Gravity modelling in the western Bushveld Complex, South Africa, using integrated geophysical data

A 10 km x 10 km study area in the western Bushveld Complex, south of the Pilanesberg Complex, was selected for testing the inversion of vertical component gravity (Gz) data to determine the geometry of the Bushveld Complex/Transvaal Supergroup contact. This contact has a density contrast of ~0.350 g.cm-3 making it a suitable target for gravity inversion. The resulting 3D gravity model agrees well with the 3D seismic interpretation, indicating that the depths determined from the seismic data are appropriate. The gravity inversion could be extended laterally to investigate regions without seismic data coverage. This methodology may prove useful where upwellings in the floor of the Bushveld Complex distort seismic data, but can be imaged by gravity inversions. The Gz dataset was created from converted Airborne Gradient Gravity (AGG) data, combined with upward continued ground Gz gravity data, providing extensive coverage. This combined dataset was used in an interactive, iterative 3D gravity inversion methodology used to model the geometry of the Bushveld Complex/Transvaal Supergroup contact and densities of the Bushveld Complex, Transvaal Supergroup and Iron-Rich Ultramafic Pegmatoids (IRUPs). The resulting 3D gravity model provides an acceptable first-pass model of the Bushveld Complex/Transvaal Supergroup contact. In the shallow south-west region of the study area, the steeply dipping contact was determined from borehole intersections. 3D seismic data was the only constraint towards the north-east, where the contact flattens out to a sub-parallel contact, at ~2 000 m depth. In the north-western section, the Bushveld Complex/Transvaal Supergroup contact is fault-bounded by a conjugate set of the Rustenburg Fault, causing the Bushveld to onlap the Transvaal sediments. In the southern region, the contact changes as the conjugate fault dies out, and the Bushveld Complex becomes layered/sub-parallel to Transvaal sediments. This, and other geological features (e.g. faulting, folding, dykes), can be explained in relation to the regional tectonic history, relating to motion along the Thabazimbi-Murchison Lineament (TML). Pre-Bushveld emplacement NW-SE far-field stress caused NW trending extensional features in the region (e.g. Rustenburg Fault). Re-orientation of the compressive force to NE-SW, in syn- to post-emplacement, caused compressive features in the region (e.g. open folds with axes trending NW). Ground gravity data (100 m x 100 m station- and line-spacing) were also inverted to obtain a 3D model of the overburden, constrained by borehole data. However, the inversion failed to satisfy the gravity data and borehole data simultaneously, relating to difficulties in modelling the regional gravity field and the gradational nature of the weathered contact. Several rapid variations in overburden thickness were mapped, with particular success in the high frequency ground gravity survey (30 m x 30 m station- and line-spacing) with the identification of a deeply weathered (~10 m deep) channel relating to an mapped fault

Models of <i>KPTN</i>-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.</p

Management and Outcomes Following Surgery for Gastrointestinal Typhoid: An International, Prospective, Multicentre Cohort Study

Background: Gastrointestinal perforation is the most serious complication of typhoid fever, with a high disease burden in low-income countries. Reliable, prospective, contemporary surgical outcome data are scarce in these settings. This study aimed to investigate surgical outcomes following surgery for intestinal typhoid. Methods: Two multicentre, international prospective cohort studies of consecutive patients undergoing surgery for gastrointestinal typhoid perforation were conducted. Outcomes were measured at 30 days and included mortality, surgical site infection, organ space infection and reintervention rate. Multilevel logistic regression models were used to adjust for clinically plausible explanatory variables. Effect estimates are expressed as odds ratios (ORs) alongside their corresponding 95% confidence intervals. Results: A total of 88 patients across the GlobalSurg 1 and GlobalSurg 2 studies were included, from 11 countries. Children comprised 38.6% (34/88) of included patients. Most patients (87/88) had intestinal perforation. The 30-day mortality rate was 9.1% (8/88), which was higher in children (14.7 vs. 5.6%). Surgical site infection was common, at 67.0% (59/88). Organ site infection was common, with 10.2% of patients affected. An ASA grade of III and above was a strong predictor of 30-day post-operative mortality, at the univariable level and following adjustment for explanatory variables (OR 15.82, 95% CI 1.53–163.57, p = 0.021). Conclusions: With high mortality and complication rates, outcomes from surgery for intestinal typhoid remain poor. Future studies in this area should focus on sustainable interventions which can reduce perioperative morbidity. At a policy level, improving these outcomes will require both surgical and public health system advances

Global economic burden of unmet surgical need for appendicitis

Background There is a substantial gap in provision of adequate surgical care in many low- and middle-income countries. This study aimed to identify the economic burden of unmet surgical need for the common condition of appendicitis. Methods Data on the incidence of appendicitis from 170 countries and two different approaches were used to estimate numbers of patients who do not receive surgery: as a fixed proportion of the total unmet surgical need per country (approach 1); and based on country income status (approach 2). Indirect costs with current levels of access and local quality, and those if quality were at the standards of high-income countries, were estimated. A human capital approach was applied, focusing on the economic burden resulting from premature death and absenteeism. Results Excess mortality was 4185 per 100 000 cases of appendicitis using approach 1 and 3448 per 100 000 using approach 2. The economic burden of continuing current levels of access and local quality was US $92 492 million using approach 1 and$73 141 million using approach 2. The economic burden of not providing surgical care to the standards of high-income countries was $95 004 million using approach 1 and$75 666 million using approach 2. The largest share of these costs resulted from premature death (97.7 per cent) and lack of access (97.0 per cent) in contrast to lack of quality. Conclusion For a comparatively non-complex emergency condition such as appendicitis, increasing access to care should be prioritized. Although improving quality of care should not be neglected, increasing provision of care at current standards could reduce societal costs substantially

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AimThe SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery.MethodsThis was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin.ResultsOverall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P ConclusionOne in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease