analysis. RESULTS: Twelve articles were reviewed, with 10 longitudinal studies with a total of 297 patients included in the meta-analysis. The pooled standardized mean difference (SMD) from baseline HOMA was -0.82 (95% CI: -1.38 to -0.25) suggesting significant beneficial effects of anti-TNF-α therapy on insulin resistance. CONCLUSION: Current evidence supports the significant clinical efficacy of anti-TNF-α biologics in alleviating insulin resistance and improving insulin sensitivity in patients with active RA.

Chromatin targeting of the RNF12/RLIM E3 ubiquitin ligase controls transcriptional responses.

Protein ubiquitylation regulates key biological processes including transcription. This is exemplified by the E3 ubiquitin ligase RNF12/RLIM, which controls developmental gene expression by ubiquitylating the REX1 transcription factor and is mutated in an X-linked intellectual disability disorder. However, the precise mechanisms by which ubiquitylation drives specific transcriptional responses are not known. Here, we show that RNF12 is recruited to specific genomic locations via a consensus sequence motif, which enables co-localisation with REX1 substrate at gene promoters. Surprisingly, RNF12 chromatin recruitment is achieved via a non-catalytic basic region and comprises a previously unappreciated N-terminal autoinhibitory mechanism. Furthermore, RNF12 chromatin targeting is critical for REX1 ubiquitylation and downstream RNF12-dependent gene regulation. Our results demonstrate a key role for chromatin in regulation of the RNF12-REX1 axis and provide insight into mechanisms by which protein ubiquitylation enables programming of gene expression.

Retrospective analysis of enhancer activity and transcriptome history.

Cell state changes in development and disease are controlled by gene regulatory networks, the dynamics of which are difficult to track in real time. In this study, we used an inducible DCM-RNA polymerase subunit b fusion protein which labels active genes and enhancers with a bacterial methylation mark that does not affect gene transcription and is propagated in S-phase. This DCM-RNA polymerase fusion protein enables transcribed genes and active enhancers to be tagged and then examined at later stages of development or differentiation. We apply this DCM-time machine (DCM-TM) technology to study intestinal homeostasis, revealing rapid and coordinated activation of enhancers and nearby genes during enterocyte differentiation. We provide new insights in absorptive-secretory lineage decision-making in intestinal stem cell (ISC) differentiation and show that ISCs retain a unique chromatin landscape required to maintain ISC identity and delineate future expression of differentiation-associated genes. DCM-TM has wide applicability in tracking cell states, providing new insights in the regulatory networks underlying cell state changes.

Efficient generation of ETX embryoids that recapitulate the entire window of murine egg cylinder development.

The murine embryonic-trophoblast-extra-embryonic endoderm (ETX) model is an integrated stem cell-based model to study early postimplantation development. It is based on the self-assembly potential of embryonic, trophoblast, and hypoblast/primitive/visceral endoderm-type stem cell lines (ESC, TSC, and XEN, respectively) to arrange into postimplantation egg cylinder-like embryoids. Here, we provide an optimized method for reliable and efficient generation of ETX embryoids that develop into late gastrulation in static culture conditions. It is based on transgenic Gata6-overproducing ESCs and modified assembly and culture conditions. Using this method, up to 43% of assembled ETX embryoids exhibited a correct spatial distribution of the three stem cell derivatives at day 4 of culture. Of those, 40% progressed into ETX embryoids that both transcriptionally and morphologically faithfully mimicked in vivo postimplantation mouse development between E5.5 and E7.5. The ETX model system offers the opportunity to study the murine postimplantation egg cylinder stages and could serve as a source of various cell lineage precursors.

Characteristics and Postoperative Outcomes for High Cervical versus Subaxial Cervical Intradural Extramedullary Tumors: A Multicenter Study.

BACKGROUND: High cervical intradural extramedullary tumors are uncommon. Their relationship to surrounding neural structures and vertebral arteries makes surgical excision challenging. No previous studies have compared high cervical to subaxial cervical intradural extramedullary spinal tumors to elucidate their unique characteristics and surgical outcomes. METHODS: We performed a retrospective study in which patients who underwent excision of a cervical intradural extramedullary tumor were divided into a high cervical group and a subaxial cervical group. Variables included sex, age, Charlson Comorbidity Index, volume, laterality, preoperative weakness, use of neuromonitoring and drains, instrumented fusion, complications, length of stay, histology, discharge location, recurrence, and duration of follow-up. Variables were compared between the 2 groups. Limb power and Nurick classification were charted preoperatively, at discharge, and at 6 months to plot their recovery trajectory. RESULTS: Eighty-four patients with a total of 90 tumors were enrolled, including 40 patients in the high cervical group and 44 patients in the subaxial spine group. More patients with neurofibromas (P = 0.011) and bilateral tumors (P = 0.044) were in the high cervical group. A greater prevalence of neurofibromatosis type 1 was significant for bilateral high cervical tumors (P = 0.033). More patients in the subaxial group had instrumented fusion (P = 0.045). More patients in the high cervical group had improvement in limb power (P = 0.025) and Nurick classification (P = 0.0001) postoperatively before discharge. By 6 months, both groups had similar recovery. No mortality was attributable to surgery in either group. CONCLUSION: High cervical intradural extramedullary spine tumors have more bilateral tumors associated with neurofibromatosis type 1. Despite the challenging anatomy, surgical resection is safe with good outcomes in this group.

Rhabdomyolysis Masquerading as Cauda Equina Syndrome.

Lower back pain is a very common presenting condition, with a large proportion resulting from discogenic causes, especially after strenuous activity. In patients with a history of exertion, lower back pain, and acute urinary retention, the obvious diagnosis to exclude would be cauda equina syndrome. We present a case of a 32-year-old man who presented with lower back pain, bilateral lower limb weakness, and acute urinary retention following a recent episode of heavy lifting. He was subsequently diagnosed with rhabdomyolysis. This case highlights that rarer conditions can masquerade as cauda equina syndrome, and even in seemingly straightforward presentations, alternative diagnoses should also be considered.

SPEN is required for Xist upregulation during initiation of X chromosome inactivation.

At initiation of X chromosome inactivation (XCI), Xist is monoallelically upregulated from the future inactive X (Xi) chromosome, overcoming repression by its antisense transcript Tsix. Xist recruits various chromatin remodelers, amongst them SPEN, which are involved in silencing of X-linked genes in cis and establishment of the Xi. Here, we show that SPEN plays an important role in initiation of XCI. Spen null female mouse embryonic stem cells (ESCs) are defective in Xist upregulation upon differentiation. We find that Xist-mediated SPEN recruitment to the Xi chromosome happens very early in XCI, and that SPEN-mediated silencing of the Tsix promoter is required for Xist upregulation. Accordingly, failed Xist upregulation in Spen-/- ESCs can be rescued by concomitant removal of Tsix. These findings indicate that SPEN is not only required for the establishment of the Xi, but is also crucial in initiation of the XCI process.

Factors affecting duration of SARS-Cov-2 viral shedding in mildly symptomatic patients isolated in a community facility.

INTRODUCTION: Mildly symptomatic cases of Covid-19 in previously-well individuals form the majority of infections and also serve as potent vectors of transmission. The factors affecting the duration of SARS-CoV-2 RNA viral shedding (DVS) in these patients remain largely unknown. OBJECTIVES: To perform a systematic analysis of the clinical, radiologic, laboratory investigations in patients with few comorbidities infected with mild Covid-19 to identify factors associated with the DVS. METHODS: In this retrospective cohort study, patients with mild or asymptomatic Covid-19 were included. Baseline characteristics including age, nationality, comorbidities, concomitant medications, and type of isolation arrangement in the facility (single or in pairs) were collected. Clinical features and radiologic/haematologic findings were also collected. Taking day 28 as the cut-off, 187 patients who had a negative swab result up to day 28 (no prolonged DVS) were compared to 126 patients with a persistently positive result on or after day 28 (prolonged DVS). RESULTS: Of 964 consecutive patients included, 851 (88.3%) patients were symptomatic. 266 patients had a documented negative RT-PCR assay with a median DVS of 25 days (range: 13 to 96 days; interquartile range (IQR): 22 to 33 days). Patients isolated in pairs were associated with prolonged DVS (OR: 2.7; 95% CI: 1.7 to 4.5; p<0.0001) compared to those isolated individually. Among vital signs, only tachycardia was associated with prolonged DVS (OR: 2.6; 95% CI: 1.0 to 7.1; p = 0.03). Amongst investigations, only a raised CRP was associated with prolonged DVS (OR: 2.7; 95% CI: 1.1 to 6.8; p = 0.02). CONCLUSIONS: In young, mildly symptomatic Covid-19 patients, prolonged DVS was associated with being isolated in pairs compared to individually. In situations where a negative RT-PCR test result is required, retesting in patients who were not isolated individually, or who had baseline tachycardia or a raised CRP, may be delayed to increase the yield of a negative result.

Macular vessel density, branching complexity and foveal avascular zone size in normal tension glaucoma.

The aim of this study was to investigate the relationship between glaucoma severity and perifoveal vessel density (pfVD), branching complexity, and foveal avascular zone (FAZ) size in normal tension glaucoma (NTG). 31 patients with NTG washed out of glaucoma medications were subjected to tests including; intraocular pressure measurement; standard automated perimetry; optical coherence tomography (OCT) measurement of macular ganglion cell complex (mGCC), inner macular thickness (IMT) and circumpapillary retinal nerve fibre layer (cpRNFL); and OCT angiography measurement of pfVD, FAZ perimeter and multispectral fractal dimensions (MSFD). Eyes with more severe glaucoma had significantly thinner mGCC and cpRNFL and lower pfVD. MD decreased by 0.4 dB (95% CI 0.1 to 0.6 dB, P = 0.007) for every 1% decrease in pfVD. Lower MSFD was observed in eyes with lower pfVD and in patients with systemic hypertension. Multivariable analysis, accounting for age and OCTA quality, found lower pfVD remained significantly associated with thinner IMT, thinner mGCC and worse MD but not with MSFD. pfVD was reduced in NTG and was diminished in eyes with worse MD. Macular vessel branching complexity was not related to severity of visual field loss but was lower in patients with systemic hypertension.

Utility of a high-definition 3D digital exoscope for spinal surgery during the COVID-19 pandemic.

The COVID-19 pandemic creates unique challenges in the practice of spinal surgery. We aim to show how the use of a high-definition 3D digital exoscope can help streamline workflows, and protect both patients and healthcare staff.

Loss of function mutations in essential genes cause embryonic lethality in pigs.

Lethal recessive alleles cause pre- or postnatal death in homozygous affected individuals, reducing fertility. Especially in small size domestic and wild populations, those alleles might be exposed by inbreeding, caused by matings between related parents that inherited the same recessive lethal allele from a common ancestor. In this study we report five relatively common (up to 13.4% carrier frequency) recessive lethal haplotypes in two commercial pig populations. The lethal haplotypes have a large effect on carrier-by-carrier matings, decreasing litter sizes by 15.1 to 21.6%. The causal mutations are of different type including two splice-site variants (affecting POLR1B and TADA2A genes), one frameshift (URB1), and one missense (PNKP) variant, resulting in a complete loss-of-function of these essential genes. The recessive lethal alleles affect up to 2.9% of the litters within a single population and are responsible for the death of 0.52% of the total population of embryos. Moreover, we provide compelling evidence that the identified embryonic lethal alleles contribute to the observed heterosis effect for fertility (i.e. larger litters in crossbred offspring). Together, this work marks specific recessive lethal variation describing its functional consequences at the molecular, phenotypic, and population level, providing a unique model to better understand fertility and heterosis in livestock.