Value of psychosocial evaluation for left ventricular assist device candidates.

OBJECTIVE: Left ventricular assist devices require a psychosocial assessment to determine candidacy despite limited data correlating with outcome. Our objective is to determine whether the Stanford Integrated Psychosocial Assessment for Transplant, a tool validated for transplant and widely used by left ventricular assist device programs, predicts left ventricular assist device program hospital readmissions and death. METHODS: We performed a retrospective analysis of adults at the Cleveland Clinic with Stanford Integrated Psychosocial Assessment for Transplant scores before primary left ventricular assist device program implantation from April 1, 2013, to December 31, 2018. The primary outcome was unplanned hospital readmissions censored at death, transplantation, and transfer of care. The secondary outcome was death. RESULTS: There were 263 patients in the left ventricular assist device program with a median (Q1, Q3) Stanford Integrated Psychosocial Assessment for Transplant score of 16 (8, 28). During a median follow-up 1.2 years, 56 died, 65 underwent transplantation, and 21 had transferred care. There were 640 unplanned hospital readmissions among 250 patients with at least 1 outpatient visit at our center. In a multivariable analysis, Stanford Integrated Psychosocial Assessment for Transplant components but not total Stanford Integrated Psychosocial Assessment for Transplant score was associated with readmissions. Psychopathology (Stanford Integrated Psychosocial Assessment for Transplant C-IX) was associated with hemocompatibility (coefficient 0.21 ± standard error 0.11, P = .040) and cardiac (0.15 ± 0.065, P = .02) readmissions. Patient readiness was associated with noncardiac (Stanford Integrated Psychosocial Assessment for Transplant A-III, 0.24 ± 0.099, P = .016) and cardiac (Stanford Integrated Psychosocial Assessment for Transplant A-low total, 0.037 ± 0.014, P = .007) readmissions. Poor living environment (Stanford Integrated Psychosocial Assessment for Transplant B-VIII) was associated with device-related readmissions (0.83 ± 0.34, P = .014). Death was associated with organic psychopathology or neurocognitive impairment (Stanford Integrated Psychosocial Assessment for Transplant C-X, 0.59 ± 0.21, P = .006). CONCLUSIONS: Total Stanford Integrated Psychosocial Assessment for Transplant score was not associated with left ventricular assist device program readmission or mortality. However, we identified certain Stanford Integrated Psychosocial Assessment for Transplant components that were associated with outcome and could be used to create a left ventricular assist device program specific psychosocial tool.

Pleural space management after lung transplant: Early and late outcomes of pleural decortication.

BACKGROUND: Pleural complications after lung transplant may restrict allograft expansion, requiring decortication. However, its extent, indications, risk factors, and effect on allograft function and survival are unclear. METHODS: From January 2006 to January 2017, 1,039 patients underwent primary lung transplant and 468 had pleural complications, 77 (16%) of whom underwent 84 surgical decortications for pleural space management. Multivariable time-related analysis was performed to identify risk factors for decortication. Mixed-effect longitudinal modeling was used to assess allograft function before and after decortication. RESULTS: Cumulative number of decortications per 100 transplants was 1.8, 7.8, and 8.8 at 1 month, 1 year, and 3 years after transplant, respectively. Indications for the 84 decortications were complex effusion in 47 (56%), fibrothorax in 17 (20%), empyema in 11 (13%), and hemothorax in 9 (11%). Thoracoscopic operations were performed in 52 (62%) and full lung re-expansion was achieved in 76 (90%). Complications occurred after 30 (36%) decortications, with 15 pulmonary complications (18%), including 2 patients requiring extracorporeal support due to worsening function. Ten reinterventions occurred via thoracentesis (2), tube thoracostomy (1), and reoperation (7). In-hospital and 30-day mortality was 5.2% (n = 4/77). Forced expiratory volume in 1 second increased from 50% to 60% within the first year after decortication, followed by a slow decline to 55% at 5 years. Postdecortication survival was 87%, 68%, and 48% at 1, 3, and 5 years, respectively. CONCLUSIONS: Despite high risk of reoperative surgery, decortication after lung transplant allows salvage of pleural space and graft function with a reasonable morbidity profile.

Heart Transplantation: An In-Depth Survival Analysis.

OBJECTIVES: This study aims to understand the complex factors affecting heart transplant survival and to determine the importance of possible sex-specific risk factors. BACKGROUND: Heart transplant allocation is primarily focused on preventing waitlist mortality. To prevent organ wastage, future allocation must balance risk of waitlist mortality with post-transplantation mortality. However, more information regarding risk factors after heart transplantation is needed. METHODS: We included all adults (30,606) in the Scientific Registry of Transplant Recipients database who underwent isolated heart transplantation from January 1, 2004, to July 1, 2018. Mortality (8,278 deaths) was verified with the complete Social Security Death Index with a median follow-up of 3.9 years. Temporal decomposition was used to identify phases of survival and phase-specific risk factors. The random survival forests method was used to determine importance of mortality risk factors and their interactions. RESULTS: We identified 3 phases of mortality risk: early post-transplantation, constant, and late. Sex was not a significant risk factor. There were several interactions predicting early mortality such as pretransplantation mechanical ventilation with presence of end-organ function (bilirubin, renal function) and interactions predicting later mortality such as diabetes and older age (donor and recipient). More complex interactions predicting early-, mid-, and late-mortality existed and were identified with machine learning (i.e., elevated bilirubin, mechanical ventilation, and dialysis). CONCLUSIONS: Post-heart transplant mortality risk is complex and dynamic, changing with time and events. Sex is not an important mortality risk factor. To prevent organ wastage, end-organ dysfunction should be resolved before transplantation as much as possible.

Body mass, polymorphisms in obesity-related genes, and the risk of developing breast cancer among women with benign breast disease.

BACKGROUND: A cohort study was conducted among post-menopausal women to determine whether genetic polymorphisms in selected obesity-related genes (PPARG, LPL, LEPR, PON1, PON2, TNF-alpha) were associated with the progression of benign breast disease (BBD) to breast cancer and whether the selected polymorphisms modified the association between body mass and breast cancer among women with BBD. METHODS: Among participants in an ongoing cohort study, 994 Caucasian post-menopausal women had a breast biopsy for BBD. Of these women, 61 subsequently developed breast cancer. A short questionnaire was administered at baseline in 1989. Genotypes were determined using DNA extracted from blood collected in 1989. RESULTS: In this cohort, body mass index (BMI) was positively associated with the risk of developing breast cancer. In contrast, polymorphisms in PON1 (Gln192Arg) and LEPR (IVS2+6920) were associated with a decreased risk of developing invasive breast cancer. No statistically significant associations were observed for polymorphisms in PPARG, PON2, LPL, or TNF and breast cancer risk or for interactions between the polymorphisms and BMI and breast cancer risk. CONCLUSIONS: The findings suggest that specific polymorphisms in the PON1 and LEPR genes may play a role in progression of BBD to breast cancer among post-menopausal Caucasian women.

Mismatch repair polymorphisms and the risk of colorectal cancer.

Rare germline variants in mismatch repair genes have been linked to hereditary nonpolyposis colorectal cancer; however, it is unknown whether common polymorphisms in these genes alter the risk of colorectal cancer. To examine the association between common variants in mismatch repair genes and colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Four single nucleotide polymorphisms in 3 mismatch repair genes (MSH3 R940Q, MSH3 T1036A, MSH6 G39E and MLH1 I219V) were genotyped in 237 colorectal cancer cases and a subcohort of 2,189 participants. Incidence rate ratios (RRs) and 95% confidence intervals (95% CIs) for each polymorphism were estimated. The MSH3 1036A variant was found to be associated with an increased risk of colorectal cancer (RR=1.28, 95% CI: 0.94-1.74 and RR=1.65, 95% CI: 1.01-2.70 for the AT and TT genotypes, respectively, with p(trend)=0.02), particularly proximal colon cancer. Although the MSH3 940Q variant was only weakly associated with colorectal cancer overall (p(trend)=0.07), it was associated with a significant increased risk of proximal colon cancer (RR=1.69, 95% CI: 1.10-2.61 and RR=2.68, 95% CI: 0.96-7.47 for the RQ and QQ genotypes, respectively with p(trend)=0.005). Processed meat intake appeared to modify the association between the MSH3 polymorphisms and colorectal cancer (p(interaction) < 0.10 for both). No association was observed with the MSH6 and MLH1 polymorphisms overall. This study suggests that common polymorphisms in the mismatch repair gene, MSH3, may increase the risk of colorectal cancer, especially proximal colon cancer.

Genetic variation in the nucleotide excision repair pathway and colorectal cancer risk.

Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons, which are found in two putative risk factors for colorectal cancer, tobacco smoke and meat cooked at high temperature. To examine the association between common genetic variants in NER genes and the risk of colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in 11 NER genes were genotyped in 250 colorectal cancer cases and a subcohort of 2,224 participants. Incidence rate ratios (RR) and 95% confidence intervals (95% CI) were estimated using a modified Cox regression model and robust variance estimate. The ERCC6 1213G variant, which is thought to reduce NER capacity, was associated with an increased risk of colorectal cancer compared with the homozygous wild type (RR, 1.36; 95% CI, 1.00-1.86 and RR, 2.64; 95% CI, 1.53-4.58 for the RG and GG genotypes respectively with P(trend) = 0.0006). Having at least one XPC 492H allele was also associated with an increased risk of colorectal cancer (RR, 1.75; 95% CI, 1.20-2.57). When the combined effects of ERCC6 R1213G and XPC R492H were examined, the risk of colorectal cancer significantly increased with increasing number of variant alleles (P(trend) = 0.00003). Our study suggests that genetic polymorphisms in the NER genes, ERCC6 and XPC, may be associated with an increased risk of colorectal cancer.

Polymorphisms in estrogen-metabolizing and estrogen receptor genes and the risk of developing breast cancer among a cohort of women with benign breast disease.

BACKGROUND: A cohort study was conducted to examine the role of genetic polymorphisms in three estrogen metabolizing enzymes (COMT, CYP1A1, CYP1B1) and the two estrogen receptors (ESR1, ESR2) in the progression of benign breast disease (BBD) to breast cancer. METHODS: Among participants in an ongoing cohort study, 1438 Caucasian women had a breast biopsy for BBD and were successfully genotyped for at least one of the polymorphisms examined in this study. Genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer occurring subsequent to BBD diagnosis up to 2003 were identified through cancer registries. RESULTS: Among all participants, the ESR2 *5772G allele was associated with a significant decrease in the risk of breast cancer among women with BBD (Odds Ratio (OR) 0.38; 95% Confidence Interval (CI) 0.15, 0.96). Compared to the reference wild-type genotypes, marginally significant associations with the development of breast cancer were observed between carriers of the variant ESR1 - 104062T allele (OR 0.70, 95% CI 0.45, 1.09), the variant ESR2 *38A allele (OR 1.40; 95% CI 0.88, 2.25), and the variant CYP1B1 453Ser allele (OR 1.48, 95% CI 0.95, 2.32). CONCLUSION: The results indicate that specific polymorphisms in the CYP1B1, ESR1, and ESR2 genes may play a role in progression of BBD to breast cancer among Caucasian women. Although additional studies are needed to confirm or refute our findings, these results suggest that genetic markers may aid in the identification of women who are at risk for progression of BBD to cancer.

Flame-broiled food, NAT2 acetylator phenotype, and breast cancer risk among women with benign breast disease.

PURPOSE: The objective of this study was to examine the association between flame-broiled food consumption, a source of heterocyclic amine exposure, and the development of breast cancer among cohort of women with benign breast disease (BBD). The variation of the association by acetylation phenotype, as determined by the genotypes of selected N-acetyltransferase 2 (NAT2) enzymes, was also examined. METHODS: Among participants in an ongoing cohort study, 1187 women reported having a breast biopsy for BBD and completed a food frequency questionnaire. NAT2 G857A, NAT2 T341C, and NAT2 G590A genotypes were determined using DNA extracted from blood specimens collected in 1989. Incident cases of breast cancer were identified through linkage of the cohort participants with the Washington County Cancer Registry and the Maryland State Cancer Registry. Follow-up for the BBD cohort began at study entry in 1989 and ended on April 28, 2003. RESULTS: Of the women in this study, 77 subsequently developed breast cancer. Results showed that, among rapid acetylators, flame-broiled food intake was associated with a statistically significant increase in the risk of breast cancer (odds ratio (OR) 2.62; 95% confidence interval (CI) 1.06, 6.46). No association was observed between flame-broiled food intake and breast cancer among slow acetylators (OR 0.75; 95% CI 0.39, 1.43). CONCLUSIONS: These findings suggest that flame-broiled food may be a modifiable risk factor for the progression of BBD to invasive breast cancer among women who have genotypes consistent with rapid acetylation.

Nonsteroidal antiinflammatory drugs, cyclooxygenase polymorphisms, and the risk of developing breast carcinoma among women with benign breast disease.

BACKGROUND: Biopsy-proven benign breast disease (BBD) is a risk factor for developing breast carcinoma; however, to the authors' knowledge, little is known regarding factors related to progression to carcinoma. A cohort study was conducted to examine the role of cyclooxygenase (COX) polymorphisms and nonsteroidal anti-inflammatory drugs (NSAIDs) in the progression of BBD to breast carcinoma. METHODS: Among participants in an ongoing cohort study, 1467 women underwent a breast biopsy for BBD. Of these women, 91 subsequently developed breast carcinoma. Medication data were collected in 1989 and in 1996. COX genotypes were determined using DNA extracted from blood specimens collected in 1989. RESULTS: A decrease in breast carcinoma risk was observed among women who reported using aspirin in 1989 (odds ratio [OR] of .46; 95% confidence interval [95% CI], .22-.98) and in 1996 (OR of .47, 95% CI, .18-1.21). Furthermore, a higher frequency, dose, and longer duration of aspirin use were associated with a decrease in the odds of developing breast carcinoma. Overall, no association was observed between COX genotypes and the subsequent development of breast carcinoma. However, among women not using NSAIDs, one COX-2 polymorphism (rs2143416) was found to be significantly associated with the development of breast carcinoma. CONCLUSIONS: Findings from the current study suggest that inflammation through COX-2 pathways may play a role in the progression of BBD to breast carcinoma and that aspirin may help to lower the risk of progression to breast carcinoma among women with BBD.

Human leukocyte antigen class II alleles influence levels of antibodies to the Plasmodium falciparum asexual-stage apical membrane antigen 1 but not to merozoite surface antigen 2 and merozoite surface protein 1.

The apical membrane antigen 1 (AMA1), merozoite surface antigen 2 (MSA2), and merozoite surface protein 1 (MSP1) are asexual-stage proteins currently being evaluated for inclusion in a vaccine for Plasmodium falciparum. Accordingly, it is important to understand factors that control antibody responses to these antigens. Antibody levels in plasma from residents of Etoa, Cameroon, between the ages of 5 and 70 years, were determined using recombinant AMA1, MSA2, and the N-terminal region of MSP1 (MSP1-190L). In addition, antibody responses to four variants of the C-terminal region of MSP1 (MSP1(19)) were assessed. Results showed that all individuals produced antibodies to AMA1, MSA2, and MSP1-190L; however, a proportion of individuals never produced antibodies to the MSP1(19) variants, although the percentage of nonresponders decreased with age. The influence of age and human leukocyte antigen (HLA)-DRB1/DQB1 alleles on antibody levels was evaluated using two-way analysis of variance. Age was correlated with levels of antibodies to AMA1 and MSP1(19) but not with levels of antibodies to MSA2 and MSP1-190L. No association was found between a single HLA allele and levels of antibodies to MSA2, MSP1-190L, or any of the MSP1(19) variants. However, individuals positive for DRB1*1201 had higher levels of antibodies to the variant of recombinant AMA1 tested than did individuals of all other HLA types. Since the effect was seen across all age groups, HLA influenced the level but not the rate of antibody acquisition. This association for AMA1, combined with the previously reported association between HLA class II alleles and levels of antibodies to rhoptry-associated protein 1 (RAP1) and RAP2, indicates that HLA influences the levels of antibodies to three of the five vaccine candidate antigens that we have evaluated.

Antibodies that inhibit binding of Plasmodium falciparum-infected erythrocytes to chondroitin sulfate A and to the C terminus of merozoite surface protein 1 correlate with reduced placental malaria in Cameroonian women.

Plasmodium falciparum-infected erythrocytes often sequester in the placenta of pregnant women, producing placental malaria, a condition that can compromise the health of the developing fetus. Scientists are hopeful that a vaccine can be developed to prevent this condition. Immunological mechanisms responsible for eliminating parasites from the placenta remain unclear, but antibodies to the carboxyl-terminal 19-kDa segment of the merozoite surface protein 1 (MSP1-19), the ring-infected erythrocyte surface antigen (RESA), and an erythrocyte-surface ligand that binds chondroitin sulfate A (CSA-L) have been implicated. In addition, antibodies to sporozoite and liver-stage antigens could reduce initial parasite burdens. This study sought to determine if antibodies to the circumsporozoite protein (CSP), liver-stage antigen 1 (LSA1), RESA, MSP1-19, or CSA-L correlated with either the absence of placental parasites or low placental parasitemias. Using a frequency-matched case-control study design, we compared antibody levels in women (gravidity 1 to 11) with and without placental malaria. Results showed that women who were antibody negative for MSP1-19 were at a higher risk of having placental malaria than women with antibodies (P < 0.007). Furthermore, an association between high levels of antibodies that blocked the binding of infected erythrocytes to CSA and low placental parasitemias was observed (P = 0.02). On the other hand, women with high antibody levels at term to CSP, LSA1, and RESA were more likely to have placental malaria than antibody-negative women. Since antibodies to MSP1-19 and CSA-L were associated with reduced placental malaria, both antigens show promise for inclusion in a vaccine for women of child-bearing age.

Prostaglandin production from arachidonic acid and evidence for a 9,11-endoperoxide prostaglandin H2 reductase in Leishmania.

Lysates of Leishmania promastigotes can metabolise arachidonic acid to prostaglandins. Prostaglandin production was heat sensitive and not inhibited by aspirin or indomethacin. We cloned and sequenced the cDNA of Leishmania major, Leishmania donovani, and Leishmania tropica prostaglandin F(2alpha) synthase, and overexpressed their respective 34-kDa recombinant proteins that catalyse the reduction of 9,11-endoperoxide PGH(2) to PGF(2alpha). Database search and sequence alignment showed that L. major prostaglandin F(2alpha) synthase exhibits 61, 99.3, and 99.3% identity with Trypanosoma brucei, L. donovani, and L. tropica prostaglandin F(2alpha) synthase, respectively. Using polymerase chain reaction amplification, Western blotting, and immunofluorescence, we have demonstrated that prostaglandin F(2alpha) synthase protein and gene are present in Old World and absent in New World Leishmania, and that this protein is localised to the promastigote cytosol.

Congenital exposure to Plasmodium falciparum antigens: prevalence and antigenic specificity of in utero-produced antimalarial immunoglobulin M antibodies.

Congenital Plasmodium falciparum malaria in newborns is uncommon in sub-Saharan Africa. A significant number of infants, however, become infected or exposed to malarial antigens either in utero or at delivery and have the potential to produce antimalarial antibodies and memory cells before their first natural infection. In Yaounde, Cameroon, parasite-specific immunoglobulin M (IgM) was detected in 14% of cord blood samples. The IgM antibodies reacted with a wide range of asexual-stage antigens, with each newborn having its own unique pattern of IgM reactivity. PCR-based detection and genotyping of cord blood parasites found that the prevalence, total number of parasite genotypes, and complexity of infection were higher in newborns who had produced antimalarial IgM than those who had not. Maternal placental malaria and anemia were associated with the production of P. falciparum-specific IgM by the fetus. The effect of early immune priming on acquisition of immunity by infants is unknown and merits further investigation, since a significant proportion of Cameroonian newborns developed a humoral response to malaria before birth.

Prostaglandin production from arachidonic acid and evidence for a 9,11-endoperoxide prostaglandin H2 reductase in Leishmania.

Lysates of Leishmania promastigotes can metabolise arachidonic acid to prostaglandins. Prostaglandin production was heat sensitive and not inhibited by aspirin or indomethacin. We cloned and sequenced the cDNA of Leishmania major, Leishmania donovani, and Leishmania tropica prostaglandin F(2alpha) synthase, and overexpressed their respective 34-kDa recombinant proteins that catalyse the reduction of 9,11-endoperoxide PGH(2) to PGF(2alpha). Database search and sequence alignment alignment showed that L. major prostaglandin F(2alpha) synthase exhibits 61, 99.3, and 99.3% identity with Trypanosoma brucei, L. donovani, and L. tropica prostaglandin F(2alpha) synthase, respectively. Using polymerase chain reaction amplification, Western blotting, and immunofluorescence, we have demonstrated that prostaglandin F(2alpha) synthase protein and gene are present in Old World and absent in New World Leishmania, and that this protein is localised to the promastigote cytosol.