On the relations between focus, experience, and hospital performance.

BACKGROUND: In the United States, a long-standing debate has existed over advantages/disadvantages of general versus specialty hospitals. A recent stream of research has investigated whether general hospitals accrue performance benefits from a focus strategy; a strategy of specializing in certain clinical conditions while remaining a multiproduct firm. In contrast, a substantial and long-standing body of research on hospitals has been concerned with the absolute volume of cases in a service area as an indication of experience based largely on the idea that absolute volume confers learning opportunities. PURPOSE: We investigated whether hospital focus and experience in a service area have complementary effects or are largely substitutive for hospital performance. METHODOLOGY/APPROACH: Key data sources were patient discharge records and hospital discharge profiles from California's Office of Statewide Health Policy and Development for years 2010-2014. We specified hospital focus as the proportion of total cardiology-related discharges and hospital experience as the cumulative volume of cardiology-related discharges for each hospital. Performance was specified using quality (inpatient mortality and 30-day readmission) and efficiency (length of stay and cost) patient-level performance metrics. We analyzed the data using logistic and log-linear ordinary least squares regression models. RESULTS: Study results generally supported our hypotheses that focus and experience are related to better quality and efficiency performance and that the effects are largely substitutive for hospitals. CONCLUSION: Our study extends the literature by finding that hospitals exhibit distinct and stable patterns regarding their positioning on focus and experience and that these patterns have important implications for hospitals' performance in terms of quality and efficiency. PRACTICE IMPLICATIONS: Many general hospitals in the United States may be stretched too thin across service areas for which they lack necessary patient volumes for clinical proficiency. A viable alternative is to select a limited set of service areas on which to focus.

The impact of an epilepsy nurse competency framework on the costs of supporting adults with epilepsy and intellectual disability: findings from the EpAID study.

BACKGROUND: The development of a nurse-led approach to managing epilepsy in adults with an intellectual disability (ID) offers the potential of improved outcomes and lower costs of care. We undertook a cluster randomised trial to assess the impact on costs and outcomes of the provision of ID nurses working to a designated epilepsy nurse competency framework. Here, we report the impact of the intervention on costs. METHOD: Across the United Kingdom, eight sites randomly allocated to the intervention recruited 184 participants and nine sites allocated to treatment as usual recruited 128 participants. Cost and outcome data were collected mainly by telephone interview at baseline and after 6 months. Total costs at 6 months were compared from the perspective of health and social services and society, with adjustments for pre-specified participant and cluster characteristics at baseline including costs. Missing data were imputed using multiple imputation. Uncertainty was quantified by bootstrapping. RESULTS: The intervention was associated with lower per participant costs from a health and social services perspective of -£357 (2014/2015 GBP) (95% confidence interval -£986, £294) and from a societal perspective of -£631 (95% confidence interval -£1473, £181). Results were not sensitive to the exclusion of accommodation costs. CONCLUSIONS: Our findings suggest that the competency framework is unlikely to increase the cost of caring for people with epilepsy and ID and may reduce costs.

Bacterial community structure and response to nitrogen amendments in Lake Shenandoah (VA, USA).

Microbial processes are critical to the function of freshwater ecosystems, yet we still do not fully understand the factors that shape freshwater microbial communities. Furthermore, freshwater ecosystems are particularly susceptible to effects of environmental change, including influx of exogenous nutrients such as nitrogen and phosphorus. To evaluate the impact of nitrogen loading on the microbial community structure of shallow freshwater lakes, water samples collected from Lake Shenandoah (Virginia, USA) were incubated with two concentrations of either ammonium, nitrate, or urea as a nitrogen source. The potential impact of these nitrogen compounds on the bacterial community structure was assessed via 16S rRNA amplicon sequencing. At the phylum level, the dominant taxa in Lake Shenandoah were comprised of Actinobacteria and Proteobacteria, which were not affected by exposure to the various nitrogen treatments. Overall, there was not a significant shift in the diversity of the bacterial community of Lake Shenandoah with the addition of nitrogen sources, indicating this shallow system may be constrained by other environmental factors.

Reversible Triplet Excitation Transfer in a Trimethylene-Linked Thioxanthone and Benzothiophene-2-Carboxanilide that Photochemically Expels Leaving Group Anions.

The triplet excited state of thioxanthone produced by photolysis undergoes reversible triplet energy transfer with a trimethylene-linked benzothiophene-2-carboxanilide ring system. The ensuing electrocyclic ring closure of the anilide moiety produces a putative zwitterionic intermediate that is capable of expelling leaving groups (LG-) from the C-3 position of the benzothiophene ring. Stern-Volmer quenching studies with cyclohexadiene as quencher furnish the rate constants for the triplet excitation transfer in the forward and reverse directions, which can be expressed as an equilibrium constant K = 0.058. Overall, the rate of the triplet excited state reaction becomes K × kr = 5.7 × 104 s-1 for LG- = Cl-, where kr is the triplet decay rate of the C-3 chloro-substituted benzothiophene-2-carboxanilide, found through Stern-Volmer quenching. The high quantum efficiencies found for the trimethylene-linked systems are due to K × kr being competitive with the triplet excited state decay of the thioxanthone of kd = 7.7 × 104 s-1. On the basis of Φisc = 0.68, the overall expected quantum yield for direct photolysis should be 0.50 for LG- = Cl- as compared to 0.41 at 25 °C experimentally. Φ decreases with increasing basicity of the leaving group (LG- = Cl-, (EtO)2PO2-, PhCH2CO2-, PhS-, and PhCH2S-).

Stochastic Model of Supercoiling-Dependent Transcription.

We propose a stochastic model for gene transcription coupled to DNA supercoiling, where we incorporate the experimental observation that polymerases create supercoiling as they unwind the DNA helix and that these enzymes bind more favorably to regions where the genome is unwound. Within this model, we show that when the transcriptionally induced flux of supercoiling increases, there is a sharp crossover from a regime where torsional stresses relax quickly and gene transcription is random, to one where gene expression is highly correlated and tightly regulated by supercoiling. In the latter regime, the model displays transcriptional bursts, waves of supercoiling, and up regulation of divergent or bidirectional genes. It also predicts that topological enzymes which relax twist and writhe should provide a pathway to down regulate transcription.

Seroconversion for cytomegalovirus infection in a cohort of pregnant women in Québec, 2010-2013.

Cytomegalovirus (CMV) is the leading cause of congenital infection and non-genetic sensorineural hearing loss in children. There are no recent data on the incidence of CMV infection during pregnancy in Canada. This present study was undertaken to determine the seroprevalence of CMV IgG antibodies and the rate of seroconversion in a cohort of pregnant women in the province of Québec, Canada. We used serum samples and questionnaire data collected as part of the 3D Pregnancy and Birth Cohort Study (2010-2013) conducted in Québec, Canada. CMV IgG antibodies were determined in serum samples collected at the first and third trimesters. Associations between independent variables and seroprevalence were assessed using logistic regression, and associations with seroconversions, by Poisson regression. Of 1938 pregnant women tested, 40·4% were seropositive for CMV at baseline. Previous CMV infection was associated with: working as a daycare educator, lower education, lower income, having had children, first language other than French or English, and being born outside Canada or the United States. Of the 1122 initially seronegative women, 24 (2·1%) seroconverted between their first and third trimesters. The seroconversion rate was 1·4 [95% confidence interval (CI) 0·9-2·1]/10 000 person-days at risk or 3·9 (95% CI 2·5-5·9)/100 pregnancies (assuming a 280-day gestation). The high proportion of pregnant women susceptible to CMV infection (nearly 60%) and the subsequent rate of seroconversion are of concern.

Hospital employment of physicians and supply chain performance: An empirical investigation.

BACKGROUND: As hospital employment of physicians becomes increasingly common in the United States, much speculation exists as to whether this type of arrangement will promote hospital operating efficiency in such areas as supply chain management. Little empirical research has been conducted to address this question. PURPOSE: The aim of this study was to provide an exploratory assessment of whether hospital employment of physicians is associated with better supply chain performance. Drawing from both agency and stewardship theories, we examined whether hospitals with a higher proportion of employed medical staff members have relatively better supply chain performance based on two performance measures, supply chain expenses and inventory costs. APPROACH: We conducted the study using a pooled, cross-sectional sample of hospitals located in California between 2007 and 2009. Key data sources were hospital annual financial reports from California's Office of Statewide Health Policy and Development and the American Hospital Association annual survey of hospitals. To examine the relationship between physician employment and supply chain performance, we specified physician employment as the proportion of total employed medical staff members as well as the proportion of employed medical staff members within key physician subgroups. We analyzed the data using generalized estimating equations. FINDINGS: Study results generally supported our hypothesis that hospital employment of physicians is associated with better supply chain performance. PRACTICAL IMPLICATIONS: Although the results of our study should be viewed as preliminary, the trend in the United States toward hospital employment of physicians may be a positive development for improved hospital operating efficiency. Hospital managers should also be attentive to training and educational resources that medical staff members may need to strengthen their role in supply chain activities.

Can we see living structure in a cell?

Colloid chemistry (κολλα: glue, or gelatin) was introduced in 1861 after the discovery of protoplasm, which exhibits gelatin-like properties. Some 80 years later, colloid chemistry (and with it, the concept of protoplasm) was largely abandoned. The membrane (pump) theory, according to which cell water and cell solute like K+ are free as in a dilute KC1 solution, became dominant. Later studies revealed that rejecting the protoplasmic approach to cell physiology was not justified. Evidence against the membrane (pump) theory, on the other hand, has stood the test of time. In a new theory of the living cell called the association-induction (AI) hypothesis, the three major components of the living cell (water, proteins and K+) are closely associated; together they exist in a high- (negative)-energy-low entropy state called the living state. The bulk of cell water is adsorbed as polarized multilayers on some fully extended protein chains, and K+ is adsorbed singly on ß- and γ-carboxyl groups carried on aspartic and glutamic residues of cell proteins. Extensive evidence in support of the AI hypothesis is reviewed. From an extension of the basic concepts of the AI hypothesis and the new knowledge on primary structure of the proteins, one begins to understand at long last what distinguishes gelatin from other proteins; in this new light, new definitions of protoplasm and of colloid chemistry have been introduced. With the return of the concept of protoplasm, living structure takes on renewed significance, linking cell anatomy to cell physiology. Finally, evidence is presented showing that electron microscopists have come close to seeing cell structure in its living state.

A 2004 unanswered letter to the Economist magazine requesting a retraction (and apology).

This is a copy of (the bulk of) a letter I mailed on May 13, 2004 to Sir Robert P. Wilson, President, and three editors of the magazine, the Economist. With the letter, I also sent each recipient a copy of my latest book, "Life at the Cell and Below-Cell Level" as a gesture of good will.

COVID-19 as an enabler for enhancing online learning and teaching skills for nurse educators at the University of Namibia: Prospects and challenges.

Background: The coronavirus disease 2019 (COVID-19) pandemic has caused instability in the education system and has compelled higher education institutions (HEIs) to find alternative ways of teaching and learning by making use of the latest online teaching approaches. Aim: The purpose of the study was to explore how COVID-19 could serve as an enabler for the enhancement of online learning and teaching skills for nurse educators at the University of Namibia with specific emphasis on prospects and challenges. Setting: Semi-structured interviews were conducted in English at a public nursing education institution located in the northeast of Namibia. Methods: A qualitative explorative, descriptive and contextual research design was used. Data were collected by means of in-depth semi-structured interviews with 18 nurse educators from the School of Nursing. Data were analysed using thematic analysis. Field notes were simultaneously taken to enrich the data. Results: The study revealed three themes: nurse educators' experiences of the use of online learning and teaching skills, COVID-19 as an enabler for enhancing online learning and teaching skills and strategies to sustain online teaching and learning. Conclusion: Internet technology has generated a surge in demand for web-based teaching and learning. The online learning mode was not effectively utilised during the COVID-19 era because of inadequate technological skills on the part of nurse educators. Contribution: These findings can be used by universities to equip students and academic staff with skills to adapt to e-learning as the new modus operandi in learning and teaching in the post-COVID-19 era.

Truth in basic biomedical science will set future mankind free.

It is self-evident that continued wellbeing and prosperity of our species in time to come depends upon a steady supply of major scientific and technologic innovations. However, major scientific and technical innovations are rare. As a rule, they grow only in the exceptionally fertile minds of men and women, who have fully mastered the underlying basic sciences. To waken their interest in science at an early critical age and to nurture and enhance that interest afterward, good textbooks at all level of education that accurately portray the relevant up-to-date knowledge are vital. As of now, the field of science that offers by far the greatest promise for the future of humanity is the science of life at the most basic cell and below-cell level. Unfortunately, it is precisely this crucial part of the (standardized) biological textbooks for all high schools and colleges in the US and abroad that have become, so to speak, fossilized. As a result, generation after generation of (educated) young men and women have been and are still being force-fed as established scientific truth an obsolete membrane (pump) theory, which has been categorically disproved half a century ago (see Endnote 1.) To reveal this Trojan horse of a theory for what it really is demands the concerted efforts of many courageous individuals especially young biology teachers who take themselves and their career seriously. But even the most courageous and the most resourceful won't find the task easy. To begin with, they would find it hard to access the critical scientific knowledge, with which to convert the skeptic and to rally the friendly. For the wealth of mutually supportive evidence against the membrane (pump) theory are often hidden in inaccessible publications and/or in languages other than English. To overcome this seemingly trivial but in fact formidable obstacle and to reveal the beauty and coherence of the existing but untaught truth, I put together in this small package a collection of the major clenching theoretical and experimental findings. These findings will remove the last trace of uncertainty about the total disproof of the membrane theory. In addition, I have also included an introduction of the association-induction hypothesis, which is the one and only unifying theory of the living cell that has survived and unwaveringly grown more comprehensive and powerful after more than half of a century of worldwide testing.

Complex small-world regulatory networks emerge from the 3D organisation of the human genome.

The discovery that overexpressing one or a few critical transcription factors can switch cell state suggests that gene regulatory networks are relatively simple. In contrast, genome-wide association studies (GWAS) point to complex phenotypes being determined by hundreds of loci that rarely encode transcription factors and which individually have small effects. Here, we use computer simulations and a simple fitting-free polymer model of chromosomes to show that spatial correlations arising from 3D genome organisation naturally lead to stochastic and bursty transcription as well as complex small-world regulatory networks (where the transcriptional activity of each genomic region subtly affects almost all others). These effects require factors to be present at sub-saturating levels; increasing levels dramatically simplifies networks as more transcription units are pressed into use. Consequently, results from GWAS can be reconciled with those involving overexpression. We apply this pan-genomic model to predict patterns of transcriptional activity in whole human chromosomes, and, as an example, the effects of the deletion causing the diGeorge syndrome.

Participation of Multifunctional RNA in Replication, Recombination and Regulation of Endogenous Plant Pararetroviruses (EPRVs).

Pararetroviruses, taxon Caulimoviridae, are typical of retroelements with reverse transcriptase and share a common origin with retroviruses and LTR retrotransposons, presumably dating back 1.6 billion years and illustrating the transition from an RNA to a DNA world. After transcription of the viral genome in the host nucleus, viral DNA synthesis occurs in the cytoplasm on the generated terminally redundant RNA including inter- and intra-molecule recombination steps rather than relying on nuclear DNA replication. RNA recombination events between an ancestral genomic retroelement with exogenous RNA viruses were seminal in pararetrovirus evolution resulting in horizontal transmission and episomal replication. Instead of active integration, pararetroviruses use the host DNA repair machinery to prevail in genomes of angiosperms, gymnosperms and ferns. Pararetrovirus integration - leading to Endogenous ParaRetroViruses, EPRVs - by illegitimate recombination can happen if their sequences instead of homologous host genomic sequences on the sister chromatid (during mitosis) or homologous chromosome (during meiosis) are used as template. Multiple layers of RNA interference exist regulating episomal and chromosomal forms of the pararetrovirus. Pararetroviruses have evolved suppressors against this plant defense in the arms race during co-evolution which can result in deregulation of plant genes. Small RNAs serve as signaling molecules for Transcriptional and Post-Transcriptional Gene Silencing (TGS, PTGS) pathways. Different populations of small RNAs comprising 21-24 nt and 18-30 nt in length have been reported for Citrus, Fritillaria, Musa, Petunia, Solanum and Beta. Recombination and RNA interference are driving forces for evolution and regulation of EPRVs.

Hypoglycaemia in severe malaria, clinical associations and relationship to quinine dosage.

BACKGROUND: Hypoglycaemia is an independent risk factor for death in severe malaria and a recognized adverse treatment effect of parenteral quinine. In 2006 our hospital changed quinine treatment policy from 15 mg/kg loading (plus 10 mg/kg 12-hourly) to 20 mg/kg loading (plus 10 mg/kg 8-hourly) to comply with new WHO guidelines. This presented us with the opportunity to examine whether there was any dose relationship of quinine and hypoglycaemia occurrence. METHODS: Retrospective case notes review of all children admitted to hospital with severe falciparum malaria between April 2002 - July 2009, before and after the introduction of the new WHO quinine regimen. Four-hourly bedside glucose levels were measured until intravenous quinine was discontinued. Clinical events immediately preceding or concurrent with each episode of hypoglycaemia (glucose < = 3.0 mmol/l) were recorded. RESULTS: 954 children received the old quinine regime and 283 received the new regime. We found no evidence of an increased prevalence of hypoglycaemia (< = 3.0 mmol/L) on the new regime compared to former (15% vs. 15%); similar findings were noted for profound hypoglycaemia (< 2.2 mmols/L) 8% v 5%, P = 0.07. Episodes were co-incident with disease severity markers: coma (57%), circulatory failure (38%) and respiratory distress (21%) but less commonly with seizures (10%). Disruption of maintenance fluids and/or blood transfusion concurred with 42% of the hypoglycaemia episodes. Post admission hypoglycaemia increased odds of fatal outcome (24%) compared to euglycaemic counterparts (8%), odds ratio = 3.45 (95% confidence interval = 2.30-5.16) P < 0.01. CONCLUSION: There was no evidence to indicate a dose relationship between quinine and occurrence of hypoglycaemia. Hypoglycaemia concurred with severity features, disruption of glucose infusion and transfusion. Careful glucose monitoring should be targeted to these complications where resources are limited.

Heat recovery ventilators prevent respiratory disorders in Inuit children.

UNLABELLED: Inuit infants have high rates of reported hospitalization for respiratory infection, associated with overcrowding and reduced ventilation. We performed a randomized, double-blind, placebo controlled trial to determine whether home heat recovery ventilators (HRV) would improve ventilation and reduce the risk of respiratory illnesses in young Inuit children. Inuit children under 6 years of age living in several communities in Nunavut, Canada were randomized to receive an active or placebo HRV. We monitored respiratory symptoms, health center encounters, and indoor air quality for 6 months. HRVs were placed in 68 homes, and 51 houses could be analyzed. Subjects had a mean age of 26.8 months. Active HRVs brought indoor carbon dioxide concentrations to within recommended concentrations. Relative humidity was also reduced. Use of HRV, compared with placebo, was associated with a progressive fall in the odds ratio for reported wheeze of 12.3% per week (95%CI 1.9-21.6%, P = 0.022). Rates of reported rhinitis were significantly lower in the HRV group than the placebo group in month 1 (odds ratio 0.20, 95%CI 0.058-0.69, P = 0.011) and in month 4 (odds ratio 0.24, 95%CI 0.054-0.90, P = 0.035). There were no significant reductions in the number of health center encounters, and there were no hospitalizations. Use of HRVs was associated with in improvement in air quality and reductions in reported respiratory symptoms in Inuit children. PRACTICAL IMPLICATIONS: Reduced ventilation is common in the houses of Inuit children in arctic Canada, and is associated with an increased risk of respiratory infection. Installation of HRV brings indoor carbon dioxide concentration, as a marker of adequate ventilation, to within recommended concentrations, although relative humidity is also reduced. Installation of HRV is associated with improvements in indoor air quality, and a reduced risk of wheezing and rhinitis not associated with cold air exposure in young Inuit children. Further research is required to explore traditional Inuit cultural attitudes about air movement in dwellings.

A preliminary report on the survival of fully-hydrated living (cancer) cells to liquid helium exposure.

Fully-hydrated Ehrlich carcinoma ascites cells under the protective action of DMSO fully survived exposure to near-absolute zero temperature provided by liquid helium.

A historically significant study that at once disproves the membrane (pump) theory and confirms that nano-protoplasm is the ultimate physical basis of life--yet so simple and low-cost that it could easily be repeated in many high school biology classrooms worldwide.

In 1889 Abderhalden reported his discovery that there is no (or as shown later, little) sodium ion (Na+) in human red blood cells even though these cells live in a medium rich in Na+. History shows that all major theories of the living cell are built around this basic phenomenon seen in all the living cells that have been carefully examined. One of these theories has been steadily evolving but is yet-to-be widely known. Named the association-induction hypothesis (AIH), it has been presented thus far in four books dated 1962, 1984, 1992 and 2001 respectively. In this theory, the low Na+ in living cells originates from (i) an above-normal molecule-to-molecule interaction among the bulk-phase cell water molecules, in consequence of (ii) their (self-propagating) polarization-orientation by the backbone NHCO groups of (fully-extended) cell protein(s), when (iii) the protein(s) involved is under the control of the electron-withdrawing cardinal adsorbent (EWC), ATP. A mature human red blood cell (rbc) has no nucleus, nor other organelle. 64% of the rbc is water; 35% belongs to a single protein, hemoglobin (Hb). This twofold simplicity allows the concoction of an ultra-simple model (USM) of the red blood cell's cytoplasmic protoplasm, which comprises almost entirely of hemoglobin, water, K+ and ATP. Only in the USM, the ATP has been replaced by an artificial but theoretically authentic EWC, H+ (given as HCl). To test the theory with the aid of the USM, we filled dialysis sacs with a 40% solution of pure (ferri-) hemoglobin followed by incubating the sacs till equilibrium in solutions containing different amounts of HCI (including zero) but a constant (low) concentration of NaCl. We then determined the equilibrium ratio of the Na+ concentration inside the sac over that in the solution outside and refer to this ratio as qNaCl. When no H+ was added, the qNaCl stayed at unity as predicted by the theory. More important (and also predicted by the theory,) when the right amount of H+ had been added, qNaCl fell to the 0.1- 0.3 range found in living red blood (and other) cells. These and other findings presented confirm the AIH's theory of life at the most basic level: in the resting living state, microscopic, or nano-protoplasm, is the ultimate physical basis of life. (See Post Script on page 111.)

[Intravesical salpingiosis: case report and review of the literature]. / Intravesikale Salpingiose ­ Fallbericht und Literaturüberblick.

Endosalpingiosis of the urinary bladder is a rare benign condition characterised by the presence of ectopic endosalpingeal tissue in the bladder. If histology shows two or more Müllerian-derived components, this condition is referred to as Müllerianosis.To our knowledge less than 20 cases of Müllerianosis and 5 cases of endosalpingiosis have been documented in the literature.Although the pathogenesis remains unclear, two theories exist. The implantation theory assumes that Müllerian-derived tissue gets implanted in the wall of the urinary bladder during pelvic surgery. The second theory proposes a metaplastic origin of the disease.Patients suffering from endosalpingiosis or Müllerianosis may present with symptoms such as suprapubic pain, frequent urination, dysuria or gross haematuria, possibly with a cyclical appearance.We present the case of a 40-year-old female patient, who primarily presented with painful haematuria and was diagnosed with endosalpingiosis and treated by transurethral resection. Also we review the current literature.

Effect of Seminar on Compassion on student self-compassion, mindfulness and well-being: A randomized controlled trial.

OBJECTIVE: Mindfulness-based interventions have been shown to have psychological benefits in college students. We explored the effects of an academic Seminar on Compassion on student psychological health. PARTICIPANTS: Forty-one participants (14 male, 27 female, mean age 19.8 ± 1.4 years) were assessed pre- and post- spring semesters 2013 and 2014. METHODS: Students were randomized to the Seminar on Compassion or a wait-list control group. Participants completed self-report measures on anxiety, depression, perceived stress, self-compassion, compassion and mindfulness. Salivary alpha-amylase was also assessed. RESULTS: At baseline, self-compassion and mindfulness were negatively correlated with depression, anxiety, and perceived stress. There were significant changes between the intervention and control group from Time 1 to Time 2 in mindfulness, self-compassion, compassion, and salivary alpha-amylase; however, there were no significant changes in depression, anxiety, and perceived stress. CONCLUSIONS: The course was effective in increasing mindfulness, self-compassion and compassion, and decreasing a salivary marker of stress.

Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer. We sought to evaluate the tolerability and pharmacokinetics (PK) of weekly doses of DN-101 in patients with advanced cancer. METHODS: Patients who completed a previously reported single dose escalation study of DN-101 [Beer et al. (2005) Clin Cancer Res 11:7794-7799] were eligible for this continuation weekly dosing study. Cohorts of 3-10 patients were treated at doses of 15, 30, 45, 60, and 75 microg calcitriol. Once 45 microg was established as the maximum tolerated dose (MTD), this cohort was expanded to include 18 patients. Dose limiting toxicity (DLT) was defined as > or =grade 2 hypercalcemia or > or =grade 3 persistent treatment-related toxicities. RESULTS: Thirty-seven patients were recruited. DLT of transient reversible grade 2 hypercalcemia (serum calcium of 11.6-12.5 mg/dL) occurred in two of six patients treated with 60 microg of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 microg. Overall, DN-101 was well tolerated. The most frequent adverse events were fatigue (27%), hypercalcemia (19%, including five grade 1, two grade 2, and no grade 3 or 4 events), and grade 1 nausea (16%). PK parameters following repeat dosing were comparable to those for the initial dose (n = 4). CONCLUSION: The MTD for weekly DN-101 was established as 45 mug. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 microg weekly. Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.