Impact of Previous Abdominal Surgery and Timing of Peritoneal Metastases on Accuracy of Imaging in Predicting the Surgical PCI: A Report From the PRECINCT Study.

BACKGROUND AND AIM: In this report from Phase 1 of the prospective, observational, PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumours) study, a correlation was performed between the radiological PCI (peritoneal cancer index; rPCI) and surgical PCI (sPCI). The impact of timing of peritoneal malignancy (PM) and previous abdominal surgery was also studied. METHODS: The rPCI and sPCI were considered the 'same' if they differed by ≤ 3 points. The agreement was assessed using Bland-Altman analysis and the strength of the agreement was assessed using the concordance correlation coefficient (CCC). The extent of prior surgery was classified according to prior surgical score (PSS). RESULTS: In 707 (79.4%) patients, rPCI and sPCI concurred in 280 (39.6%). In the Bland-Altman analysis, < 40% patients were in the ±3 PCI points limit of acceptable difference. The average difference between the two scores was 4.5 points (95% CI- -5.16 to -3.92). The CCC- was 0.59 for the whole cohort ('moderate' concordance) and was not influenced by imaging modality, timing of PM or PSS. CONCLUSIONS: The rPCI underestimated sPCI by an average of 4.5 points. The role of peritoneal MRI in patients undergoing iterative procedures and the performance of imaging according to sites of recurrence need further evaluation.

Impact of Nebulized BromAc® on Mucus Plug Clearance in a Mechanically Ventilated Ex Vivo Ovine Lung Model of Obstructive Respiratory Conditions.

Mucus plugging of the respiratory tract occurs in airway diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis. It can cause blockage of the airways, leading to breathlessness and lung failure. Here, we used a ventilatory setup to demonstrate the effect of BromAc® in dissolving mucus plugs in a novel ex vivo ovine obstructive lung model. Mucus simulant was filled into the trachea of freshly slaughtered ovine lungs and ventilated via an endotracheal tube (ETT) using Continuous Mandatory Ventilation. Predetermined single or repeated doses of Bromelain, Acetylcysteine (Ac), BromAc®, and saline control were administered via an Aerogen® vibrating nebulizer and ventilated for 30 or 60 min. Ventilatory recording of resistance, compliance, and tidal volume was conducted, and rheology pre- and post-treatment were measured. A significant decline in airway resistance (p < 0.0001) compared to the saline control was observed when treated with Bromelain, Ac, and BromAc®, with the latter showing a stronger mucolytic effect than single agents. The decline in resistance was also effective in shorter time points (p < 0.05) at lower doses of the drugs. Changes in compliance, peak pressure, and tidal volume were not observed after administration of the drugs. Rheology measurements revealed that BromAc®TM significantly reduced the viscosity of the mucin at the end of 30 min and 60 min time points (p < 0.001) compared to the saline control. BromAc® showed complete dissolution of the respiratory mucus simulant and improved ventilatory airflow parameters in the ex vivo ovine model.

Correlation of Morphological Appearance of Peritoneal Lesions at Laparotomy and Disease at Pathological Assessment in Patients Undergoing Cytoreductive Surgery for Peritoneal Malignancy: Results of Phase I of the PRECINCT Study in 707 Patients.

BACKGROUND: The PRECINCT (Pattern of peritoneal dissemination and REsponse to systemic Chemotherapy IN Common and uncommon peritoneal Tumors) is a prospective, multicenter, observational study. This report from phase I of PRECINCT outlines variations in recording the surgical peritoneal cancer index (sPCI) at experienced peritoneal malignancy centers and the incidence of pathologically confirmed disease in morphologically different peritoneal lesions (PL). METHODS: The sPCI was recorded in a prespecified format that included the morphological appearance of PL. Six prespecified morphological terms were provided. The surgical and pathological findings were compared. RESULTS: From September 2020 to December 2021, 707 patients were enrolled at 10 centers. The morphological details are routinely recorded at two centers, structure bearing the largest nodule, and exact size of the largest tumor deposit in each region at four centers each. The most common morphological terms used were normal peritoneum in 3091 (45.3%), tumor nodules in 2607 (38.2%) and confluent disease in 786 (11.5%) regions. The incidence of pathologically confirmed disease was significantly higher in 'tumor nodules' with a lesion score of 2/3 compared with a lesion score of 1 (63.1% vs. 31.5%; p < 0.001). In patients receiving neoadjuvant chemotherapy, the incidence of pathologically confirmed disease did not differ significantly from those undergoing upfront surgery [751 (47.7%) and 532 (51.4%) respectively; p = 0.069]. CONCLUSIONS: The sPCI was recorded with heterogeneity at different centers. The incidence of pathologically confirmed disease was 49.2% in 'tumor nodules'. Frozen section could be used more liberally for these lesions to aid clinical decisions. A large-scale study involving pictorial depiction of different morphological appearances and correlation with pathological findings is indicated.

Clinician-Reported Management Recommendations in Response to Universal Germline Genetic Testing in Patients With Prostate Cancer.

PURPOSE: Identification of pathogenic germline variants in patients with prostate cancer can help inform treatment selection, screening for secondary malignancies, and cascade testing. Limited real-world data are available on clinician recommendations following germline genetic testing in patients with prostate cancer. MATERIALS AND METHODS: Patient data and clinician recommendations were collected from unselected patients with prostate cancer who underwent germline testing through the PROCLAIM trial. Differences among groups of patients were determined by 2-tailed Fisher's exact test with significance set at P < .05. Logistic regression was performed to assess the influence of test results in clinical decision-making while controlling for time of diagnosis (newly vs previously diagnosed). RESULTS: Among 982 patients, 100 (10%) were positive (>1 pathogenic germline variant), 482 (49%) had uncertain results (>1 variant of uncertain significance), and 400 (41%) were negative. Patients with positive results were significantly more likely than those with negative or uncertain results to receive recommendations for treatment changes (18% vs 1.4%, P < .001), follow-up changes (64% vs 11%, P < .001), and cascade testing (71% vs 5.4%, P < .001). Logistic regression demonstrated that positive and uncertain results were significantly associated with both changes to treatment and follow-up (P < .001) when controlling for new or previous diagnosis. CONCLUSIONS: Germline genetic testing results informed clinical recommendations for patients with prostate cancer, especially in patients with positive results. Higher than anticipated rates of clinical management changes in patients with uncertain results highlight the need for increased genetic education of clinicians treating patients with prostate cancer.

Single-atom alloy structure and unique bonding properties of Au104Ag40(PET)60 nanoclusters.

The detailed characterization of AuAg alloy nanoclusters is essential to guide the discovery of species ideal for applications in various fields including catalysis and biomedicine. This work presents structural analysis of the Au104Ag40(PET)60 species through X-ray absorption spectroscopy (XAS). First, XAS fitting is utilized to model the distribution of Au and Ag atoms within the structure. Our proposed model assigns Ag atoms to the vertex sites of the second shell of the metal core, as well as the outermost staple sites. This distribution reveals Au104Ag40(PET)60 to be a Ag single-atom alloy. The proposed model shows outstanding agreement with the coordination number values derived from XAS. XAS near-edge analysis is employed to investigate the alloy bonding interactions between Au and Ag. Substantial d-electron transfer from Au to Ag is observed in this sample, beyond the magnitude of previously studied AuAg NCs. This work enhances the understanding of the structure-property relationship of AuAg alloy NCs, offering insights which can be applied to other large NCs and even NPs. These insights will in turn aid the discovery of new materials for use in various applications.

Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism. METHODS: We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms. RESULTS: Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression. CONCLUSIONS: These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.

A semi-structured interview to capture manual wheelchair use for mobility activities among individuals with spinal cord injury in real-life situations: development and content validity of the Wheelchair Mobility Activity Log (WC-MAL).

STUDY DESIGN: Mixed-method approach. OBJECTIVES: To develop and assess the content validity of a semi-structured interview that captures the lived experience of using a manual wheelchair among individuals with SCI in the real world, the Wheelchair Mobility Activity Log (WC-MAL). SETTING: SCIR-Group (UDESC)/Brazil. METHODS: Developing the WC-MAL comprised five steps: (1) defining the construct-based on the International Classification of Functioning, Disability and Health (ICF); (2) identifying relevant activities from other assessment instruments and interviews with the end-users (14 Individuals with SCI and 13 rehabilitation professionals); (3) Selecting the items - activities were linked to ICF codes and grouped into sets; (4) developing the scoring scales based on interviews with the end-users; and, (5) evaluating content validity in accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The content validity ratio (CVR) for each item and scale and the overall instrument content validity index (CVI) were calculated. RESULTS: From an initial draft of 295 activities identified, a set of 222 activities was linked to the ICF domain of "Mobility (d4)" and further refined to generate the 23 items in the WC-MAL. Three scales were developed to assess Frequency (how often), Performance (how well), and Assistance (assistance needed) levels. The items and scales showed a CVR superior to the critical value established (≥0.64). The general CVI value was 0.96. CONCLUSION: The WC-MAL is a promising clinical instrument with adequate content validity to assess the spontaneous use of the manual wheelchair in the real world among individuals with SCI.

Variants of the P3 event-related potential operate as indicators of distinct mechanisms contributing to problematic alcohol use.

Considerable research has linked relative reduction in the amplitude of the P3 event-related potential (ERP) during cognitive task performance (i.e., Target-P3) with increased risk of alcohol-related problems. A separate literature indicates that a relative increase in the amplitude of the P3 elicited by cues signaling alcohol availability (i.e., ACR-P3) also is associated with alcohol use and problems. To date, no research has integrated these seemingly discrepant findings. Here, we aimed to demonstrate that P3 amplitudes elicited in different task contexts reflect distinct domains of functioning relevant to problematic alcohol involvement (PAI), and therefore can inform heterogeneity in the etiology of PAI. 156 emerging adults (61% women; 88% White/Non-Hispanic) completed a mental rotation task and a picture-viewing task while ERPs were recorded. Participants also completed questionnaire measures of trait disinhibition, alcohol use, and alcohol-related problems. Findings from regression analyses indicated that (a) Target-P3 was negatively associated and ACR-P3 was positively associated with a PAI latent variable; (b) the two P3s accounted for unique variance in PAI, beyond that accounted for by recent drinking; and (c) the association between Target-P3 and PAI-but not ACR-P3 and PAI-was statistically mediated by trait disinhibition. The present findings highlight the unique contributions of distinct functional domains associated with disinhibition and incentive salience in the etiology of PAI. Moreover, findings are consistent with a nuanced understanding of the P3 ERP, whereby its specific meaning varies according to the task context in which it is elicited.

Low-Titer Type O Whole Blood for Transfusing Perinatal Patients after Acute Hemorrhage: A Case Series.

Objective Acute and massive blood loss is fortunately a rare occurrence in perinatal/neonatal practice. When it occurs, typical transfusion paradigms utilize sequential administration of blood components. However, an alternative approach, transfusing type O whole blood with low anti-A and anti-B titers, (LTOWB) has recently been approved and utilized in trauma surgery. Study Design Retrospective analysis of all perinatal patients who have received LTOWB after acute massive hemorrhage at the Intermountain Medical Center. Results LTOWB was the initial transfusion product we used to resuscitate/treat 25 women with acute and massive postpartum hemorrhage and five infants with acute hemorrhage in the first hours/days after birth. We encountered no problems obtaining or transfusing this product and we recognized no adverse effects of this treatment. Conclusion Transfusing LTOWB to perinatal patients after acute blood loss is feasible and appears at least as safe a serial component transfusion. Its use has subsequently been expanded to multiple hospitals in our region as first-line transfusion treatment for acute perinatal hemorrhage. Key Points Low-titer type O whole blood (LTOWB) was our initial transfusion product for 30 perinatal patients with acute hemorrhage. Twenty-five of these were obstetrical patients and five were neonatal patients. We encountered no problems with, or adverse effects from LTOWB in any of these patients. LTOWB transfusions to women were ten days since donor draw (interquartile range, 8-13) and to neonates was six days (5-8).

Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

Palliative care in the emergency department: An observational study of doctors in KwaZulu-Natal.

BACKGROUND:  The World Health Organization advocates the early, appropriate provision of palliative care (PC) to patients throughout the life course. Patient consultations to the emergency department (ED) have been recognised as opportunities to initiate or optimise their PC needs. This study aimed to assess the knowledge of and attitudes towards PC among doctors at emergency physician staffed EDs in KwaZulu-Natal, South Africa. METHODS:  A cross-sectional survey was conducted between November 2021 and February 2022 for doctors employed out at emergency physician staffed EDs in KwaZulu-Natal, South Africa, using the validated Palliative Care Attitude and Knowledge questionnaire. The variables assessed were the self-rated and basic knowledge and attitudes towards core domains of PC. Ordinal data were compared using the t-test or ANOVA as appropriate, using MedCalc® Statistical Software version 22.009. RESULTS:  Of the 39 participants, the scores for the knowledge questions showed that 15.3% participants had good knowledge, 53.8% had fair knowledge and 30.7% had poor knowledge. Participants had either favourable (58.8%) or an uncertain (41.0%) attitude towards PC. No correlation was seen between the knowledge and attitudes scores (Spearman's rho = 0.13, 95% CI -0.19 to 0.43, p = 0.43). CONCLUSION:  There appears to be a deficit in knowledge of PC among doctors in the ED and a need for in-service training in PC for emergency care physicians.Contribution: This study provides new knowledge around PC practices at EDs in KwaZulu-Natal, South Africa.

Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.

INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line. PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment. RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs. CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.

Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.

Transhepatic Bromelain and Acetylcysteine for Treatment of Posterior Gastric Pseudomyxoma Peritonei: A Case Report.

BACKGROUND/AIM: Pseudomyxoma peritonei (PMP) is a rare condition characterized by diffuse spread of mucinous tumors within the peritoneal cavity. Traditional treatment modalities, such as cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are challenging in cases of recurrent disease, owing to anatomical complexities and increasing morbidity and mortality risk. BromAc® has emerged as a novel, targeted therapy for PMP with evidence for intra-tumoral administration to break down mucin deposits. CASE REPORT: We present a 70-year-old female with confirmed diagnosis of symptomatic appendiceal PMP situated behind the stomach, refractory to prior CRS and HIPEC. Transhepatic intra-tumor injection of BromAc® was performed, guided by imaging, with catheter placement into the posterior gastric mucinous tumor. The procedure was well-tolerated, and post-treatment imaging revealed a significant 40% reduction in tumor burden. The patient had fever on cycle days two and three, which self-resolved and septic screen performed was negative. Following BromAc® administration, the patient demonstrated improvement in symptoms and quality of life. CONCLUSION: This case highlights the potential efficacy and safety of transhepatic administration of BromAc® for the treatment of recurrent PMP behind the stomach. The targeted delivery of BromAc® directly into a mucinous tumor via the transhepatic route offers a minimally invasive alternative for cases where traditional surgical interventions pose challenges. However, further research and clinical trials are warranted to validate the broader applicability of this novel approach, assess long-term outcomes, and optimize procedural parameters for enhanced therapeutic outcomes in PMP treatment.

The burden of Finke Desert race-related trauma: A 10-year retrospective descriptive analysis.

INTRODUCTION: The Finke Desert Race is an annual motorsport race (motorbikes, cars and buggies) held in Alice Springs resulting in a significant major trauma burden. This imposes unique challenges in one of the world's most remote healthcare settings. OBJECTIVES: To quantify the volume and characteristics of Finke Desert Race-related trauma presenting to the Alice Springs Hospital. DESIGN: A retrospective descriptive study was undertaken to review all patients presenting to the Alice Springs Hospital with Finke Desert Race-related trauma over a 10-year period. Information collected included demographic data, injury characteristics, patient disposition and required management. FINDINGS: Over the 9 years the event was held, 325 patients were admitted to the Alice Springs Hospital. Patients were almost exclusively male (98.8%), with a mean age of 34.75 and residing outside of Alice Springs (82.2%). There were a total of 460 distinct injuries with the clavicle, spine and ribs the three most commonly injured sites. A total of 129 operations were required, of which 19 required retrieval to an interstate centre. DISCUSSION: Alice Springs is one of the most remote and geographically isolated centres on Earth. This rurality poses unique challenges when trying to coordinate medical and retrieval services, exacerbated for a concentrated, yet highly resource intensive event such as Finke. It has far reaching impacts, placing additional stresses on all aspects of healthcare provision. CONCLUSION: This review has quantified the trauma burden of the event for the first time, enabling local and interstate stakeholders' ability to plan an adequate and sustainable response while also enabling the future effectiveness evaluation of recent safety reforms.