Prospective external validation of IOTA methods for classifying adnexal masses and retrospective assessment of two-step strategy using benign descriptors and ADNEX: a Portuguese multicenter study.

OBJECTIVE: This study aimed to externally and prospectively validate the International Ovarian Tumor Analysis (IOTA) Simple Rules (SRs), Logistic Regression model 2 (LR2) and Assessment of Different NEoplasias in the adneXa (ADNEX) in a Portuguese population, comparing them with operator subjective assessment (SA), Risk-of-Malignancy Index (RMI), as well as with each other. This study also aimed to retrospectively validate IOTA two-step strategy, using modified benign descriptors (MBDs) followed by the application of ADNEX in cases where MBDs were not applicable (MBDs + ADNEX). METHODS: In this multicenter diagnostic accuracy study, conducted between January 2016 and December 2021, three tertiary referral centers prospectively included consecutive patients with ultrasound diagnosis of at least one adnexal tumor who underwent surgery. All ultrasound assessments were performed by level II or III sonologists with IOTA certification. Patient clinical data and serum cancer antigen (CA125) levels were collected from the hospital databases. Each adnexal mass was classified as benign or malignant using SA, RMI, IOTA SRs, LR2 and ADNEX (with and without CA125). The reference standard was histopathological diagnosis. In the second phase, all adnexal tumors were retrospectively classified using the two-step strategy (MBDs + ADNEX). The sensitivity, specificity, positive (PPV) and negative predictive value (NPV), positive (LR+) and negative likelihood ratio (LR-) as well as overall accuracy were determined for SA, RMI, IOTA SRs, LR2, ADNEX and two-step strategy (MBDs + ADNEX). Receiver-operator characteristic curves were constructed and corresponding areas under the curve (AUC) determined for RMI, LR2 and ADNEX and two-step strategy (MBDs + ADNEX). The ADNEX calibration plots were constructed and estimated by LOESS smoother. RESULTS: Of the 571 included patients, 428 had benign disease, 42 borderline ovarian tumors, 93 primary invasive adnexal cancers and 8 metastatic tumors in adnexa (malignancy prevalence: 25.0%). The operator SA had an overall sensitivity of 97.9% and a specificity of 83.6% for distinguishing between benign and malignant lesions. RMI showed high specificity (95.6%) but very low sensitivity (58.7%), with an AUC of 0.913. The IOTA SRs were applicable in 80.0% of patients, with a sensitivity of 94.8% and a specificity of 98.6%. LR2 revealed a sensitivity of 84.6%, a specificity of 86.9% and an AUC of 0.939, at the malignancy risk cut-off of 10%. At the same cut-off, ADNEX with and without CA125 had a sensitivity of 95.8% and 98.6%, respectively, and a specificity of 82.5% and 79.7%, respectively. The AUC of ADNEX with vs. without CA125 was 0.962 vs. 0.960. The ADNEX model provided heterogeneous results in distinguishing between benign and different subtypes of malignancy, with the highest AUC (0.991) for discriminating benign masses from primary adnexal cancer stage II-IV, and the lowest AUC (0.696) for distinguishing primary adnexal cancer stage I and metastatic lesion in adnexa. The ADNEX calibration plots suggested an underestimation of the predicted risk in relation with the observed proportion of malignancies. The MBDs were applicable in 26.3% of cases (150/571 tumors, none of which were malignant). Similar to the ADNEX model applied in all patients, the two-step strategy using ADNEX in the second step only, with and without CA125, had an AUC of 0.964 and 0.961, respectively. CONCLUSIONS: Our results showed a good to excellent performance of the IOTA methods in the studied Portuguese population, outperforming RMI. ADNEX was superior in accuracy, but interpretation of its ability to distinguish malignant subtypes was fundamentally limited not only by sample size but also by large differences in the prevalence of tumor subtypes. The IOTA MBDs have been shown to be reliable in identifying benign disease. The two-step strategy based on the application of MBDs, followed by the ADNEX model if MBDs are not applicable, has proven to be suitable for daily practice circumventing the need to use electronic support in all patients. This article is protected by copyright. All rights reserved.

Quality of Life According to Urgency Status in De Novo Heart Transplant Recipients.

INTRODUCTION: Elective heart transplantation (HTX) aims to improve physical ability, increase survival, and improve health-related quality of life (HRQoL) in patients with chronic heart failure. Nevertheless, most patients who undergo urgent HTX are previously healthy, and a transplant could be perceived as a limitation. The aim of this study is to compare HRQoL between elective and urgent heart transplant recipients. METHODS: Cohort study including patients undergoing heart transplantation between January 1998 and March 2012 in a single center. Patients with retransplantation or multiorgan transplantation were excluded. Clinical variables including comorbidities were collected. For assessment of HRQoL, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was completed by the survivors on March 2013. Univariate analysis (Mann-Whitney U test) was performed. RESULTS: Questionnaires were collected from 95 of 106 elective recipients and 28 of 33 urgent recipients. Urgent heart recipients were younger, with more cardiovascular risk factors, and ischemic etiology was the leading cause of transplant. All domain results were higher in elective heart transplant recipients, but after univariate analysis only the punctuation of the self-efficacy domain remained superior in the elective HTX group (87.5 vs 79.7, P = .034). CONCLUSION: Both urgent and elective heart transplant patients reported a good HRQoL, and there were no significant differences between their scores.

Effect of early conversion to everolimus together with prophylaxis with valganciclovir in the prevention of cytomegalovirus infection in heart transplant recipients.

INTRODUCTION: Viral infections, especially cytomegalovirus (CMV), are a leading cause of early death and morbidity after heart transplantation. Several strategies have been used to minimize the risk, including universal prophylaxis with ganciclovir or valganciclovir and preemptive therapy. Lately, everolimus (EVE) efficacy studies have shown a protective effect against CMV infection. METHODS: We studied retrospectively a series of 223 heart transplant patients, dividing them into 5 groups according to CMV prevention strategy: 16 patients were at low risk for infection (negative recipient [R-]/negative donor [D-]) and received no treatment; 26 patients received prophylactic therapy with ganciclovir, 8 patients prophylaxis with valganciclovir, 145 patients received preemptive therapy and 28 patients prophylaxis with valganciclovir and early conversion to EVE. RESULTS: There were no cases of CMV infection in the low-risk group. There was 1 case of CMV infection in the group that received valganciclovir and conversion to EVE. Among the patients who received prophylaxis with ganciclovir or valganciclovir or preemptive therapy, CMV infection was detected in 68 patients (37%). CONCLUSIONS: Early conversion to EVE in addition to valganciclovir prophylaxis was superior to other strategies in our series for the prevention of CMV infection.

Effect of CYP3A5, CYP3A4, and ABCB1 genotypes as determinants of tacrolimus dose and clinical outcomes after heart transplantation.

BACKGROUND: Tacrolimus (Tac) is mainly metabolized by cytochrome P450 3A isoenzymes. In a cohort of heart transplant recipients, we investigated the effect of CYP3A5, CYP3A4, and ABCB1/MDR1 polymorphisms on Tac dose requirements and the risk of developing new-onset diabetes after transplantation (NODAT). METHODS: A total of 65 heart transplant recipients were genotyped for 3 single nucleotide polymorphisms (SNPs) in the CYP3A5 (SNP rs776746), CYP3A4 (SNP rs2740574), and ABCB1 (SNP rs104564). The mean Tac dose values were compared between the genotypes. RESULTS: CYP3A5 3 homozygotes (nonexpressers; n = 55, 85%) received significantly higher Tac dose compared with CYP3A5 1 carriers (expressers). No different NODAT frequencies were found between the genotypes. CONCLUSIONS: The CYP3A5 polymorphism was the main determinant of Tac dose requirements among heart transplant recipients. This common functional polymorphism had no influence on the risk of developing NODAT.

N-terminal pro-brain natriuretic peptide as a potential non-invasive marker of cardiac transplantation rejection.

BACKGROUND: Transplantation is the main palliative treatment for patients with heart failure. Clinical signs of cardiac rejection can be very non-specific or even absent. Thus, successful management relies on early diagnosis, ideally before the onset of clinical features of cardiac dysfunction. Although endomyocardial biopsy (EMB) is the reference diagnostic method, several non-invasive methods have been proposed to reduce the number of EMB performed during the follow-up of the transplanted patient. The aim of the present work was to study the potential relationship between rejection and serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) as well as cardiac troponin T (cTnT) in post-transplantation patients. METHODS: Twenty-three consecutive orthotopic heart transplantation recipients with a mean age of 51 years (range 22-66) were prospectively recruited from the cardiac transplantation programme at the Hospital Universitario Central de Asturias. Serum NT-proBNP and cTnT were measured during the follow-up of these patients (ranging from 9-13 months post-transplantation) and compared with the results of EMB. RESULTS: Serum NT-proBNP concentrations progressively decrease during the first year post-transplantation, reaching concentrations slightly higher than the reference values. NT-proBNP concentrations increase significantly in those patients with a rejection episode graded >or=3A on the basis of the EMB (P<0.001, Mann-Whitney U-test). No relation between cTnT and rejection was observed. CONCLUSIONS: The potential of NT-proBNP as a non-invasive marker of transplantation rejection shows promising results, since NT-proBNP concentrations increase whenever a significant rejection event takes place in the first year of follow-up.

Recognizing borderline personality disorder in the family practice setting.

The first step in the management of borderline personality disorder is making the correct diagnosis. A clinical example illustrates symptoms of a patient with borderline personality disorder in a family practice setting. Major characteristics of borderline personality disorder include severe mood instability, fear of abandonment, chronic boredom, self-injury, unstable interpersonal relationships, "splitting," identity instability and borderline rage. Early diagnosis may help prevent potential management problems and possible doctor-patient conflicts.

Large scale production of the vertebrate infective stage (L3) of Onchocerca volvulus (Filarioidea: Onchocercidae).

Laboratory-derived Simulium yahense and S. sanctipauli females were used to produce large numbers of Onchocerca volvulus infective stage larvae (L3) for use in assessing the possible chemoprophylactic potential of ivermectin in the chimpanzee model. Engorgement rates and subsequent post-prandial survival were correlated with the time at which adult flies were offered a carbohydrate source following emergence and the age of flies that fed on microfiladermic volunteers.

The effects of ivermectin on transmission of Onchocerca volvulus.

Ivermectin, given to onchocerciasis patients as a single oral dose of 200 micrograms per kilogram of body weight, substantially reduced the uptake of Onchocerca volvulus microfilariae by Simulium yahense, an efficient black fly vector of the parasite in the tropical rain forests of West Africa. Three months after treatment, patients given ivermectin infected flies at a significantly lower rate than those who had received diethylcarbamazine or placebo, thereby reducing the number of developing larvae in the vector population. This diminished rate of infectiousness was also evident 6 months after treatment. These results strongly suggest that ivermectin could be effective in interrupting transmission of Onchocerca volvulus for epidemiologically important periods of time.

Development of onchocerca lienalis and O. volvulus from the third to fourth larval stage in vitro.

Third-stage larvae of Onchocerca volvulus and O. lienalis were observed to molt to the fourth stage in various cell-free in vitro systems. The percentage of O. lienalis completing the molt was similar in the three culture media and two gas phases tested ranging from 44.8% (1:1 IMDM:NCTC + 5% CO2: 95% N2) to 56.7% (L-15 + 5% CO2: 95% air). Percent molting in O. volvulus ranged from 0% (F12(K) + 5% CO2: 95% N2) to 33.3% (L-15 + 5% CO2: 95% N2). All media were supplemented with either 20% FCS or 20% horse serum. Molting by O. lienalis occurred on days 2-5 in culture. Molting by O. volvulus was observed as early as day 5 and as late as day 10. Incomplete casting of the third-stage cuticle was frequently observed in O. volvulus. Larvae of both species entered a lethargus 24-48 hours prior to the onset of molting. Maximum survival in culture was 42 days for O. lienalis and 25 days for O. volvulus. Significant growth of larval O. lienalis was noted early in the culture period, but neither species continued development to the fifth stage.

Simulium jenningsi Malloch (Diptera: Simuliidae): a vector of Onchocerca lienalis Stiles (Nematoda: Filarioidea) in New York.

Biting flies were collected from the umbilical areas of Onchocerca lienalis-infected cattle in New York (state) from June through September of 1980. Of the 766 flies collected, 705 were Simulium jenningsi. Microfilariae were detected in the midguts of 37 (50%) of 73 females dissected immediately after the flies had fed. The mean number of larvae per positive fly (fly with microfilariae) was 15.2. Third-stage larvae were recovered from 25 (21.9%) of 114 S jenningsi dissected 8 to 13 days after they had fed on the infected cattle; the mean number of 3rd-stage larvae per positive fly was 3.5. Dissections of flies performed on days 1 through 7 after feeding yielded various numbers of 1st and 2nd-stage larvae from the thoracic muscles. Ovarian dissections performed on 304 S jenningsi attacking cattle indicated an overall parous rate of 58%. Naturally occurring infections with filarial larvae indistinguishable from O lienalis were found in 7.3% of the parous females. Three of these flies, or 1.7% of the parous collection, harbored 3rd-stage larvae. The onset of naturally occurring filarial infections in the population of S jenningsi coincided with a peak in the parous rate in late June. Thereafter, filarial infections were generally detected when the parous rate was above 50%.

Further studies on the development of onchocerca spp. (Nematoda: Filarioidea) in Nearctic black flies (Diptera: Simuliidae).

Of three species of Nearctic black flies tested, Simulium pictipes Hagen proved the most efficient laboratory vector of the bovine parasite Onchocerca lienalis. Among flies inoculated intrathoracially with 40 microfilariae, numbers of 3rd-stage larvae per fly were 7.63 for S. pictipes, 7.54 for S. vittatum Zetterstedt, and 0.83 for S. decorum Walker. S. pictipes survived the longest under laboratory conditions, with 83.3% of the females remaining alive 10 days after inoculation with 40 microfilariae of O. lienalis. Using an artificial membrane feeding system, S. pictipes could be routinely infected with O. lienalis by mouth. This black fly was also susceptible to infection with the Guatemalan strain of O. volvulus. Among flies injected with 10 microfilariae the rate of infection with 3rd-stage larvae was 93%, with a mean of three 3rd-stage larvae per fly. Successful techniques for the large-scale recovery and cryopreservation of 3rd-stage larvae of O. lienalis were also developed. A motility rate of 92.7% was observed in larvae cryopreserved within vector black flies.

Complete generation rearing of Simulium damnosum s.l. (Diptera: Simuliidae) in the laboratory.

A closed system of water circulation previously devised for rearing nearctic black flies was used for two cohorts of Simulium damnosum s.l. (Ghana strain). Complete generation development from field-collected eggs occurred in both instances with the production of F1 adults and F1 pupae respectively. Survival of larvae form the 3rd instar to pupation was extremely high for both parental and filial generations and ranged form 63-98%. In 3 of the 4 rearings (1P, 2P, 1F1), pupal survival ranged form 98-100%. Mating attempts were frequently seen but insemination rates were low (greater than 1%). Nulliparous females were anthropophilic and exhibited bloodfeeding rates ranging form 67.5-87.5%. Parous females also readily engorged on humans. Porcine and rabbit hosts proved less attractive while two membrane systems (Baudruche, chicken skin)using equine, bovine, or chicken blood elicited practically no engorgement. Gravid females readily deposited fertile and infertile eggs in an oviposition chamber designed originally for Simulium decorum.

Laboratory colonization and life table statistics for geographic strains of Simulium decorum (Diptera: Simuliidae).

Colonization techniques were developed in order to select mating strains from four geographic populations of Simulium decorum. Although mating strains were established from each locale, emphasis was shifted toward developing permanent colonies from Dryden Lake, New York, USA and Warm Springs, Georgia, USA. The net reproductive rate (Ro) was computed for the parental, F1, and F2 generations of each strain in order to assess the effects of colonization through successive generations. Ro increased rapidly for both strains from parental (range of 0.34-3.5) through F2 generations (range of 16.2-21.6). Analysis of Ro components indicated that the increases in Ro were the result of two parameters that reflect the propensity of flies to mate in confinement, suggesting that selection for mating is rapid. Multiple regression analysis indicated no significant differences between strains or generations when tested against fecundity (range of 391-519) and survival of immatures (range of 90.3-97.2%). A slight positive correlation (regression coefficient of 0.0016, P less than .01) was observed between larval density (range of 284-4,439 larvae per rearing) and survival of immatures, suggesting that the limits of the rearing system with regard to crowding were not approached. Both strains readily adapt to the laboratory and are currently in the fifth generation.

The development of Onchocerca spp. in Simulium decorum Walker and Simulium pictipes Hagen.

Two species of Nearctic black fly, Simulium decorum and S. pictipes, exhibit partial susceptibility to infection with the bovine parasite, Onchocerca lienalis, when inoculated intrathoracically with microfilariae. In addition, a proportion of S. decorum females will support the development of the human parasite, O. volvulus, to the third larvae stage. Infection rates with second- or third-stage larvae seven or more days after varied among geographic strains of S. decorum, ranging from 6.5% in a strain from northern New York State to 48.7% in a strain from Georgia. The average number of larvae per infected female ranged from 1.00 to 1.78 in the three strains examined. Partial susceptibility to O. lienalis was found to persist in colonized strains of s. decorum, and cryopreserved microfilariae of this parasite retained their infectivity. Seven or more days after inoculation with microfilariae of the Guatemalan strain of O. volvulus, 16.7% of the females of S. decorum harbored second- or third-stage larvae. Development of O. lienalis and O. volvulus proceeded normally in these black flies, and moderate increases in susceptibility rate and number of infective larvae were noted in response to increased microfilarial dosages.