Management of acute appendicitis during the COVID-19 pandemic: a retrospective cohort study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic profoundly impacted delivery of health care. South Western Sydney Local Health District (SWSLHD) experienced some of the highest cases, admissions and deaths during the Delta and Omicron waves in New South Wales. This study aims to determine the impact of the pandemic on emergency surgery services for adults presenting with acute appendicitis. METHODS: A retrospective review of patient records was performed of adults presenting with acute appendicitis between 1st March 2021 and 31st March 2022, which was compared to a pre-COVID control period of the same dates in 2019-2020. Patients managed operatively or conservatively were included. RESULTS: 1556 patients were included in the operative arm; 723 and 833 respectively in the study and control groups, which were comparable at baseline. 1.66% were COVID positive. During the pandemic, patients were significantly more likely to be investigated with computered tomography (CT) scan (p ≤ 0.001), present with complicated appendicitis (p = 0.03), and require caecectomy (p = 0.005). They had higher American Society of Anaesthesiology (ASA) scores (p = 0.001) and significantly lower negative appendectomy rates (p = 0.001). Fifty-two patients were included in the conservative arm; 29 and 23 respectively in the pandemic and control groups. Patients were comparable at baseline. There were two COVID positive patients. During the pandemic, there was a significant reduction in complications (p = 0.033), readmissions (0.044) and interval appendicectomy (p = 0.0044). CONCLUSION: We identified higher rates of complicated appendicitis, caecectomies and greater reliance on CT imaging preoperatively during the pandemic in SWSLHD.

Appropriate Minimal Dose of Gadobutrol for 3D Time-Resolved MRA of the Supra-Aortic Arteries: Comparison with Conventional Single-Phase High-Resolution 3D Contrast-Enhanced MRA.

BACKGROUND AND PURPOSE: The development of nephrogenic systemic fibrosis and neural tissue deposition is gadolinium dose-dependent. The purpose of this study was to determine the appropriate minimal dose of gadobutrol with time-resolved MRA to assess supra-aortic arterial stenosis with contrast-enhanced MRA as a reference standard. MATERIALS AND METHODS: Four hundred sixty-two consecutive patients underwent both standard-dose contrast-enhanced MRA and low-dose time-resolved MRA and were classified into 3 groups; group A (a constant dose of 1 mL for time-resolved MRA), group B (2 mL), or group C (3 mL). All studies were independently evaluated by 2 radiologists for image quality by using a 5-point scale (from 0 = failure to 4 = excellent), grading of arterial stenosis (0 = normal, 1 = mild [<30%], 2 = moderate [30%-69%], 3 = severe to occlusion [≥70%]), and signal-to-noise ratio. RESULTS: The image quality of time-resolved MRA was similar to that of contrast-enhanced MRA in groups B and C, but it was inferior to contrast-enhanced MRA in group A. For the grading of arterial stenosis, there was an excellent correlation between contrast-enhanced MRA and time-resolved MRA (R = 0.957 for group A, R = 0.988 for group B, R = 0.991 for group C). The SNR of time-resolved MRA tended to be lower than that of contrast-enhanced MRA in groups A and B. However, SNR was higher for time-resolved MRA compared with contrast-enhanced MRA in group C. CONCLUSIONS: Low-dose time-resolved MRA is feasible in the evaluation of supra-aortic stenosis and could be used as an alternative to contrast-enhanced MRA for a diagnostic technique in high-risk populations.

Influence of shear on nitrification rates in a membrane bioreactor.

Grundfos BioBooster (GBB) installed and operated a membrane bioreactor (MBR) test plant in 2012. During the period it became evident that the nitrification rate was lower than expected and a study was carried out to investigate the possible reasons for the observed low-nitrification rate. Tests were conducted at a pilot plant and the effect of shear from the BioBooster membrane system and the pressure reduction component on the nitrification rate was investigated. The possible effect of selection of microbial communities caused by the filtration unit was also investigated. The results revealed an unchanged nitrification rate when exposed to shear from the filtration unit and the pressure reduction component. When testing the effect of selection, the nitrification rate was also unchanged.

The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options.

Obesity is one of the greatest public health challenges of the 21st century. Obesity is currently responsible for ∼0.7-2.8% of a country's health costs worldwide. Treatment is often not effective because weight regulation is complex. Appetite and energy control are regulated in the brain. Melanocortin-4 receptor (MC4R) has a central role in this regulation. MC4R defects lead to a severe clinical phenotype with lack of satiety and early-onset severe obesity. Preclinical research has been carried out to understand the mechanism of MC4R regulation and possible effectors. The objective of this study is to systematically review the literature for emerging pharmacological obesity treatment options. A systematic literature search was performed in PubMed and Embase for articles published until June 2012. The search resulted in 664 papers matching the search terms, of which 15 papers remained after elimination, based on the specific inclusion and exclusion criteria. In these 15 papers, different MC4R agonists were studied in vivo in animal and human studies. Almost all studies are in the preclinical phase. There are currently no effective clinical treatments for MC4R-deficient obese patients, although MC4R agonists are being developed and are entering phase I and II trials.

Effects of precursor concentration on the properties of ZnO nanowires grown on (1-102) r-plane sapphire substrates by hydrothermal synthesis.

In this study, we grew ZnO nanowires hydrothermally on (1-102) r-plane sapphire substrates in an aqueous solution which contained zinc nitrate hexahydrate and hexamethylenetetramine (HMT) at 90 °C. First, the AZO seed layer of 80 nm thickness was deposited on the r-plane sapphire substrate by a radio frequency magnetron sputter. After that, we grew the ZnO nanowires on the seed layer by changing the precursor concentration of the aqueous solution from 0.025 M to 0.01 M. When the molar concentration of the precursor was changed, the diameter, length, density and number of ZnO nanowires also changed significantly: diameter, length and density increased with increasing molar concentration but the number of ZnO nanowires decreased. The ZnO nanowires grown at the higher molar concentration tended to grow along with the c-axis direction, as revealed by atomic force microscope and X-ray diffraction peaks. Furthermore, the PL spectra measured at room-temperature revealed a UV emission of 380 nm which can be attributed to the radiative recombination of free and bound excitons (Near Band edge Emission). The NBE emission was also increased with increasing molar concentration.

Ecklonia cava promotes hair growth.

BACKGROUND: Previous studies have reported the protective effects on skin elasticity of the edible marine seaweed Ecklonia cava, which acts through regulation of both antioxidative and anti-inflammatory responses. AIM: We evaluated the effect of E. cava and one of its components, dioxinodehydroeckol, on hair-shaft growth in cultured human hair follicles and on hair growth in mice. METHODS: The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to check cell viability of human dermal papilla cells (DPCs) and outer root sheath (ORS) cells after treatment with E. cava and its metabolite, dioxinodehydroeckol. Hair-shaft growth was measured using the in vitro hair-follicle organ-culture system, in the presence or absence of E. cava and dioxinodehydroeckol. Anagen induction activity was examined by topical application of E. cava to the dorsal skin of C57BL/6 mice. Insulin-like growth factor (IGF)-1 expression was measured by reverse transcriptase PCR and ELISA. RESULTS: The proliferation activity was found to be highest for the ethyl acetate-soluble fraction of E. cava (EAFE) in DPCs and in ORS cells. Treatment with EAFE resulted in elongation of the hair shaft in cultured human hair follicles, and promoted transition of the hair cycle from the telogen to the anagen phase in the dorsal skin of C57BL/6 mice. In addition, EAFE induced an increase in IGF-1 expression in DPCs. Dioxinodehydroeckol, a component of E. cava, induced elongation of the hair shaft, an increase in proliferation of DPCs and ORS cells, and an increase in expression of IGF-1 in DPCs. CONCLUSIONS: These results suggest that E. cava containing dioxinodehydroeckol promotes hair growth through stimulation of DPCs and ORS cells.

Removal of APIs and bacteria from hospital wastewater by MBR plus O(3), O(3) + H(2)O(2), PAC or ClO(2).

The objective of this study has been to develop technologies that can reduce the content of active pharmaceutical ingredients (APIs) and bacteria from hospital wastewater. The results from the laboratory- and pilot-scale testings showed that efficient removal of the vast majority of APIs could be achieved by a membrane bioreactor (MBR) followed by ozone, ozone + hydrogen peroxide or powdered activated carbon (PAC). Chlorine dioxide (ClO(2)) was significantly less effective. MBR + PAC (450 mg/l) was the most efficient technology, while the most cost-efficient technology was MBR + ozone (156 mg O(3)/l applied over 20 min). With MBR an efficient removal of Escherichia coli and enterococci was measured, and no antibiotic resistant bacteria were detected in the effluent. With MBR + ozone and MBR + PAC also the measured effluent concentrations of APIs (e.g. ciprofloxacin, sulfamethoxazole and sulfamethizole) were below available predicted no-effect concentrations (PNEC) for the marine environment without dilution. Iodinated contrast media were also reduced significantly (80-99% for iohexol, iopromide and ioversol and 40-99% for amidotrizoateacid). A full-scale MBR treatment plant with ozone at a hospital with 900 beds is estimated to require an investment cost of €1.6 mill. and an operating cost of €1/m(3) of treated water.

CD8+ T-cell responses rapidly select for antigen-negative tumor cells in the prostate.

Stimulation of patients' immune systems for the treatment of solid tumors is an emerging therapeutic paradigm. The use of enriched autologous T cells for adoptive cell therapy or vaccination with antigen-loaded dendritic cells have shown clinical efficacy in melanoma and prostate cancer, respectively. However, the long-term effects of immune responses on selection and outgrowth of antigen-negative tumor cells in specific tumor types must be determined to understand and achieve long-term therapeutic effects. In this study, we have investigated the expression of a tumor-specific antigen in situ after treatment with tumor-specific CD8(+) T cells in an autochthonous mouse model of prostate cancer. After T-cell treatment, aggregates of dead antigen-positive tumor cells were concentrated in the lumen of the prostate gland and were eventually eliminated from the prostate tissue. Despite the elimination of antigen-positive tumor cells, prostate tumor continued to grow in T-cell-treated mice. Interestingly, the remaining tumor cells were antigen negative and downregulated MHC class I expression. These results show that CD8(+) T cells are effective in eliminating antigen-bearing prostate tumor cells but they also can select for the outgrowth of antigen-negative tumor cells. These findings provide insights into the requirements for an effective cancer immunotherapy within the prostate that not only induces potent immune responses but also avoids selection and outgrowth of antigen-negative tumor cells.

Analytical and numerical modelling of Newtonian and non-Newtonian liquid in a rotational cross-flow MBR.

Fouling is the main bottleneck of the widespread use of MBR systems. One way to decrease and/or control fouling is by process hydrodynamics. This can be achieved by the increase of liquid cross-flow velocity. In rotational cross-flow MBR systems, this is attained by the spinning of, for example, impellers. Validation of the CFD (computational fluid dynamics) model was made against laser Doppler anemometry (LDA) tangential velocity measurements (error less than 8%) using water as a fluid. The shear stress over the membrane surface was inferred from the CFD simulations for water. However, activated sludge (AS) is a non-Newtonian liquid, for which the CFD model was modified incorporating the non-Newtonian behaviour of AS. Shear stress and area-weighted average shear stress relationships were made giving error less that 8% compared with the CFD results. An empirical relationship for the area-weighted average shear stress was developed for water and AS as a function of the angular velocity and the total suspended solids concentration. These relationships can be linked to the energy consumption of this type of systems.

Differential requirement for CD70 and CD80/CD86 in dendritic cell-mediated activation of tumor-tolerized CD8 T cells.

A major obstacle to efficacious T cell-based cancer immunotherapy is the tolerizing-tumor microenvironment that rapidly inactivates tumor-infiltrating lymphocytes. In an autochthonous model of prostate cancer, we have previously shown that intratumoral injection of Ag-loaded dendritic cells (DCs) delays T cell tolerance induction as well as refunctionalizes already tolerized T cells in the tumor tissue. In this study, we have defined molecular interactions that mediate the effects of DCs. We show that pretreating Ag-loaded DCs with anti-CD70 Ab abolishes the ability of DCs to delay tumor-mediated T cell tolerance induction, whereas interfering with 4-1BBL, CD80, CD86, or both CD80 and CD86 had no significant effect. In contrast, CD80(-/-) or CD80(-/-)CD86(-/-) DCs failed to reactivate already tolerized T cells in the tumor tissue, whereas interfering with CD70 and 4-1BBL had no effect. Furthermore, despite a high level of programmed death 1 expression by tumor-infiltrating T cells and programmed death ligand 1 expression in the prostate, disrupting programmed death 1/programmed death ligand 1 interaction did not enhance T cell function in this model. These findings reveal dynamic requirements for costimulatory signals to overcome tumor-induced tolerance and have significant implications for developing more effective cancer immunotherapies.

Phenotypic and functional delineation of murine CX(3)CR1 monocyte-derived cells in ovarian cancer.

Ovarian tumor progression is marked by the peritoneal accumulation of leukocytes. Among these leukocytes, an immunosuppressive CD11b(+)CD11c(+) population has been identified in both human and ovarian tumors. The use of transplantable models of murine ovarian tumors has demonstrated that this population promotes ovarian tumor growth, whereas elimination of this population has been shown to inhibit ovarian tumor progression. Despite the demonstrated importance of these cells to ovarian tumor progression, the mechanisms by which these cells are recruited to the peritoneal tumor are largely unknown. Therefore, this study analyzes the mechanisms these cells use to migrate to the peritoneum with the goal of therapeutically blocking their recruitment and subsequent immunosuppressive activity. Recent studies have identified that CX(3)CR1, Gr-1, and CCR2 delineate phenotypic and functional murine monocyte subsets. Here, we report that CX(3)CR1(lo)Gr-1(hi) cells dominate the population of peritoneal CD11b(+) leukocytes early in murine tumor development; however, the CX(3)CR1(hi) population of cells present in the peritoneum dramatically increases in both total numbers and percentage during tumor progression. Functional analyses reveal that both of these CX(3)CR1 subsets are immunosuppressive to naive CD8(+) and CD4(+) T-cell responses. Importantly, we demonstrate that CCR2 is a critical functional facilitator of leukocyte recruitment to the ovarian tumor microenvironment, and its genetic deletion results in a reduced tumor burden compared with wild-type mice. These results demonstrate that subsets of immunosuppressive leukocytes are recruited to the ovarian tumor environment through the CCR2 pathway, which offers a viable therapeutic target to inhibit their migration to the tumor site.

Murine ovarian cancer vascular leukocytes require arginase-1 activity for T cell suppression.

The predominant leukocyte population present in both human and murine peritoneal ovarian tumors is the Vascular Leukocyte (VLC). VLCs are recruited en masse to the ovarian tumor microenvironment whereupon they promote tumor progression. Importantly, the presence of VLCs is requisite for peritoneal ovarian cancer progression: selective elimination of VLCs inhibits tumor burden and ascites accumulation. Despite the critical importance of VLCs to ovarian tumors, their derivation and the mechanisms by which they facilitate tumor progression are not well understood. Here we demonstrate in vivo that the murine ID8 ovarian tumor model can usurp the host peritoneal macrophage pathway to elicit and recruit VLCs. Moreover, we demonstrate that VLCs express CD11b and Gr-1, a characteristic phenotype shared amongst heterogeneous populations of leukocytes referred to as myeloid-derived suppressor cells (MDSCs). In accord with their MDSC phenotype, both murine and human VLCs express arginase-1 (ARG1). Importantly, we demonstrate that the VLCs suppress both CD8(+) and CD4(+) T cells responses and that this immunosuppression is ARG1-dependent, since blockade of VLC ARG1 activity with nor-NOHA reversed the immunosuppression. These data further characterize the tumor-associated leukocytes in ovarian cancer and provide insights into the mechanisms by which they promote tumor growth.

Calreticulin requires an ancillary adjuvant for the induction of efficient cytotoxic T cell responses.

Molecular chaperones stimulate the immune system to induce both protective immune responses and therapeutic tumor rejection. However, the underlying basis for this immunogenic activity is not well understood. A variety of chaperones, including calreticulin, hsp70 and grp94, function as vehicles to efficiently traffic associated peptides into professional antigen presenting cells. Importantly, these chaperones have also been proposed to function as adjuvants by stimulating the dendritic cell activation and co-stimulatory responses required to elicit peptide-specific CD8(+) T cell cytolytic activity. The efficacy of chaperone-mediated tumor rejection has been attributed to the ability of chaperones to function in both of these capacities. However, purified calreticulin has not previously been assessed for its ability to elicit DC maturation and, moreover, recent data indicates that it is not efficient at inducing Nf-kappaB activity which often accompanies or stimulates DC maturation. Here we use two complementary methods to produce endotoxin-free calreticulin and demonstrate that it does not measurably mature or activate dendritic cells both in vitro and in vivo. Additionally, a calreticulin/peptide complex required the addition of an exogenous adjuvant to elicit in vivo cytotoxic CD8(+) T cell responses. These data are discussed with respect to current models for chaperone-derived immune responses and in regard to rational vaccine design.

Scavenger receptor-A-targeted leukocyte depletion inhibits peritoneal ovarian tumor progression.

Immunosuppressive leukocytes are emerging as a critical factor in facilitating tumor progression. These leukocytes are converted by the tumor microenvironment to become tolerogenic, facilitate metastasis, and to aid in neovascularization. The predominant variety of suppressive leukocytes found in human and murine ovarian cancer are called vascular leukocytes (VLC), due to sharing functions and cell surface markers of both dendritic cells and endothelial cells. Using the ID8 murine model of ovarian cancer, the aim of this study was to test the efficacy of VLC elimination as an ovarian tumor therapy. We show that carrageenan-mediated depletion of peritoneal tumor-associated leukocytes inhibits ovarian tumor progression. We then identified scavenger receptor-A (SR-A) as a cell surface receptor that is robustly and specifically expressed within human and murine ovarian tumor ascites upon VLCs. Administration of anti-SR-A immunotoxin to mice challenged with peritoneal ID8 tumors eliminated tumor-associated VLCs and, importantly, substantially inhibited peritoneal tumor burden and ascites accumulation. Moreover, the toxin required targeting to SR-A because mice that received untargeted toxin did not exhibit inhibition of tumor progression. We conclude that SR-A constitutes a novel and specific target for efficacious immunotherapeutic treatment of peritoneal ovarian cancer.

Lymph, lymphocytes, and lymphatics.

This is a summary of recent developments regarding the role of the lymphatic system in immune responses. Emphasis is on physiological considerations from experiments in sheep. Cell- and tissue-specific lymphocyte traffic patterns measured over several days are considered. Particular attention is given to recent data on the relationship between the central nervous system and the lymphatic system, to cell labeling in situ, and to the entry of immune cells into afferent lymph from the interstitial tissues.

Serial measurements of N-terminal pro-brain natriuretic peptide after acute ischemic stroke.

BACKGROUND: The exact time-course of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the prognostic importance in the immediate phase of ischemic stroke have not been established. METHODS: NT-proBNP was measured daily from admission to day 5 and again at 6-month follow-up in 250 consecutive patients with acute ischemic stroke. RESULTS: NT-proBNP peaked the day after onset of symptoms (p = 0.007) followed by a decrease until day 5 (p = 0.001, ANOVA). At 6-month follow-up the difference in the level of NT-proBNP was unchanged compared to day 5 (p = 0.42). NT-proBNP levels > or =615 pg/ml at day 2 after onset of symptoms was associated with 6-month mortality. CONCLUSION: NT-proBNP peaks the day after onset of symptoms in patients with acute ischemic stroke. A single measurement of NT-proBNP appears to be an indicator of 6-month mortality.

Long-term effects of migraine on cognitive function: a population-based study of Danish twins.

OBJECTIVE: To investigate the cognitive functioning of migraineurs vs nonmigraineurs in a large population-based sample of middle-aged twins where headache diagnoses were established by neurologists. METHODS: Twins identified through the population-based Danish Twin Registry participated in face-to-face structured interviews, which included cognitive tests and two previously validated questions screening for migraine. Twins who screened positive for migraine and their co-twins were invited to participate in a telephone-based interview conducted by neurologists, who established headache diagnoses according to the International Headache Society criteria. Cognitive scores on fluency, digit span, delayed word recall, and symbol digit substitution test were compared between migraineurs and nonmigraineurs. Comparisons within monozygotic and dizygotic same sex twin pairs discordant for migraine were also performed. RESULTS: Of the 1,789 twins who were eligible for inclusion in the present study, 1,393 (77.8%) were interviewed. A diagnosis of migraine was established in 536 twins (migraine without aura n = 347; migraine with aura n = 157). Average scores on cognitive tests in twins with migraine or one of the migraine subtypes did not differ from those of nonmigraineurs in any of the tests. Comparisons within twin pairs discordant for migraine produced highly comparable results. Adjustment for possible confounders and stratification by cumulated number of lifetime attacks did not influence the results. CONCLUSIONS: A lifetime diagnosis of migraine was not associated with cognitive deficits in middle-aged subjects.

Relationship between infant sleep position and motor development in preterm infants.

To determine whether motor development in premature infants varies according to sleep position, we evaluated 213 infants <1750 g birth weight enrolled in the Collaborative Home Infant Monitoring Evaluation (CHIME). At 56 weeks postconceptional age (PCA), sleep position was determined by maternal report, and the Bayley Scales of Infant Development 2nd Edition (BSID-II) were performed. Infants who slept supine were less likely than infants who slept prone to receive credit for maintaining the head elevated to 45 degrees (p = .021), and infants who slept nonprone were less likely than prone sleepers to receive credit for maintaining the head elevated to 90 degrees and lowering with control (p = .001). The Psychomotor and Mental Development Indices at 56 and 92 weeks PCA were not altered by usual sleep position at 56 weeks PCA. In summary, infants sleeping supine are less able to lift the head and lower with control at 56 weeks PCA, but global developmental status was unaffected. Supine sleeping has been associated with decreased risk for sudden infant death syndrome, but compensatory strategies while awake may be needed to avoid delayed acquisition of head control.