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PubMed2026

Select Contemporary Statistical Concepts in Heart Failure Clinical Trials: Insights From the Heart Failure Collaboratory.

Evolving statistical concepts and innovative trial designs for heart failure (HF) clinical trials seek to improve the conduct, efficiency, and likelihood of meaningful evidence generation crucial for advancing therapeutic development and optimizing patient care. HF trials with conventional statistical frameworks often require large sample sizes, long follow-up times, and high cost to generate sufficient evidence. Novel statistical methodologies would be of interest if they could address these issues while retaining or enhancing the clinical relevance and reliability of results. The HFC (Heart Failure Collaboratory), comprising clinical investigators, clinicians, statisticians, patients, government representatives, payors, and industry collaborators, leads efforts to improve HF research methodologies. HFC discussions have included statistical concepts such as the estimand framework, HR drift, and analytic methods, including the win ratio and restricted mean survival time, that have not been used frequently in HF trials. The estimand framework encourages precise definition and alignment of trial objectives with trial design. The win ratio method attempts to incorporate and prioritize multiple clinically meaningful outcomes by using a hierarchy of clinical importance. The restricted mean survival time provides an alternative to the HR as a measure of therapeutic effect by quantifying the mean time gained or lost during a fixed time after randomization. This paper provides a critical review of some evolving HF trial design methodologies and statistical concepts for the HF community as discussed within the HFC. Our goal is to foster collaboration among diverse stakeholders and advance the development of effective treatments and improve patient care outcomes.

Heart Failure↗

PubMed2026

Matching-adjusted indirect comparison of fruquintinib versus ramucirumab in advanced gastric or gastroesophageal junction adenocarcinoma.

Aim: Fruquintinib (Fruq), a selective VEGFR 1/2/3 inhibitor, showed a significant progression-free survival (PFS) benefit in the Phase III FRUTIGA trial for advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Ramucirumab (RAM), an anti-VEGFR2 antibody, demonstrated efficacy in the RAINBOW-Asia trial. This anchored matching-adjusted indirect comparison (MAIC) evaluated Fruq plus paclitaxel versus RAM plus paclitaxel as second-line therapy for G/GEJ adenocarcinoma in the absence of head-to-head trials. Materials & methods: Data from individual patients in the FRUTIGA study (N = 703) and aggregated data from the RAINBOW-Asia study (N = 440) were analyzed. Baseline characteristics were balanced using entropy balancing. The placebo plus paclitaxel (PBO + PTX) groups served as the common comparators. The primary outcome was PFS; secondary outcomes included overall survival, objective response rate (ORR) and disease control rate (DCR). Rates of treatment-emergent adverse events (TEAEs) were also compared as an exploratory outcome using an adjusted indirect risk difference. Sensitivity analyses included restricted mean survival time and simulated treatment comparison. Results: After weighting (effective sample size = 564), baseline covariates were balanced. The anchored MAIC demonstrated that Fruq + PTX significantly improved PFS compared with RAM + PTX (HR: 0.70; 95% CI: 0.51-0.96; p = 0.0280), corresponding to a 30% reduction in progression risk, with a significant restricted mean survival time benefit of 1.18 months at 20 months (95% CI: 0.08-2.27; p = 0.024). Fruq achieved significantly higher ORR (OR: 1.76, 95% CI: 1.16-2.68; p = 0.008) and DCR (OR: 1.94, 95% CI: 1.33-2.83; p < 0.001). Overall survival was similar (0.97; 95% CI: 0.73-1.30; p = 0.8640). Subgroup analyses showed PFS benefits with Fruq in patients with ECOG PS 1, peritoneal metastases and two or fewer metastatic sites. In sensitivity analysis, the simulated treatment comparison also suggested a PFS benefit for Fruq + PTX (HR: 0.40, 95% CI: 0.32-0.50; p < 0.0001). For any-grade TEAEs, the indirect comparison showed higher adjusted relative incidences of increased bilirubin with Fruq + PTX than with RAM + PTX (RD: 12.3%; 95% CI: 2.3-22.4%, p < 0.05) and of hypokalemia (RD: 9.0%; 95% CI: 1.5-16.4%, p < 0.05). For grade ≥3 TEAEs, the adjusted relative incidence of decreased body weight was higher with Fruq + PTX than with RAM + PTX (RD: 2.9%; 95% CI: 0.6-5.2%, p < 0.05). The adjusted relative incidences of increased AST, ALT and hypocalcemia were numerically lower in the fruquintinib group than in the RAM group. Conclusion: This MAIC indicates that Fruq + PTX may be more effective than RAM + PTX in second-line advanced G/GEJ adenocarcinoma, with potentially improved PFS, ORR and DCR, and similar overall survival. Safety analyses suggested generally comparable safety profiles across the two regimens. Fruq + PTX remains a valuable treatment option, offering important comparative evidence for clinical and health technology assessment decisions. Trial Registration: Clinicaltrials.gov identifiers: NCT07144995.

Adult↗

PubMed2026

Pembrolizumab-Chemotherapy Versus Pembrolizumab in Head and Neck Squamous Cell Carcinoma: A PD-L1 CPS-Stratified Analysis of Updated KEYNOTE-048 Data.

Based on KEYNOTE-048, pembrolizumab monotherapy and pembrolizumab-chemotherapy are established category 1 first-line treatments for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) with programmed death ligand-1 (PD-L1) combined positive score (CPS) ≥ 1. We compared their efficacy using updated trial data. We analyzed 4-year progression-free survival on next-line therapy (PFS2) and 5-year overall survival (OS) data from KEYNOTE-048 by reconstructing time-to-event data using KMSubtraction. Efficacy was compared in CPS 1-19 and CPS ≥ 20 subgroups using Kaplan-Meier estimates, Cox models, restricted mean survival time (RMST), and landmark analyses. Among 499 patients with CPS ≥ 1, 240 (48.1%) had CPS 1-19 and 259 (51.9%) had CPS ≥ 20. In the CPS 1-19 subgroup, pembrolizumab-chemotherapy showed numerically longer median PFS2 (10.1 vs. 8.0 months; hazard ratio [HR]: 0.81; 95% confidence interval [CI]: 0.62-1.06) and OS (12.8 vs. 10.8 months; HR: 0.87; 95% CI: 0.67-1.15) versus monotherapy, without statistical significance. For CPS ≥ 20 patients, efficacy was comparable between regimens, with similar median PFS2 (11.3 vs. 11.7 months; HR: 0.95) and OS (14.7 vs. 14.9 months; HR: 0.96). RMST and landmark analyses showed an early PFS2 benefit and a trend toward OS benefit with pembrolizumab-chemotherapy in CPS 1-19, with comparable outcomes in CPS ≥ 20. Pembrolizumab-chemotherapy showed a trend toward improved outcomes in the CPS 1-19 subgroup, with comparable efficacy in the CPS ≥ 20 subgroup, supporting a refined first-line strategy: monotherapy for CPS ≥ 20 to minimize toxicity, and combination therapy for CPS 1-19 to potentially enhance disease control.

Humans↗

PubMed2026

Transvalvular Flow Rate is Associated With Mortality Rate and Lifetime Loss in Aortic Valve Stenosis: A Meta-Analysis of Reconstructed Time-to-Event Data.

Low-flow states are associated with adverse outcomes in aortic stenosis (AS), but the prognostic value of transvalvular flow rate (TFR) has not been consistently established across studies. This study is a systematic review and meta-analysis of reconstructed time-to-event data was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses. PubMed/MEDLINE, EMBASE, and Cochrane Library were searched for studies (published by November 14, 2025) comparing low versus normal TFR in AS. Data were collected from Kaplan-Meier curves. The primary endpoint was all-cause mortality. Survival was assessed using pooled Kaplan-Meier curves, Cox regression, flexible parametric survival models, and restricted mean survival time (RMST) analysis. A total of 9 studies including 6,494 patients were analyzed; 2,575 (39.7%) had low TFR. At 8 years of follow-up, estimated survival was 34.1% (95% confidence interval [CI] 24.7% to 47%) in the low-TFR group and 63% (95% CI 58.9% to 67.4%) in the normal-TFR group. Low TFR was associated with higher all-cause mortality (hazard ratio 1.59, 95% CI 1.45 to 1.74, p < 0.001). We observed a progressively greater hazard over time, with the hazard ratio approaching 1.9 by 8 years. At 8 years, RMST in the normal-TFR group was 7.37 years (95% CI 7.21 to 7.53 years) versus 5.07 years (95% CI 4.91 to 5.23 years) in the low-TFR group, representing a lifetime loss of 2.3 years in the low-TFR group (ΔRMST -2.30 years, 95% CI -2.53 to -2.07 years, p < 0.001). In patients with AS, low TFR is associated with significantly higher mortality and lifetime loss. These findings support TFR as a clinically meaningful marker for risk stratification in AS.

Aortic Valve Stenosis↗

PubMed2026

Oncotype DX-guided vs physician-directed chemotherapy and survival in HR+/HER2- breast cancer.

BACKGROUND: Oncotype DX testing guides adjuvant chemotherapy decisions in early-stage hormone receptor-positive/HER2-negative breast cancer, but testing is not universally performed, and outcomes associated with genomic-informed versus clinicopathologic-based chemotherapy decision pathways remain unclear. METHODS: Using the 2022 National Cancer Database Breast Participant User File, we identified women diagnosed from 2010 to 2022 with pathologic T1b-T2, node-negative, hormone receptor-positive/HER2-negative invasive breast cancer who received adjuvant chemotherapy and endocrine therapy. Patients were classified into an Oncotype-guided group, defined by Oncotype DX testing with a recurrence score of 26 or higher, and a physician-directed group, defined by receipt of chemotherapy without genomic testing. The primary outcome was overall survival. Analyses used multivariable Cox models, logistic-IPTW and MLP-IPTW, restricted mean survival time analysis, and a Bayesian latent confounding survival model. RESULTS: Among 56,625 women, 27,278 were in the Oncotype-guided group and 29,347 in the physician-directed group. Median ages were 59 and 56 years, respectively. The Oncotype-guided group had more favorable overall survival than the physician-directed group in multivariable Cox analysis (HR, 0.906; 95% CI, 0.856-0.959; P < 0.001), with similar findings in IPTW analyses. The association was concentrated among patients aged 56 years or older (HR, 0.866; 95% CI, 0.809-0.927; P < 0.001). The Bayesian model showed no strong residual confounding signal. CONCLUSIONS: Among chemotherapy-treated women, an Oncotype-guided pathway was associated with more favorable overall survival than a physician-directed pathway, particularly among older patients, which indicating prognostic heterogeneity selected using genomic versus conventional clinicopathologic information.

Humans↗

PubMed2026

The combined impact of HLA and non-HLA mismatch between donors and recipients on kidney transplant survival: a genomic analysis in a prospective cohort.

BACKGROUND: Kidney transplantation outcomes are strongly influenced by immunological compatibility between donor and recipient. While genetic mismatches in the human leukocyte antigen (HLA) region have long been recognised as key determinants of graft survival, increasing evidence, including our own previous work, suggests that non-HLA alloimmunity also plays a critical role. METHODS: We sequenced exomes of deceased kidney donor and recipient pairs in the prospective kidney transplant cohort at the Vienna General Hospital, recruited between January 1, 2012, and June 15, 2023. Out of 1209 pairs, 1187 passed quality control for analysis. Non-HLA mismatch was computed by considering non-synonymous single nucleotide polymorphisms specifically encoding trans-cell membrane or secreted proteins in the kidney (nsSNP-tcmsk). Using adjusted Cox proportional hazards models, we replicated results from our earlier work in recipients with primary graft function after 90 days, and extended the analysis to the combination of nsSNP-tcmsk with eplet mismatch to assess their associations with graft loss in the full cohort. FINDINGS: Of 20,421 human proteins, 2371 were considered for the nsSNP-tcmsk score. In our replication analysis we estimated for nsSNP-tcmsk a hazard ratio (HR) of 1.33 (95% CI 1.02-1.74) for graft loss per increase of one interquartile range. The nsSNP-tcmsk and eplet mismatch were uncorrelated (Spearman correlation coefficient 0.02, p = 0.47). A composite score of nsSNP-tcmsk and eplet mismatch was associated with graft loss with a HR of 1.76 (95% CI 1.20-2.57) corresponding to an absolute difference in 7-year restricted mean survival time between the first and fourth quartiles of 0.52 years (95% CI 0.16-0.87 years). INTERPRETATION: The impact of non-HLA donor-recipient mismatch on transplant loss is of the same magnitude as established mismatch scores in the HLA region. Together, these scores may be further validated as guiding markers for the required strength of maintenance immunosuppression. FUNDING: Vienna Science and Technology Fund, NIH/NIAID.

Humans↗

PubMed2026

Long-Term Cardiovascular Impact of Postpartum Treatment After Hypertensive Disorders of Pregnancy: Population-Based Cohort Study.

OBJECTIVE: To assess whether early antihypertensive treatment after Hypertensive Disorders of Pregnancy (HDP) influences subsequent development of cardiovascular complications. DESIGN AND SETTING: Population-based nationwide cohort of health data set in France. POPULATION: 108 906 women with HDP (excluding pre-existing Chronic Hypertension (CH)) who delivered between 2010 and 2014, with 35 878 (33%) receiving at least one antihypertensive treatment in the month after giving birth. METHODS: Traditional Cox model, estimated 10-year cardiovascular risk. Extended Cox Step Function model and Restricted Mean Survival Time evaluated time trends. MAIN OUTCOME MEASURES: New-onset CH, heart failure, coronary, cerebrovascular, peripheral artery diseases and 2 composite events (one including CH, the other excluding it) over 10 years following giving birth. RESULTS: Women receiving early postnatal antihypertensive treatment had a higher long-term risk of complications over 10 years than non-treated women (CH: aHR = 3.067, 95% CI [2.996-3.139]; composite event including CH: aHR = 3.025 [2.956-3.096]; composite event excluding CH: aHR = 1.451 [1.305-1.614]). Treated women had events earlier than non-treated women, presenting a higher risk at the beginning of the postpartum period. The 10-year absolute risk for CH remained high in both groups: 44% for treated women and 18% for non-treated women. CONCLUSION: Our study shows that women receiving early postpartum antihypertensive treatment are at higher long-term cardiovascular risk, with 44% of them having CH within 10 years. Besides, approximately 1 in 5 women non-treated in the postpartum period subsequently developed CH, demonstrating that many high-risk women are not being identified in the peripartum period and may be missing opportunities for timely intervention.

Humans↗

PubMed2026

Commensal Dysbiosis Alters Primary Bile Acid Signaling to Drive Mammary Gland Inflammation and Breast Tumor Dissemination.

UNLABELLED: Breast cancer is the most commonly diagnosed malignancy and a leading cause of cancer-related mortality. Hormone receptor-positive (HR+) tumors represent the most prevalent metastatic subtype, and early dissemination remains a major clinical challenge. Commensal dysbiosis, defined as an inflammatory gut microbiome with low biodiversity, promotes metastasis by inducing mammary gland inflammation. In this study, we investigated systemic mechanisms governing dysbiosis-induced metastasis. Metabolomic profiling revealed elevated primary bile acids (BA) in the dysbiotic fecal microbiome. Sequestration and supplementation approaches demonstrated that beyond driving metabolic disease and mammary gland inflammation, primary BAs orchestrated enhanced HR+ tumor dissemination via a prostaglandin E2 (PGE2)-dependent pathway. Analysis of The Cancer Genome Atlas showed that BA, insulin resistance, and PGE2 gene signatures are associated with reduced survival in patients with HR+ tumors. In complementary analyses using the Epic Cosmos electronic health record database, BA sequestrant use was associated with longer restricted mean survival time among patients with metastatic disease. Together, these findings reveal that commensal dysbiosis-associated loss of microbial BA metabolism elevates primary BAs and promotes HR+ metastatic progression through PGE2 signaling. SIGNIFICANCE: Dysbiosis-induced bile acids drive systemic and mammary tissue-specific inflammation that promotes HR+ breast tumor metastasis, supporting the development of strategies targeting microbiome-derived metabolites to reduce metastatic risk in vulnerable populations.

Female↗

PubMed1979

Late right heart reconstruction following repair of tetralogy of Fallot.

Twenty-two symptomatic patients underwent a total of 28 reoperative procedures after initial surgical repair of tetralogy of Fallot. Sixteen of the patients were considered to have unfavorable anatomy of the right ventricular outflow tract (RVOT) or pulmonary artery at the time of initial repair. Pulmonary or tricuspid valve replacement, or replacement of both valves, utilizing a xenograft bioprosthesis was performed in 1 of the 22 initial repairs, 7 of the 22 first reoperations, and 5 of the 6 second reoperations. Ultimately, 14 patients received transannular RVOT patches. The interval between the first and second reoperations for 6 patients who required 2 late reconstructive procedures was 5.8 years. No operative deaths occurred. There were 2 late deaths (1 sudden and 1 due to aspiration). Actuarial survival probability (+/- standard error of the mean) 16 years after initial repair was 72 +/- 21%. Eighteen of the 20 current survivors in the present series are completely asymptomatic without physical restrictions; the other 2 are considered to be in New York Heart Association Functional Class II. No xenograft bioprosthetic dysfunction has occurred to date, but cumulative valve follow-up is limited (13 patient-years). In selected patients, earlier pulmonary or tricuspid valve replacement or replacement of both of these valves can provide some degree of protection against recurrent deterioration.

Adolescent↗

PubMed1977

On the classification of penis carcinoma and its 10-year survival.

With respect to the primary tumor there is no difference between the proposal of the UICC and the Heidelberg version for TNM classification of the penis carcinoma. Clinically the Heidelberg scheme seems more practical, but there were no statistical differences between them. With respect to the prognosis for the patient, the size and localization of the primary tumor are of secondary importance. What is important is the degree of tumor spreading in the lymph system. From this point of view, one needs only to differentiate between T1 (tumor restricted to the penis) and T2 (tumor extending the bounds of the penis). On the other hand, size, localization, and degree of infiltration of penis carcinoma do have different therapeutic consequences, so from this point of view the differentiation of the primary tumor from T1 up to T4 should be retained. With respect to the classification of the state of the corresponding lymph system it is our opinion that the UICC proposal is too differentiated and has little meaning. In its stead, the Heidelberg scheme is clear and simple. Any examiner can complete it. With the help of life tables extending beyond 10 years after diagnosis we were able to determine that 5 years is not a sufficiently long time to clsoe a case of penis cancer. Even with proper treatment, the patient may suffer up to 10 years or more from the disease. In patients aged between 50 and 59 years of age the cancer seems to grow faster; in spite of proper and intensive treatment those patients had a clearly limited life expectancy. In patients aged 60-69 and more so in those between 70 and 79 years of age the tumor seemed to grow slowly and often had no effect on the survival rate.

Follow-Up Studies↗

PubMed1979

Investigations on the methods of clinical application of a soluble BCG fraction (F70) in lung cancer.

Several parameters for an optimal treatment scheme of a soluble BCG fraction (F70) were investigated. Among lung cancer patients treated with F70 a restricted selection was made of patients treated with small doses (5--10 U) every second or third month (sparing scheme) and of patients treated every month with sharply increasing doses up to tens of thousands units (aggressive scheme). It was found that the survival rate and the rate of marked X-ray regressions were higher in the former group. As it was previously established for lung cancer patients treated with living BCG, in the group of sparing scheme-treated patients the longest survival period pertained to patients treated once and patients treated twice or three times and an inverse correlation existed between the number of applications of F70 and the mean survival period. It was concluded that, as with living BCG, a sparing approach to the immunotherapy of lung cancer with F70 is to be preferred to an aggressive approach. Illustrative cases treated once, twice and three times are presented.

Aged↗

PubMed1978

Characteristics of the 'life spanning' phenomenon in Amoeba proteus. Independent nuclear and cytoplasmic ability to impose finite 'life span'.

Amoeba proteus given adequate food grows exponentially and clones of amoebae are normally immortal. After periods of food supply restriction to that necessary for maintenance, or food intake restriction by agitation, cells subsequently given a normal growth diet produce clones of finite life span. Reciprocal nuclear transfer between maintained and normal cells demonstrated that the nucleus and cytoplasm of maintained cells have acquired the independent ability to impose a finite life span on clones developing from cells whose other components are normal. In clones developing from maintained cells, inviable cell production is enhanced and inter-division times are prolonged. Inter-division times and clones mean doubling times do not show normal distribution.

Amoeba↗

PubMed1977

Long-term tryptophan restriction and aging in the rat.

Growth-retarded rats fed a tryptophan deficient diet at 21 days for periods of 6-22 months were shown to reach normal body weight when subsequently fed Purina Rat Chow. They demonstrated an increased ability over similar aged controls to recover from hypothermia induced by 3-minute whole-body ice water immersion, were able to bear litters at 17--28 months of age, showed a delay in the age of onset of visible tumors, and indicated an increase in their average lifespan at late ages. Animals fed on this diet from 3 months of age revealed a similar ability to reproduce at advanced ages, but not as marked as those placed on the diet earlier. The average lifespan (in months +/- the standard error of the mean) of the rats recovering from the long-term tryptophan-deficient diets was 36.31 +/- 2.26 while the control rats survived an average of 30.5 +/- 1.90 months. The last of 8 rats surviving the period of tryptophan-deficiency died at 45.50 months (1387 days) while the last of 14 control rats died at 41.75 months (1266 days). It is hypothesized that some kind of subtle mechanism exerts its influence on the rats during the period of tryptophan deficiency which caused an accelerated morbidity and mortality as they approached senescence approximately 1 to 2 years after refeeding. This is parallel to the situation with immature animals subjected to long-term caloric restriction and then fed on normal diets.

Aging↗

PubMedDate not supplied

[Prolonged survival with weekly peritoneal dialysis in chronic uremic patients].

We show our experience in 12 patients treated during a year with weekly intermittent dialysis whit a rigid catheter for 36 hours a week. Patients were on a diet of 50 g. of proteins a day, normocaloric without sodium or fluid restriction. They received supplementation whith iron, calcium, vitamins B, C and folic acid, anabolic hormonal and, in some cases, furosemide hypotensives and antibiotics. Patients received the procedure for a mean of 8 months. The results show the following mean values: blood pressure: 143 +/- 12/99 +/- 3 mm. Hg., plasma urea 208 +/- 62 ng./dl.; creatinine 21 +/- 2 mg./dl., hematocrit 25 mm. and 8.0 g. hemoglobin. There was light increase of glucose, K, P, Mg, alkaline phosphatase. Na, CO2, proteins cholesterol, albumin and Ca keep in normal values. Nine patients passed to hemodialysis after a mean period of nine months and three of them received a kidney transplant. Three are still in peritoneal dialysis, one of them for 18 months. We compared our results with a similar group of patients who were treated with non-regular peritoneal dialysis. Our group had less cardiovascular complaints, or infections and keep more adequate body weight, and also got more survival in better conditions with less days in hospital, they received less blood transfusion. We concluded that weekly peritoneal dialysis is an alternative method of treatment in uremic patients for longer period of time even though frequently paracentesis.

Adult↗

PubMed1977

[Physical and mental development after early surgery of myeloceles].

These investigations are based on 143 myelocele operations (=93 % spina bifida cystica), with a follow-up period of 3-15 years. There was an associated hydrocephalus in 88%. In 114 (89%) of the children with hydrocephalus a ventriculo-atrial shunt was inserted. In three quarters of the cases this was done within the first three months of life. In general the chindren remained "shunt-dependent" and only in 9% was it possible to remove it later. Of the surviving children about 25% were restricted to a wheel-chair and of them 7% had severe mental defects. Their physical state as regards head growth,height and weight showed about 70% of average values. Neurogenic disturbances of bladder emptying were present in 90% of the children. The expectation of survival to age 13 was 65%. Using the Hamburg Wechsler Intelligence Test for Children (Hawik) the intellectual development showed an average of 97 +/- 15-219 With only a trifling deviation this corresponds to the normal mean. The Bühler-Hetzer test also showed normal values in 70%. All the children are able to receive some training, which ranged from special schools right up to grammar school. We have particularly gone into the problem of the social rehabilitation of these children.

Adolescent↗

PubMed1975

Temperature-sensitive cell-lethal mutants of drosophila: isolation and characterization.

One hundred and twenty-one sensitive (ts) sex-linked lethals were screened by means of X-ray-induced somatic crossing over to determine if any were ts cell-lethal mutants. Cell-lethal mutations were identified by their ability to block the development of homozygous clones when raised under restrictive conditions (29degrees). Twenty-two ts cell-lethal mutants were isolated and categorized into three classes, depending upon the patterns of damage observed in larval and imaginal tissues. The phenotypes produced by these mutations ranged from those which affected only a limited set of structures (i.e., genital discs only) to those which affected diverse tissues at all stages of the life cycle. Each mutation has its own characteristic time-dependent pattern, frequency, and type of damage. All the mutations affect imaginal tissue, but only one-third of the mutations affect both larval and imaginal tissue. The fastest-acting lethals need 15 hours at the restrictive temperature to kill the cells and the slowest-acting lethals require at least 48 hours. By choosing the appropriate mutant and by manipulating the times of exposure to the restrictive temperature, it has proven possible to produce duplications and deficiencies in specific structures of the adult. A mechanism by which lethality might yield such structures is suggested. In addition, 15 of the mutants are ts female sterile mutants. Only one of these 15 mutants can recover its fertility when shifted back down to the permissive temperature (22degrees).

Animals↗

PubMed1978

Hemodynamic effects of dopamine in patients with resistant congestive heart failure.

Twelve patients with clinical and hemodynamic evidence of severe congestive heart failure, unresponsive to the usual therapy of salt restriction, oxygen, bed rest, digitalis, and massive doses of diuretics, were studied during a control period and after intravenous dopamine. Seven patients survived and 5 died with intractable failure and shock despite transiently improved hemodynamic indices. At control period and after optimal dose of dopamine, there were no significant changes in heart rate (HR) and mean systemic arterial pressure. The mean pulmonary artery (PA) and pulmonary capillary wedge (PCW) pressures decreased slightly. Cardiac index (CI), stroke volume (SVI), and stroke work indices (SWI) rose (p less than 0.005) from the control values of 1.4 +/- 0.1, 15.3 +/- 5, and 13.6 +/- 1.7 to 2.2 +/- 0.1, 24.1 +/- 4, and 24 +/- 2.3, respectively; pulmonary arteriolar (PAR), total pulmonary vascular (TPVR), and systemic vascular (SVR) resistances fell (p less than 0.01). Urine output increased from 13.5 ml/hr before to 58.2 ml/hr after dopamine (p less than 0.005). After 24 and 48 hr of dopamine, in addition to the above hemodynamic changes, PA pressure fell from 38 +/- 4 to 33 +/- 3 and 28 +/- 2, and PCW from 30 +/- 2 to 24 +/- 3 and 18 +/- 3 (p less than 0.05). Compared with nonsurvivors, survivors had significant decreases in PA and PCW pressures, PAR, and TPVR and an increase in SWI. These data indicate that dopamine is effective in some patients with refractive congestive heart failure associated with acute oliguric renal failure and that the prognosis may be improved.

Aged↗