Prognosis and conditional survival among women with newly diagnosed ovarian cancer.

OBJECTIVE: An important question in determining long-term prognosis for women with ovarian cancer is whether risk of death changes the longer a woman lives. Large real-world datasets permit assessment of conditional survival (CS) given both prior overall survival (OS) and real-world progression-free survival (rwPFS). METHODS: Using a longitudinal dataset from US oncology centers, this study included 6778 women with ovarian cancer. We calculated CS rates as the Kaplan-Meier probability of surviving an additional 1 or 5 years, given no mortality (OS) or disease progression (rwPFS) event in the previous 0.5-5 years since first-line chemotherapy initiation, adjusted for factors associated with OS based on multivariable Cox regression. RESULTS: Median study follow-up was 9 years (range, 1-44) from first-line initiation to data cutoff (17-Feb-2021). Median OS was 58.0 months (95% CI, 54.9-60.8); median rwPFS was 18.4 months (17.4-19.4). The adjusted 1-year CS rate (ie, rate of 1 year additional survival) did not vary based on time alive, whereas the adjusted 5-year CS rate increased from 48.5% (47.0%-50.1%) for women who had already survived 6 months to 66.4% (63.3%-69.6%) for those already surviving 5 years (thus surviving 10 years total). The adjusted 1-year CS rate increased from 90.4% (89.5%-91.4%) with no rwPFS event at 6 months to 97.6% (96.4%-98.8%) with no rwPFS event at 5 years; adjusted 5-year CS rate increased from 53.7% (52.0%-55.5%) to 85.0% (81.2%-88.9%), respectively. CONCLUSIONS: This analysis extends the concept of CS by also conditioning on time progression-free. Patients with longer rwPFS experience longer survival than patients with shorter rwPFS.

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.

Aging phenotype(s) in kidneys of diabetic mice are p66ShcA dependent.

The p66ShcA protein controls cellular responses to oxidative stress, senescence, and apoptosis. Here, we test the hypothesis that aging phenotype(s) commonly associated with the broad category of chronic kidney disease are accelerated in diabetic kidneys and linked to the p66ShcA locus. At the organ level, tissue stem cells antagonize senescent phenotypes by replacing old dysfunctional cells. Using established methods, we isolated a highly purified population of stem cell antigen-1-positive mesenchymal stem cells (Sca-1+ MSCs) from kidneys of wild-type (WT) and p66 knockout (p66 KO) mice. Cells were plated in culture medium containing normal glucose (NG) or high glucose (HG). Reactive oxygen species (ROS) metabolism was substantially increased in WT MSCs in HG medium in association with increased cell death by apoptosis and acquisition of the senescent phenotype. DNA microarray analysis detected striking differences in the expression profiles of WT and p66 KO-MSCs in HG medium. Unexpectedly, the analysis for p66 KO-MSCs revealed upregulation of Wnt genes implicated in self-renewal and differentiation. To test the in vivo consequences of constitutive p66 expression in diabetic kidneys, we crossed the Akita diabetic mouse with the p66KO mouse. Homozygous mutation at the p66 locus delays or prevents aging phenotype(s) in the kidney that may be precursors to diabetic nephropathy.

The non-human primate model of tuberculosis.

Non-human primates (NHPs) are used to model human disease owing to their remarkably similar genomes, physiology, and immune systems. Recently, there has been an increased interest in modeling tuberculosis (TB) in NHPs. Macaques are susceptible to infection with different strains of Mycobacterium tuberculosis (Mtb), producing the full spectrum of disease conditions, including latent infection, chronic progressive infection, and acute TB, depending on the route and dose of infection. Clearly, NHPs are an excellent model of human TB. While the initial aim of the NHP model was to allow preclinical testing of candidate vaccines and drugs, it is now also being used to study pathogenesis and immune correlates of protection. Recent advances in this field are discussed in this review. Key questions such as the effect of hypoxia on the biology of Mtb and the basis of reactivation of latent TB can now be investigated through the use of this model.

Reducing mortality in mucormycosis of the head and neck in diabetic patients: A CARE case series.

INTRODUCTION: Rhinocerebral mucormycosis is extremely fatal, with mortality rates ranging from 85-93% despite the best treatment in immunocompromised patients. We emphasize the importance of early diagnosis, repeated debridement, and aggressive antifungal treatment to reduce mortality. CASE SUMMARY: We report six cases (five male and one female), with a mean age of 51 years who were diagnosed to have mucormycosis from 2017 to 2019. All patients were diabetic. Intracranial involvement and orbital involvement were found in four cases. Facial nerve palsy was seen in two cases, one without any apparent otological involvement. Aggressive serial debridement and amphotericin B was started. Posaconazole was added subsequently to the treatment in two cases. One patient succumbed to the disease five months after discharge. The other five patients are on regular follow-up for a mean duration of 14 months at the end of which two had residual disease which was under control. DISCUSSION: Repeated surgical debridement with an early aggressive and combination antifungal therapy can result in good outcomes even in advanced mucormycosis. Concurrent management of the underlying pathology, monitoring of liver and kidney functions, and therapeutic drug monitoring are useful to ensure smooth and effective treatment.

Real-World Healthcare Resource Utilization in Patients with Classical Hodgkin Lymphoma Treated with Pembrolizumab and Nivolumab in the USA.

BACKGROUND: Patients with classical Hodgkin lymphoma (cHL) relapsed or refractory (R/R) disease who relapse after or are ineligible for autologous stem cell transplantation have a poor prognosis. Recently, the anti-PD1 monoclonal antibodies nivolumab and pembrolizumab were approved by the US Food and Drug Administration (FDA; May 2016 and March 2017, respectively) as treatment options for R/R cHL patients. OBJECTIVE: In the absence of comparative clinical trials between these agents, this observational study was conducted to evaluate the healthcare resource utilization (HRU) of patients with cHL initiated on pembrolizumab compared to nivolumab in the USA. PATIENTS AND METHOD: Healthcare insurance claims from Symphony Health's IDV® (Integrated Dataverse) (July 2014-June 2018) were used in this retrospective study. The study population included adult patients with cHL initiated on pembrolizumab or nivolumab (index date). Inverse probability of treatment weighting was used to adjust for differences in patient characteristics between cohorts. All-cause and cHL-related hospitalizations and outpatient visits were measured during the observation (post-index) period and reported per patient-year (PPY). Rates of HRU were compared between cohorts using rate ratios (RRs). RESULTS: A total of 92 and 218 patients initiated on pembrolizumab and nivolumab, respectively, were included in the study population. After weighting, the mean age was similar at 55 years in both cohorts, while the proportion of females was lower in the pembrolizumab cohort (35.3%) compared to the nivolumab cohort (44.1%). Mean Quan-Charlson Comorbidity Index score was well balanced after weighting in the pembrolizumab and nivolumab cohorts (4.2 and 4.3, respectively). During the observation period, patients in the pembrolizumab cohort had significantly lower rates of all-cause hospitalizations (RR [95% CI] 0.33 [0.09-0.80]) and cHL-related hospitalizations (RR [95% CI] 0.14 [0.02-0.37]) than those in the nivolumab cohort. Rates of all-cause and cHL-related outpatient visits were not statistically different between patients in the pembrolizumab and nivolumab cohorts. CONCLUSIONS: In this real-world study, adult cHL patients initiated on pembrolizumab had significantly lower rates of all-cause and cHL-related hospitalizations compared to patients initiated on nivolumab.

Post-rhinoplasty outcomes in an Indian population assessed using the FACE-Q appraisal scales: a prospective observational study.

OBJECTIVES: The primary goal of rhinoplasty is patient satisfaction and improved quality of life. The present study was conducted to assess patient satisfaction with face and nose appearance, and quality of life after rhinoplasty. METHODS: Patients presenting for rhinoplasty completed the FACE-Q survey. This is a new instrument that measures patient-reported outcomes in those undergoing aesthetic procedures. The FACE-Q scales include satisfaction with facial appearance overall, satisfaction with the nose, psychological well-being, psychosocial distress and social function. RESULTS: Sixty-five patients completed the FACE-Q at pre-operative and at post-operative follow-up visits. Post-operative scores increased significantly in terms of: satisfaction with facial appearance (p < 0.0001, t = 15.639, degrees of freedom = 64); social function (p < 0.0001, t = 12.208, degrees of freedom = 64); psychosocial distress (p < 0.0001, t = 13.864, degrees of freedom = 64); psychological function (p < 0.0001, t = 12.681, degrees of freedom = 64); and satisfaction with nose (p < 0.0001, t = 16.421, degrees of freedom = 64). Most patients reported more than 79 per cent satisfaction with the post-operative outcome. CONCLUSION: The FACE-Q is an adequate instrument for determining successful aesthetic surgery based on patient satisfaction.

Correlation of cochlear nerve cross-sectional area and auditory performance after cochlear implantation in prelingual children with bilateral profound hearing loss.

OBJECTIVE: To assess whether cochlear nerve (CN) cross-sectional area as measured with parasagittal magnetic resonance imaging (MRI) in prelingual pediatric deaf patients correlates with auditory performance after cochlear implantation. STUDY DESIGN: Prospective Cohort study. METHODS: Thirty-two prelingual children with bilateral profound sensorineural hearing loss (SNHL) who received unilateral cochlear implant were included in this study. Diameters of CN at Internal auditory canal (IAC) fundus and mid-point of IAC were retrospectively measured on parasagittal images of FIESTA (Fast Imaging Employing Steady-state Acquisition) sequence MRI by two independent observers. Cross-sectional areas [π (Height/2) (Width/2)] were then correlated with post-operative CAPS (Categories of Auditory Performance) and IT-MAIS (Infant-Toddler Meaningful Auditory Integration Scale) scores regularly assessed at 3 monthly intervals post device activation. RESULTS: The cochlear nerve was identified in all the 32 patients. Mean cross-sectional areas (CSA) of cochlear nerve were 0.71 ± 0.16 mm2 at IAC fundus and 0.73 ± 0.18 mm2 at mid-point of IAC. The correlation value between CSA at mid-point of IAC and CAPS score at 6 months was 0.271 (p-value- 0.140) and correlation value between CSA at mid-point of IAC and IT-MAIS score at 6 months was 0.282 (p-value- 0.124) which were statistically not significant. CONCLUSION: There was no significant correlation between the cross-sectional areas of the cochlear nerve on MRI and postoperative auditory scores as measured by CAPS and IT-MAIS scores at six months from the device activation. Hence, we conclude that above an adequate diameter, which can affect the minimum required neurons, the changes in the diameter do not have significant bearing on auditory outcomes after cochlear implantation.

Expression of the stem cell self-renewal gene Hiwi and risk of tumour-related death in patients with soft-tissue sarcoma.

Self-renewal is considered as a common property of stem cells. Dysregulation of stem cell self-renewal is likely a requirement for the development of cancer. Hiwi, the human Piwi gene, encodes a protein responsible for stem cell self-renewal. In this study, we investigated the expression of Hiwi at the RNA level by real-time quantitative PCR in 65 primary soft-tissue sarcomas (STS) and ascertained its impact on prognosis for STS patients. In a multivariate Cox's proportional hazards regression model, we found that an increased expression of Hiwi mRNA is a significant negative prognostic factor for patients with STS (P=0.017; relative risk 4.6, 95% confidence interval (CI) 1.3-16.1) compared to medium expression of Hiwi transcript. However, a low expression of Hiwi transcript is correlated with a 2.4-fold (CI 0.7-8.0) increased risk, but this effect was not significant (P=0.17). Altogether, high-level expression of Hiwi mRNA identifies STS patients at high risk of tumour-related death. This is the first report showing a correlation between expression of a gene involved in stem cell self-renewal and prognosis of cancer patients.

Stem cell-associated genes are extremely poor prognostic factors for soft-tissue sarcoma patients.

Cancer stem cells can play an important role in tumorigenesis and tumor progression. However, it is still difficult to detect and isolate cancer stem cells. An alternative approach is to analyse stem cell-associated gene expression. We investigated the coexpression of three stem cell-associated genes, Hiwi, hTERT and survivin, by quantitative real-time-PCR in 104 primary soft-tissue sarcomas (STS). Multivariate Cox's proportional hazards regression analyses allowed correlating gene expression with overall survival for STS patients. Coexpression of all three stem cell-associated genes resulted in a significantly increased risk of tumor-related death. Importantly, tumors of patients with the poorest prognosis were of all four tumor stages, suggesting that their risk is based upon coexpression of stem cell-associated genes rather than on tumor stage.

The Learning Curve of Pure Retroperitoneoscopic Donor Nephrectomy.

BACKGROUND: Retroperitoneoscopic donor nephrectomy (RDN) is a well-established modality for the procurement of kidneys for renal transplantation. However the learning curve of pure RDN is not yet defined. Defining the learning curve will help in proper mentorship of the new donor surgeons besides providing safety to the donors. OBJECTIVE: To define the learning curve of pure RDN. METHODS: We analyzed the prospectively collected data of 102 voluntary kidney donors who underwent RDN by a single surgeon between August 2012 and April 2015 at our center. The donors were classified into group A (1-34), group B (35-68), and group C (69-102) according to the chronological order of their surgery. Left RDN was performed in 28 (82%), 25 (74%), and 28 (82%) donors of group A, B, and C, respectively. Right RDN was performed in 6 (18%), 9 (26%), and 6 (18%) donors of group A, B, and C, respectively. The clinical data were analyzed for each group. RESULTS: Statistically significant difference was observed for the mean operative time (p<0.01) and warm ischemia time (p<0.04). The operative time remained around 200 minutes after the initial 35 cases. CONCLUSION: The learning curve of pure RDN was 35 cases, although the mastery requires more number of cases to be performed.

Novel role for IL-22 in protection during chronic Mycobacterium tuberculosis HN878 infection.

Approximately 2 billion people are infected with Mycobacterium tuberculosis (Mtb), resulting in 1.4 million deaths every year. Among Mtb-infected individuals, clinical isolates belonging to the W-Beijing lineage are increasingly prevalent, associated with drug resistance, and cause severe disease immunopathology in animal models. Therefore, it is exceedingly important to identify the immune mechanisms that mediate protection against rapidly emerging Mtb strains, such as W-Beijing lineage. IL-22 is a member of the IL-10 family of cytokines with both protective and pathological functions at mucosal surfaces. Thus far, collective data show that IL-22 deficient mice are not more susceptible to aerosolized infection with less virulent Mtb strains. Thus, in this study we addressed the functional role for the IL-22 pathway in immunity to emerging Mtb isolates, using W-Beijing lineage member, Mtb HN878 as a prototype. We show that Mtb HN878 stimulates IL-22 production in TLR2 dependent manner and IL-22 mediates protective immunity during chronic stages of Mtb HN878 infection in mice. Interestingly, IL-22-dependent pathways in both epithelial cells and macrophages mediate protective mechanisms for Mtb HN878 control. Thus, our results project a new protective role for IL-22 in emerging Mtb infections.

Construction of shuttle vectors for genetic manipulation and molecular analysis of mycobacteria.

Two novel shuttle vectors for mycobacteria are described which have been derived from the expression system pSD5 developed in our laboratory. Plasmid pSD5B is a promoter-selection vector containing a promoterless lacZ gene and allows the identification of mycobacterial promoters by the blue colour of the colonies on solid media containing XGal. Moreover, the chronological order of appearance of blue colonies and intensity of colour provide a qualitative index of transcriptional strengths of the cloned promoters. Plasmid pSD5C has been designed to construct mycobacterial genomic libraries and express the cloned DNA inserts as fusion proteins with maltose binding protein in mycobacteria. Libraries in pSD5C provide feasibility for their screening with either DNA probes or specific antisera for identifying the genes of interest and for isolation of specific genetic loci by complementation of Escherichia coli and mycobacterial mutants. These vectors combine the ease of working in E. coli with the advantage of directly propagating them in mycobacteria without further manipulations. Finally, we demonstrate that these vectors function efficiently both in fast growing Mycobacterium smegmatis and slow growing mycobacteria including Mycobacterium tuberculosis and Mycobacterium bovis BCG.

Characterization of antigens on mosquito midgut stages of Plasmodium gallinaceum. III. Changes in zygote surface proteins during transformation to mature ookinete.

Proteins expressed on the surface of zygotes of Plasmodium gallinaceum during their development from fertilization to mature ookinetes have been examined by lactoperoxidase catalysed surface radioiodination and immunoprecipitation with stage-specific immune rabbit sera and sodium dodecyl sulfate polyacrylamide gel electrophoresis. Surface-labelled proteins of apparent Mr equal to or greater than 55 000 on the female gametes and newly fertilized zygotes were shed during transformation and were recovered quantitatively and apparently intact from the culture supernatant. Zygote surface proteins of Mr 50 000, 19 000 and 17 000 remained bound to the surface throughout the transformation. Three proteins were expressed de novo on the surface of the mature ookinete of which Mr 26 000 and 28 000 represented major surface components and Mr 52 000 a relatively minor component.

Characterization of antigens on mosquito midgut stages of Plasmodium gallinaceum. II. Comparison of surface antigens of male and female gametes and zygotes.

Surface proteins of male and female gametes of Plasmodium gallinaceum were radioiodinated by the lactoperoxidase method, immunoprecipitated with stage specific antisera and separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Stage specificity of the surface antigens was further studied by competition between surface iodinated gametes and unlabeled extracts of gametes, zygotes, or asexual parasites during immunoprecipitation reactions. These studies have identified four proteins: 250 kDa (PgZ-1), 215 kDa (PgZ-3) and 56 and 54 kDa (PgZ-13a and b), which were present in indistinguishable antigenic form on both male and female gametes. Three immunogenic proteins, 48 kDa (PgZ-14) and 19 and 17 kDa (PgZ-17a and b), were present on female but not male gametes as were several weakly labeled, non-immunogenic proteins of less than 45 kDa. A 26 kDa protein (PgZ-16) was present on male but not female gametes. Two proteins of 205 and 83 kDa (PgZ-4 and PgZ-11) were labeled on female but not male gametes. Nevertheless preparations of male gametes appeared to contain epitopes cross-reacting with these two proteins since anti-male gamete serum precipitated PgZ-4 and 11. Immune competition studies indicated that each of the surface proteins labeled on sexual stages was antigenically distinct from material present in asexual parasites.

Characterization of antigens on mosquito midgut stages of Plasmodium gallinaceum. I. Zygote surface antigens.

We have defined the surface protein antigens on Plasmodium gallinaceum zygotes using radioiodination methods and rabbit anti-zygote serum which blocks transmission of the parasite to Aedes aegypti mosquitoes. Fifteen protein bands (1-15) in the molecular weight range of 40 000-240 000 and one band at the bromophenol blue dye marker were labelled by the lactoperoxidase and IODOGEN (1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenylglycoluril) methods. The localization of these radioiodinated components on the cell surface was confirmed in two ways: (1) They were completely degraded by trypsin or Streptomyces griseus protease treatment of intact viable zygotes. (2) They were immunoprecipitated following incubation of intact zygotes with antibody prior to detergent solubilization. Reactivity with immune rabbit serum demonstrated that the major surface immunogens were components with Mr 240 000, 200 000, 180 000, 80 000, 55 000, 50 000 and the band at the dye marker. A band of Mr 180 000 was shown immunologically to be a host serum protein selectively adsorbed to the zygote surface. The identity of this protein and the significance of its adsorption to the surface of the zygote are unknown.

Neurobiology of receptor-mediated lysophospholipid signaling. From the first lysophospholipid receptor to roles in nervous system function and development.

Identification of the first lysophospholipid receptor, LPA1/Vzg-1, cloned by way of neurobiological analyses on the embryonic cerebral cortex, has led to the realization and demonstration that there exist multiple, homologous LP receptors, including those encoded by a number of orphan receptor genes known as "Edg," all of which are members of the G-protein-coupled receptor (GPCR) superfamily. These receptors interact with apparent high affinity for lysophosphatidic acid (LPA) or sphingosine-1-phosphate (S1P or SPP), and are referred to based upon their functional identity as lysophospholipid receptors: LPA and LPB receptors, respectively, with the expectation that additional subgroups will be identified (i.e., LPC, etc.). Here an update is provided on insights gained from analyses of these receptor genes as they relate to the nervous system, particularly the cerebral cortex, and myelinating cells (oligodendrocytes and Schwann cells).

Biokinetics of lead in various organs of rats using radiotracer technique.

Uptake, distribution, and elimination of lead in various organs of rats have been studied using a radiotracer technique. The elimination data for various organs, except whole blood, is fitted to a double-exponential function using a computer program. The biological half-lives along with the percent elimination of lead by two different decay modes in testis, epididymis, prostate, and seminal vesicles are being reported together with that in liver, kidney, blood, and whole body. It is evident from this study that the elimination of lead is limited for all the organs and permits lead accumulation in the bone, where it is stored and becomes almost unavailable for elimination. Lead levels in blood, testis, and femur of lead acetate-fed rats measured using atomic absorption spectroscopy have been correlated to the uptake of 210Pb in various organs.

Monoclonal antibodies against lactate dehydrogenase of Plasmodium knowlesi.

Lactate dehydrogenase (LDH) of malarial parasites has been demonstrated to be biochemically and immunochemically distinct from the equivalent host enzyme. The polyclonal antibodies raised against the purified plasmodial LDH showed specificity to Plasmodium spp. Six hybridoma cell lines secreting monoclonal antibodies specific to Plasmodium knowlesi LDH have been obtained. The two monoclonal antibodies (2A3B7 and 4A6A7) showed high reactivity with LDH from simian (P. knowlesi. P. cynomolgi), human (P. falciparum, P. vivax) and rodent (P. berghei, P. yoelii) malarial parasites and did not cross-react with red cell LDH as well as with isoenzymic forms of mammalian LDH (A4, B4 and C4). One monoclonal antibody (4A6A7) strongly inhibited the enzyme activity specifically of plasmodial LDH and did not have any effect on the activity of red cell LDH. The other monoclonal (2A3B7) did not show inhibitory effect on parasite LDH. These findings as well as competitive immunoassay studies suggest the presence of at least two parasite specific epitopes on plasmodial LDH.

Monoclonal antibodies against antigenic epitopes common between Setaria cervi and Brugia malayi.

Several common antigens between the bovine (Setaria cervi) and human (Brugia malayi) filarial parasites have been demonstrated [Immunol Investig, 16 (1987) 139]. Hybridoma cell lines producing monoclonal antibodies against such common antigenic epitopes were obtained by immunizing the BALB/c mice with S. cervi antigen, fusing the spleen cells with Sp2/0 myeloma cells and screening the culture supernatants for antibody against both S. cervi and B. malayi antigens by ELISA. Nine monoclonal antibodies directed against antigenic epitopes common between the bovine and human filarial parasites were identified. Two monoclonal antibodies (I3B4 and I5D6) showed reactivity with the antigen(s) present in filariasis patients serum and thus may have potential for detecting circulating antigen in filaria infected individuals.