Inflammatory myofibroblastic tumours of the liver - a systematic review.

BACKGROUND: Hepatic inflammatory myofibroblastic tumours (HIMTs) are rare and poorly described in the literature. Most publications are single patient case reports and lack detailed reporting on characteristics, management, and outcomes. This systematic review aimed to assess the demography, clinical presentation, typical imaging features, histopathology, treatment, and outcomes of patients presenting with HIMTs. METHODS: A systematic literature search was performed in MEDLINE (PubMed), EMBASE (Scopus), JSTOR, Cochrane CENTRAL (Cochrane Library), and the databases included in the Web of Science for studies published between 1940 and 2023 on HIMTs, including its reported synonyms. Case series or cohort studies that reported on the management and outcomes of at least four patients with histologically confirmed HIMTs were included in the analysis. RESULTS: After screening 4553 publications, 22 articles including a total of 440 patients with confirmed HIMTs were eligible for inclusion. The average age was 53.4 years (range 42.0-65.0) with a male to female ratio of 1.7:1. Abdominal pain, discomfort, fever, and loss of weight were the most common presenting symptoms. Surgical resection is the standard of care for HIMTs and is associated with low mortality of 3.4% and low disease recurrence. CONCLUSION: HIMT is a disease more often affecting middle-aged males. The lesions are typically solitary with low recurrence after treatment. The relative roles of surgical versus medical treatment remain unclear. Differences in clinical presentation, histopathology, and treatment of HIMTs compared to inflammatory myofibroblastic tumour (IMT) at extrahepatic sites could challenge the current view of IMT as a single pathological entity.

Radiotherapy for Recurrent Medulloblastoma in Children and Adolescents: Survival after Re-Irradiation and First-Time Irradiation.

BACKGROUND: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. METHODS: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. RESULTS: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7-28.7) vs. 12.0 (CI: 8.1-21.0) months] and OS [31.5 (CI: 27.6-64.8) vs. 20.0 (CI: 14.0-36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4-45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7-41.5) vs. 8.0 (CI: 6.6-12.2)/OS: 31.5 (CI: 27.6-NA) vs. 13.3 (CI: 8.1-20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8-60.6) vs. 6.6 (CI: 1.5-NA) months] and OS [40.2 (CI: 18.7-NA) vs. 12.4 (CI: 4.4-NA) months]. CONCLUSIONS: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival.

Outcomes of jaundice in advanced hepatocellular carcinoma - a sub-Saharan perspective.

BACKGROUND: Jaundice is a marker of advanced disease and poor outcomes in hepatocellular carcinoma (HCC). The aim of this study was to describe and analyse the management and outcomes of jaundiced HCC patients at a large academic referral centre in sub-Saharan Africa (SSA). METHODS: Treatment-naïve adult HCC patients who presented with jaundice between 1990 and 2023 were analysed. RESULTS: During the inclusion period, 676 HCC patients were treated at Groote Schuur Hospital. The mean age of the 126 (18.6%) who were jaundiced was 48.8 (± 13.2) years. Eighty-nine (70.6%) were male. Ninety-four (74.6%) patients with jaundice secondary to diffuse tumour infiltration had best supportive care (BSC) only. Thirty-two had obstructive jaundice (OJ); four were excluded because of missing hospital records. In 28 of these patients, 16 underwent biliary drainage (BD) and 12 received BSC only. The mean overall survival (OS) of the 126 patients was 100.5 (± 242.3) days. The patients with diffuse tumour infiltration had an OS of 105.9 (± 273.3) days. The patients with OJ survived 86.5 (± 135.0) days. There was no significant difference in OS between the three patient groups (p = 0.941). In the OJ group, patients who underwent BD survived longer than the BSC group (117.9 ± 166.4 vs. 29.2 ± 34.7 days, p = 0.015).

Does the textbook outcome in pancreatic surgery score after pancreaticoduodenectomy for ampullary carcinoma have prognostic value?

BACKGROUND: The value of the textbook outcome in pancreatic surgery (TOPS) score, a composite measure of surgical performance for quality assurance, was evaluated in a South African tertiary hospital cohort of pancreaticoduodenectomies (PD) performed for adenocarcinoma of the ampulla of Vater (AAV). METHODS: A review of all patients undergoing a PD for AAV at a single centre between January 1999 and December 2023 was performed. Demographic, operative, pathological and postoperative variables were recorded. Ten clinical and histological variables were used to construct a TOPS score. These included an R0 resection, no postoperative pancreatic fistula (POPF), no bile leak, no post-pancreatectomy haemorrhage, no delayed gastric emptying, no major postoperative complications (< Gr 3 Clavien-Dindo), no readmission to ICU, length of stay ≤ 10 days, no 30-day readmission or intervention and no 30-day mortality. A textbook outcome (TO) was defined as the fulfilment of all 10 variables. In patients in whom TO was not achieved, the reasons for failure were identified. In addition, the number of patients who had major complications and died were categorised as failure to rescue (FTR). RESULTS: A positive TOPS score was achieved in 27 of 79 (34.2%) patients undergoing a PD. Overall five-year survival after PD was 33.9%. TOPS conferred a significant 1-year survival benefit, 88.9% vs 66.7% (OR 4.12, 95% CI 1.08-15.67, p = 0.038). There was no significant difference in 5-year survival between TOPS and non-TOPS patients, 40.0% vs 32.4% (OR 1.39, 95% CI 0.48-3.99, p = 0.54). A POPF occurred in 31.6% patients, resulting in a significantly longer hospital admission, 17 vs 10 days (95% CI 2.66-11.34, p = 0.0019). Twenty-one (26.6%) patients developed a major complication, five of whom died (FTR = 6.3%). CONCLUSION: This study confirmed the value of TOPS as a useful measurement to assess hospital quality metrics and short-term survival after PD for AAV. One quarter of patients developed a major complication with a 6.3% FTR.

Pancreaticoduodenectomy for distal cholangiocarcinoma at a South African centre.

BACKGROUND: Surgical resection of distal cholangiocarcinoma (dCCA) offers the only chance for cure and long-term survival. The current literature provides limited data regarding the surgical management and long-term outcomes of dCCA. This study aims to describe the presentation, management, and outcomes of dCCA at a large academic referral centre in South Africa. METHODS: A retrospective study was performed of all patients who underwent curative-intended surgery for dCCA at Groote Schuur Hospital from 2000 to 2020. RESULTS: Over 21 years, 25 patients underwent pancreaticoduodenectomy (PD) for dCCA. Most patients were male (68%), and the mean age was 56.8 years. Of the patients, 22 (84%) underwent preoperative biliary drainage (PBD). There were 29 recorded complications in 25 patients; postoperative pancreatic fistula (POPF) and surgical site infection (SSI) each occurred in 24% of the cohort. The mean hospital stay was 17.2 days without perioperative mortality. With none lost to follow-up, the 1, 3, 5, 10, and 20-year survival rates were 84%, 24%, 16%, 12%, and 4%, respectively. Only T3 status was associated with significantly lower overall survival (OS). Age, albumin levels, PBD, margin status (R0 vs. R1), and nodal status (N0 vs. N1/N2) did not influence OS. CONCLUSION: This is the first study detailing the management and outcomes of dCCA from sub-Saharan Africa (SSA). Despite the complete resection of dCCA, the prognosis is poor, and the long-term survival rate in our study is equivalent to that reported in the literature. T3 disease is an important prognostic factor and is associated with poor OS. Surprisingly, nodal disease and margin status did not affect OS in the cohort of patients.

Liver resection for hepatocellular and fibrolamellar carcinoma in a South African tertiary referral centre - an observational cohort analysis.

BACKGROUND: More than 80% of global hepatocellular carcinomas (HCC) occur in sub-Saharan Africa (SSA) and South- East Asia. Compared with the rest of the world, HCC in SSA has the lowest resection and survival rates. This study assessed outcome following liver resection for HCC and fibrolamellar carcinoma (FLC) at a tertiary referral centre in South Africa. METHODS: A retrospective analysis was done of all liver resections for HCC and FLC at Groote Schuur Hospital and the University of Cape Town Private Academic Hospital between January 1990 and December 2021. Three groups were compared, (i) HCC occurring in normal livers, (ii) HCC occurring in cirrhotic livers, and (iii) fibrolamellar carcinoma. Postoperative complications were classified as per the expanded accordion severity grading system. Median overall survival (OS) and 95% confidence intervals (CI) were calculated. RESULTS: Forty-eight patients were included in the study, 25 for HCC in non-cirrhotic livers, 15 in cirrhotic livers and eight for FLC. Thirty-six patients (75%) underwent a major resection. No mortality occurred but 16 patients (33%) developed grade 1 to 4 complications postoperatively. Thirty-three patients (69%) developed recurrence of HCC following their initial resection of whom 29 (60%) ultimately died. Median overall survival (OS) for the total cohort after surgery was 57.2 months, 95% CI (29.7-84.6), 64.2 months (29.7-84.6), 61.9 months (28.1-95.6), and 31.7 months (1.5-61.8) for patients with HCC in non-cirrhotic livers, FLC and HCC in cirrhotic livers respectively. CONCLUSION: Liver resection for HCC and FLC was safe with no mortality, but one-third of patients had associated postoperative morbidity. The high long-term recurrence rate remains a major obstacle in achieving better survival results after resection.

The role of endoscopic retrograde cholangiopancreatography in the treatment of hepatic cystic Echinococcus in a high HIV prevalence population: a retrospective cohort study.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a useful, minimally invasive intervention in managing complicated hepatic cystic echinococcosis (HCE). This study aims to assess the use of ERCP in a South African HCE cohort with and without human immunodeficiency virus (HIV) co-infection. METHODS: An analysis was performed of patients with HCE who were assessed for surgery and underwent ERCP at a tertiary hospital in South Africa between 2011 and 2023. Demographics, clinical data, imaging characteristics, operative management, and postoperative complications were compared between HIV-negative (HIV-) and HIV-positive (HIV+) cohorts. RESULTS: Of the 91 patients assessed, 45 (mean age 34.6 years, 73.3% females, 23 HIV+) required ERCP. HIV status did not significantly affect cyst characteristics or surgical outcomes. HIV+ patients had a higher incidence of intraoperative bile leaks (p = 0.025). There were 18 patients who underwent preoperative ERCPs, mainly for biliary-cyst complications primarily causing obstructive jaundice. A total of 40 patients required postoperative ERCPs, mainly for bile leaks. There were no ERCP-related mortalities and only one case of pancreatitis. ERCP success rates were comparable in both cohorts, with an overall success rate of 86.7%. CONCLUSION: HIV co-infection did not significantly impact the clinical course or outcomes of cystic echinococcosis (CE) patients undergoing ERCP. Perioperative ERCP proved effective in managing biliary complications of HCE as well as postoperative complications, regardless of HIV status. This study underscores the importance of endoscopic interventions in the comprehensive management of CE.

Effect of preoperative biliary drainage on intraoperative biliary cultures and surgical outcomes after pancreatic resection.

BACKGROUND: Prolonged obstructive jaundice (OJ), associated with resectable pancreatic pathology, has many deleterious effects that are potentially rectifiable by preoperative biliary drainage (POBD) at the cost of increased postoperative infective complications. The aim of this study is to assess the impact of POBD on intraoperative biliary cultures (IBCs) and surgical outcomes in patients undergoing pancreatic resection. METHODS: Data from patients at Groote Schuur Hospital, Cape Town, between October 2008 and May 2019 were analysed. Demographic, clinical, and outcome variables were evaluated, including perioperative morbidity, mortality, and 5-year survival. RESULTS: Among 128 patients, 69.5% underwent POBD. The overall perioperative mortality in this study was 8.8%. The POBD group had a significantly lower perioperative mortality rate compared to the non-drainage group (5.6% vs. 25.6%). POBD patients had a higher incidence of surgical site infections (55.1% vs. 23.1%), polymicrobial growth from IBCs and were more likely to culture resistant organisms. Five-year survival was similar in the two groups. CONCLUSION: POBD was associated with a high incidence of resistant organisms on the IBCs, a high incidence of surgical site infections and a high correlation between cultures from the surgical site infection and the IBCs.

Intermediate and long-term survival prediction using prognostic scores in patients undergoing salvage TIPS for uncontrolled variceal bleeding.

BACKGROUND: This study investigated the value of prognostic scores to predict 90-day, 1-, 3- and 5-year survival after salvage TIPS (sTIPS) in patients with exsanguinating variceal bleeding who failed endoscopic intervention. METHODS: The Model for End-Stage Liver Disease (MELD), Model for End-Stage Liver Disease Sodium (MELDNa), Acute Physiology and Chronic Health Evaluation II (APACHE II) and Child-Pugh (C-P) grades and scores were calculated using Kaplan-Meier curves and Cox proportional hazards models in sTIPS patients treated between August 1991 and November 2020. RESULTS: Thirty-four patients (29 men, 5 women), mean age 52 years, SD ± 11.6 underwent sTIPS which controlled bleeding in 32 (94%) patients. Ten (29.4%) patients died in hospital at a median of 4.8 (range 1-10) days. On bivariate analysis, C-P score ≥ 10 (p = 0.017), high C-P grade (p = 0.048), MELD ≥ 15 (p = 0.010), MELD-Na score ≥ 22 (p < 0.001) and APACHE II score ≥ 15 (p < 0.001) predicted 90-day mortality. Individual clinical characteristics associated with 90-day mortality were grade 3 ascites (p = 0.029), > 10 units of blood transfused (p = 0.004), balloon tube placement (p < 0.001), endotracheal intubation (< 0.001) and inotrope support (p < 0.001). The overall 90-day, 1-, 3- and 5-year survival rates were 67.6%, 55.9%, 26.5% and 20.6% respectively. Nine patients (26.5%) were alive at a median of two years (range 1-18 years) post-TIPS. Patients with C-P grade A, C-P score < 10, MELD score < 15, MELD-Na score < 22 and APACHE II score < 15 had significantly better 90-day, 1-, 3- and 5-year survival rates. CONCLUSION: Although sTIPS controlled variceal bleeding in 94% of patients after failed endoscopic therapy, in-hospital mortality was 29% and less than one quarter were alive after five years. The selected cut-off values for the nominated scoring systems accurately predicted 90-day mortality and long-term survival.

Audit of an in-patient palliative care quality improvement process for patients with pancreatic ductal adenocarcinoma in a South African teaching hospital.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with poor survival rates. Timeously introduced palliative care (PC) improves the quality of life (QoL) for patients with terminal diseases. In 2020, an in-patient PC-quality improvement (QI) programme was implemented for PDAC patients. This study compared PC outcomes before and after the introduction of the PC-QI programme. METHODS: A focus group identified five critical intervention areas that could improve care. These were in-patient PC referral, pain and symptom control, shared decision-making, interdisciplinary collaborative care, and continuity of care. A hospital record audit of PDAC patients was conducted in pre- and post-implementation cohorts, and the results were compared. RESULTS: A total of 68 (2017 pre-PC-QI) and 39 (2022 post-PC-QI) patient records were audited. Demography, symptom duration, referral delay, and clinical findings were similar in both cohorts. In-patient PC referrals improved significantly from 54.4% in 2017 to 82.1% in 2022 (p = 0.0059). Significant improvements were also recorded in shared decisionmaking, collaboration, and continuity of care, while the reassessment of pain and symptoms after treatment improved. Fewer invasive procedures were done in the 2022 cohort (p = 0.0056). The delay from admission to an invasive diagnostic procedure decreased from a mean of 8.7 to 1.5 days (p = 0.0001). The duration of hospital admission, overall survival (OS), and readmissions during the final 30 days of life were similar. CONCLUSION: The QI programme resulted in improved use of the in-hospital PC service and made better use of scarce resources. Increasing patient and family participation and feedback will further inform the development of the quality of PC services.

Misinterpretation of the severity of bile duct injuries by MRCP.

BACKGROUND: Magnetic resonance imaging (MRI) is widely regarded as the gold standard for assessment of the bile ducts in patients with bile duct injuries (BDIs). This case series aims to highlight the shortcomings of this imaging modality and demonstrate how it may overestimate the injury severity. METHODS: Three patients treated at Groote Schuur Hospital and the University of Cape Town in whom MRI/magnetic resonance cholangiopancreatography (MRCP) overestimated the severity of BDI were included in the study. Demographic characteristics, clinical presentation, blood results and imaging findings are presented. RESULTS: All patients had an MRI/MRCP done which assessed the BDIs as major complete cut-off of the proximal common hepatic duct with substance loss. Subsequent direct cholangiography showed minor injuries and all three patients were successfully managed with endoscopic stenting. CONCLUSION: Major BDIs are complex, and assessment of severity is intricate and may be overestimated. These patients are best managed in high-volume multidisciplinary team settings.

Does HIV co-infection promote Echinococcus dissemination?

SUMMARY: The influence of human immunodeficiency virus (HIV) on the severity of hepatic cystic echinococcosis (CE) is uncertain. HIV-modulated immune suppression may increase the risk of contracting CE with less self-limiting disease, more rapid progression, and a higher likelihood of complications. A 30-year-old male with concurrent, untreated HIV underwent surgery for two large, complicated hepatic CE cysts, which were replacing the right hemiliver, and innumerable peritoneal daughter cysts. At operation, 30 kg of cystic material was removed from the liver and peritoneal cavity. Despite postoperative complications, including cardiac arrest, respiratory failure, and a bile leak, the patient made a full recovery.

Evaluation of the precision of the Plasmodium knowlesi growth inhibition assay for Plasmodium vivax Duffy-binding protein-based malaria vaccine development.

Recent data indicate increasing disease burden and importance of Plasmodium vivax (Pv) malaria. A robust assay will be essential for blood-stage Pv vaccine development. Results of the in vitro growth inhibition assay (GIA) with transgenic P. knowlesi (Pk) parasites expressing the Pv Duffy-binding protein region II (PvDBPII) correlate with in vivo protection in the first PvDBPII controlled human malaria infection (CHMI) trials, making the PkGIA an ideal selection tool once the precision of the assay is defined. To determine the precision in percentage of inhibition in GIA (%GIA) and in GIA50 (antibody concentration that gave 50 %GIA), ten GIAs with transgenic Pk parasites were conducted with four different anti-PvDBPII human monoclonal antibodies (mAbs) at concentrations of 0.016 to 2 mg/mL, and three GIAs with eighty anti-PvDBPII human polyclonal antibodies (pAbs) at 10 mg/mL. A significant assay-to-assay variation was observed, and the analysis revealed a standard deviation (SD) of 13.1 in the mAb and 5.94 in the pAb dataset for %GIA, with a LogGIA50 SD of 0.299 (for mAbs). Moreover, the ninety-five percent confidence interval (95 %CI) for %GIA or GIA50 in repeat assays was calculated in this investigation. The error range determined in this study will help researchers to compare PkGIA results from different assays and studies appropriately, thus supporting the development of future blood-stage malaria vaccine candidates, specifically second-generation PvDBPII-based formulations.

Ambiguities in Decomposing Molecular Polarizability into Atomic Charge Flow and Induced Dipole Contributions.

The molecular dipole polarizability can be decomposed into components corresponding to the charge flow between atoms and changes in atomic dipole moments. Such decompositions are recognized to depend on how atoms are defined within a molecule, as, for example, by Hirshfeld, iterative Stockholder, or quantum topology partitioning of the electron density. For some of these, however, there are significant differences between the numerical results obtained by analytical response methods and finite field calculations. We show that this difference is due to analytical response methods accounting for (only) the change in electron density by a perturbation, while finite field methods may also include a component corresponding to a perturbation-dependent change in the definition of an atom within a molecule. For some atom-in-molecule definitions, such as the iterative Hirshfeld, iterative Stockholder, and quantum topology methods, the latter effect significantly increases the charge flow component. The decomposition of molecular polarizability into atomic charge flow and induced dipole components thus depends on whether the atom-in-molecule definition is taken to be perturbation-dependent.

Evaluating the effect of rapamycin treatment in Alzheimer's disease and aging using in vivo imaging: the ERAP phase IIa clinical study protocol.

BACKGROUND: Rapamycin is an inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, and preclinical data demonstrate that it is a promising candidate for a general gero- and neuroprotective treatment in humans. Results from mouse models of Alzheimer's disease have shown beneficial effects of rapamycin, including preventing or reversing cognitive deficits, reducing amyloid oligomers and tauopathies and normalizing synaptic plasticity and cerebral glucose uptake. The "Evaluating Rapamycin Treatment in Alzheimer's Disease using Positron Emission Tomography" (ERAP) trial aims to test if these results translate to humans through evaluating the change in cerebral glucose uptake following six months of rapamycin treatment in participants with early-stage Alzheimer's disease. METHODS: ERAP is a six-month-long, single-arm, open-label, phase IIa biomarker-driven study evaluating if the drug rapamycin can be repurposed to treat Alzheimer's disease. Fifteen patients will be included and treated with a weekly dose of 7 mg rapamycin for six months. The primary endpoint will be change in cerebral glucose uptake, measured using [18F]FDG positron emission tomography. Secondary endpoints include changes in cognitive measures, markers in cerebrospinal fluid as well as cerebral blood flow measured using magnetic resonance imaging. As exploratory outcomes, the study will assess change in multiple age-related pathological processes, such as periodontal inflammation, retinal degeneration, bone mineral density loss, atherosclerosis and decreased cardiac function. DISCUSSION: The ERAP study is a clinical trial using in vivo imaging biomarkers to assess the repurposing of rapamycin for the treatment of Alzheimer's disease. If successful, the study would provide a strong rationale for large-scale evaluation of mTOR-inhibitors as a potential disease-modifying treatment in Alzheimer's disease. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT06022068, date of registration 2023-08-30.

Multimodal brain age prediction using machine learning: combining structural MRI and 5-HT2AR PET-derived features.

To better assess the pathology of neurodegenerative disorders and the efficacy of neuroprotective interventions, it is necessary to develop biomarkers that can accurately capture age-related biological changes in the human brain. Brain serotonin 2A receptors (5-HT2AR) show a particularly profound age-related decline and are also reduced in neurodegenerative disorders, such as Alzheimer's disease. This study investigates whether the decline in 5-HT2AR binding, measured in vivo using positron emission tomography (PET), can be used as a biomarker for brain aging. Specifically, we aim to (1) predict brain age using 5-HT2AR binding outcomes, (2) compare 5-HT2AR-based predictions of brain age to predictions based on gray matter (GM) volume, as determined with structural magnetic resonance imaging (MRI), and (3) investigate whether combining 5-HT2AR and GM volume data improves prediction. We used PET and MR images from 209 healthy individuals aged between 18 and 85 years (mean = 38, std = 18) and estimated 5-HT2AR binding and GM volume for 14 cortical and subcortical regions. Different machine learning algorithms were applied to predict chronological age based on 5-HT2AR binding, GM volume, and the combined measures. The mean absolute error (MAE) and a cross-validation approach were used for evaluation and model comparison. We find that both the cerebral 5-HT2AR binding (mean MAE = 6.63 years, std = 0.74 years) and GM volume (mean MAE = 6.95 years, std = 0.83 years) predict chronological age accurately. Combining the two measures improves the prediction further (mean MAE = 5.54 years, std = 0.68). In conclusion, 5-HT2AR binding measured using PET might be useful for improving the quantification of a biomarker for brain aging.

A History of Malaria and Conflict.

It is supposed that in all armed conflicts until World War II more humans died of infectious diseases than of the actual violence. Especially malaria left a crucial imprint on wars throughout history. The disease aggravates wartime conditions, is thus responsible for significant morbidity and mortality in conflict zones, and is at the same time more commonly found in these areas. Malaria has halted many military campaigns in the past, with prominent examples ranging from antiquity through the medieval period and into the modern era. The parasitosis still continues to play an important role in the outcome of warfare and follow-up events today and is of special public health importance in areas of the Global South, where most of its endemicity and some of the most brutal conflicts of our time are located. Vice versa, wars and ensuing population movements increase malaria transmission and morbidity as well as impede control efforts. Awareness of this and the development of strategies to overcome both malaria and wars will massively improve the well-being of the population affected.

Investigating Protein Binding with the Isothermal Ligand-induced Resolubilization Assay.

Target engagement assays typically detect and quantify the direct physical interaction of a protein of interest and its ligand through stability changes upon ligand binding. Commonly used target engagement methods detect ligand-induced stability by subjecting samples to thermal or proteolytic stress. Here we describe a new variation to these approaches called Isothermal Ligand-induced Resolubilization Assay (ILIRA), which utilizes lyotropic solubility stress to measure ligand binding through changes in target protein solubility. We identified distinct buffer systems and salt concentrations that compromised protein solubility for four diverse proteins: dihydrofolate reductase (DHFR), nucleoside diphosphate-linked moiety X motif 5 (NUDT5), poly [ADP-ribose] polymerase 1 (PARP1), and protein arginine N-methyltransferase 1 (PRMT1). Ligand-induced solubility rescue was demonstrated for these proteins, suggesting that ILIRA can be used as an additional target engagement technique. Differences in ligand-induced protein solubility were assessed by Coomassie blue staining for SDS-PAGE and dot blot, as well as by NanoOrange, Thioflavin T, and Proteostat fluorescence, thus offering flexibility for readout and assay throughput.

Investigating the anti-cancer potential of pyrimethamine analogues through a modern chemical biology lens.

Pharmacological inhibition of dihydrofolate reductase (DHFR) is an established approach for treating a variety of human diseases, including foreign infections and cancer. However, treatment with classic DHFR inhibitors, such as methotrexate (MTX), are associated with negative side-effects and resistance mechanisms that have prompted the search for alternatives. The DHFR inhibitor pyrimethamine (Pyr) has compelling anti-cancer activity in in vivo models, but lacks potency compared to MTX, thereby requiring higher concentrations to induce therapeutic responses. The purpose of this work was to investigate structural analogues of Pyr to improve its in vitro and cellular activity. A series of 36 Pyr analogues were synthesized and tested in a sequence of in vitro and cell-based assays to monitor their DHFR inhibitory activity, cellular target engagement, and impact on breast cancer cell viability. Ten top compounds were identified, two of which stood out as potential lead candidates, 32 and 34. These functionalized Pyr analogues potently engaged DHFR in cells, at concentrations as low as 1 nM and represent promising DHFR inhibitors that could be further explored as potential anti-cancer agents.

Embryo ranking agreement between embryologists and artificial intelligence algorithms.

OBJECTIVE: To evaluate the degree of agreement of embryo ranking between embryologists and eight artificial intelligence (AI) algorithms. DESIGN: Retrospective study. PATIENT(S): A total of 100 cycles with at least eight embryos were selected from the Weill Cornell Medicine database. For each embryo, the full-length time-lapse (TL) videos, as well as a single embryo image at 120 hours, were given to five embryologists and eight AI algorithms for ranking. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Kendall rank correlation coefficient (Kendall's τ). RESULT(S): Embryologists had a high degree of agreement in the overall ranking of 100 cycles with an average Kendall's tau (K-τ) of 0.70, slightly lower than the interembryologist agreement when using a single image or video (average K-τ = 0.78). Overall agreement between embryologists and the AI algorithms was significantly lower (average K-τ = 0.53) and similar to the observed low inter-AI algorithm agreement (average K-τ = 0.47). Notably, two of the eight algorithms had a very low agreement with other ranking methodologies (average K-τ = 0.05) and between each other (K-τ = 0.01). The average agreement in selecting the best-quality embryo (1/8 in 100 cycles with an expected agreement by random chance of 12.5%; confidence interval [CI]95: 6%-19%) was 59.5% among embryologists and 40.3% for six AI algorithms. The incidence of the agreement for the two algorithms with the low overall agreement was 11.7%. Agreement on selecting the same top two embryos/cycle (expected agreement by random chance corresponds to 25.0%; CI95: 17%-32%) was 73.5% among embryologists and 56.0% among AI methods excluding two discordant algorithms, which had an average agreement of 24.4%, the expected range of agreement by random chance. Intraembryologist ranking agreement (single image vs. video) was 71.7% and 77.8% for single and top two embryos, respectively. Analysis of average raw scores indicated that cycles with low diversity of embryo quality generally resulted in a lower overall agreement between the methods (embryologists and AI models). CONCLUSION(S): To our knowledge, this is the first study that evaluates the level of agreement in ranking embryo quality between different AI algorithms and embryologists. The different concordance methods were consistent and indicated that the highest agreement was intraembryologist agreement, followed by interembryologist agreement. In contrast, the agreement between some of the AI algorithms and embryologists was similar to the inter-AI algorithm agreement, which also showed a wide range of pairwise concordance. Specifically, two AI models showed intra- and interagreement at the level expected from random selection.