[Bed capacity management in times of the COVID-19 pandemic : A simulation-based prognosis of normal and intensive care beds using the descriptive data of the University Hospital Augsburg]. / Bettenkapazitätssteuerung in Zeiten der COVID-19-Pandemie : Eine simulationsbasierte Prognose der Normal- und Intensivstationsbetten anhand der deskriptiven Daten des Universitätsklinikums Augsburg.

BACKGROUND: Following the regional outbreak in China, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread all over the world, presenting the healthcare systems with huge challenges worldwide. In Germany the coronavirus diseases 2019 (COVID-19) pandemic has resulted in a slowly growing demand for health care with a sudden occurrence of regional hotspots. This leads to an unpredictable situation for many hospitals, leaving the question of how many bed resources are needed to cope with the surge of COVID-19 patients. OBJECTIVE: In this study we created a simulation-based prognostic tool that provides the management of the University Hospital of Augsburg and the civil protection services with the necessary information to plan and guide the disaster response to the ongoing pandemic. Especially the number of beds needed on isolation wards and intensive care units (ICU) are the biggest concerns. The focus should lie not only on the confirmed cases as the patients with suspected COVID-19 are in need of the same resources. MATERIAL AND METHODS: For the input we used the latest information provided by governmental institutions about the spreading of the disease, with a special focus on the growth rate of the cumulative number of cases. Due to the dynamics of the current situation, these data can be highly variable. To minimize the influence of this variance, we designed distribution functions for the parameters growth rate, length of stay in hospital and the proportion of infected people who need to be hospitalized in our area of responsibility. Using this input, we started a Monte Carlo simulation with 10,000 runs to predict the range of the number of hospital beds needed within the coming days and compared it with the available resources. RESULTS: Since 2 February 2020 a total of 306 patients were treated with suspected or confirmed COVID-19 at this university hospital. Of these 84 needed treatment on the ICU. With the help of several simulation-based forecasts, the required ICU and normal bed capacity at Augsburg University Hospital and the Augsburg ambulance service in the period from 28 March 2020 to 8 June 2020 could be predicted with a high degree of reliability. Simulations that were run before the impact of the restrictions in daily life showed that we would have run out of ICU bed capacity within approximately 1 month. CONCLUSION: Our simulation-based prognosis of the health care capacities needed helps the management of the hospital and the civil protection service to make reasonable decisions and adapt the disaster response to the realistic needs. At the same time the forecasts create the possibility to plan the strategic response days and weeks in advance. The tool presented in this study is, as far as we know, the only one accounting not only for confirmed COVID-19 cases but also for suspected COVID-19 patients. Additionally, the few input parameters used are easy to access and can be easily adapted to other healthcare systems.

Early manifestations of disseminated Mycobacterium avium complex disease: a prospective evaluation.

A nested case-control study was conducted in two trials of prophylaxis for Mycobacterium avium complex (MAC) infection to describe the specific signs, symptoms, and laboratory abnormalities of MAC disease in AIDS. Patients had < or =200/mm3 CD4 cells and a prior AIDS-defining illness. Of 571 patients, 102 (17.9%) developed MAC bacteremia during a mean follow-up of 256 days. Among cases of MAC disease, 90 were compared with 180 matched controls. Patients with MAC disease were more likely than controls to have lower weights (66.3 vs. 71.1 kg, P = .001) and Karnofsky scores (74.3 vs. 84.4, P < .001); a higher proportion had fever (48% vs. 26%, P = .003), abdominal pain (23% vs. 13%, P =.05), decreased hemoglobin levels (10.9 vs. 12.1 g/dL, P < .001), and elevated alkaline phosphatase (203 vs. 138 U/L, P=.04) and lactate dehydrogenase (334 vs. 280 U/L, P = .02) levels. Characteristics of MAC disease that occurred before bacteremia were weight loss (3 months prior), fever (2 months), and anemia and elevated lactate dehydrogenase (1 month). These data suggest that patients have symptomatic MAC disease for several months prior to the occurrence of bacteremia.

Geographic and seasonal variation in Mycobacterium avium bacteremia among North American patients with AIDS.

Analysis of geographic risk was performed for Mycobacterium avium complex (MAC) bacteremia among North American patients with AIDS. Monthly mycobacterial blood cultures were taken from patients who were placebo recipients in a prospective evaluation of MAC prophylaxis. Of 571 patients, 102 (17.9%) acquired MAC bacteremia during an average follow-up of 256 days. The area with the highest risk for MAC was the South Central region (27.9%; P < 0.02), whereas the area with the lowest risk was Canada (11.3%; P = 0.12). When the southern states were combined and compared with the northern states and Canada, the incidence of MAC bacteremia was higher in the southern states (21.6% versus 14.0%, P < 0.03). Proportional hazards analysis was performed for the difference between the North and South and controlled for baseline CD4 cell count. In this analysis, time to MAC was significantly longer in the North (hazard ratio = 0.587, 95% confidence interval 0.390 to 0.883, P = 0.01). Although overall variation in seasonality was not marked, there was a significant decrease in cases in the North during the summer months (P < 0.01). We conclude that geographic location is a risk factor for MAC bacteremia in patients with advanced AIDS, with decreased risk in northern North America.

Treatment of prolactin-secreting macroadenomas with the once-weekly dopamine agonist cabergoline.

Dopamine agonist administration is the primary therapy for macroprolactinomas, but bromocriptine is the only agent approved in the United States. Its use is limited by a high incidence of side effects, a short duration of action, and a lack of effectiveness in some patients. Cabergoline is a long-acting dopamine agonist specific for the D2 receptor that is more effective and better tolerated than bromocriptine in women with microadenomas or idiopathic hyperprolactinemia. However, experience with cabergoline in the treatment of patients with macroadenomas is limited. We report the first study of chronic administration of cabergoline conducted exclusively in patients with macroprolactinomas. Fifteen patients (8 women, 7 men) ages 18-76 yr were studied in an open-label 48-week dose escalation trial of cabergoline administered once per week. Eleven patients had received prior therapy with other dopamine agonists. Mean prolactin (PRL) levels decreased by 93.6%, and normal levels were attained in 73% of patients at doses of 0.5-3.0 mg per week. Three of five patients who had failed to normalize PRL on prior dopamine agonists achieved normal levels. Gonadal function was restored in all hypogonadal men and in 75% of premenopausal women with amenorrhea. Tumor size decreased in 11 of the 15 patients. Side effects were minimal. Of the 5 patients who had experienced side effects in prior dopamine agonists, 4 had none on cabergoline, and the fifth had milder symptoms. During two further years of follow up, the improvement in PRL levels, gonadal function, and tumor size has persisted during cabergoline administration, and three patients have experienced a further decline in PRL and/or tumor size. This study demonstrates the effectiveness and minimal side effects of once-weekly cabergoline for treatment of macroprolactinomas.

Worsening bone scan in the evaluation of antitumor response during hormonal therapy of breast cancer.

PURPOSE: Scintigraphic flare in association with response to therapy has been well described in the medical literature. During the course of a recent breast cancer trial, it became apparent that several patients with worsening bone scan but no other clinical evidence of disease progression might have potentially benefited from continued therapy, but had therapy discontinued. A retrospective analysis of this issue was performed to assess the magnitude and scope of this problem. MATERIALS AND METHODS: A total of 648 patients with hormone receptor-positive or unknown advanced breast cancer were treated as part of a large-scale trial of first-line hormonal therapy. Patients were assessed for response to therapy, including response duration, progression-free interval (PFI), overall survival, and quality of life. The retrospective analysis presented here was performed to assess whether patients with a possible scintigraphic flare within the first 16 weeks of therapy might have had therapy discontinued prematurely due to a worsening bone scan attributable to tumor flare, rather than due to disease progression. RESULTS: Analysis of the hormonal trial showed that of 376 assessable patients 108 (29%) with bone disease had a possible scintigraphic flare by week 8 or 16 of the trial, based on data on the case report forms and radiology reports (bone scans and x-rays). Of these, 69 patients (64%) were continued on study therapy, which resulted in clinical benefit in 50 (72%) of those patients. In contrast, 39 patients (36%) with possible scintigraphic flare were removed from the trial. CONCLUSION: We conclude that changes in bone scintigraphy that mimic progressive disease early in the course of hormonal treatment of patients with breast cancer metastatic to bone may represent scintigraphic flare associated with response. Thus, clinicians must be cognizant of the phenomenon of scintigraphic flare to avoid premature discontinuation of a potentially beneficial treatment.

Multicenter study of cabergoline, a long-acting dopamine receptor agonist, in Parkinson's disease patients with fluctuating responses to levodopa/carbidopa.

We administered cabergoline, a potent, once-a-day dopamine against, to 61 patients with advanced Parkinson's disease (PD) and response fluctuations--"wearing-off" and "on-off" phenomena. The patients were on stable doses of levodopa/carbidopa. During the first 5 weeks, patients were randomized to allow equal numbers to end titration at each of five daily doses of cabergoline from 0.5 to 2.5 mg. We evaluated the patients using the Unified Parkinson's Disease Rating Scale (UPDRS) and diaries of motor performance. This part of the study was double-blinded. After 5 weeks, the mean Activities of Daily Living (ADL) score on the UPDRS decreased by 22% (p < 0.0001), the mean Motor Score in the "off" period decreased by 14% (p < 0.0001), and the mean Motor Score in the "on" period decreased by 22% (p < 0.0001). The mean percent "off" time decreased by 9.0%. Twenty-three patients (38%) achieved at least a 25% improvement in the combined ADL and motor examination of the UPDRS. Four patients dropped out because of adverse effects. We treated 37 patients, including some patients who had experienced a transient 25% improvement, for an additional 8 weeks in an open manner until they achieved a 25% improvement or reached a maximum of 5 mg/d. The other patients were continued in a double-blind manner on the dose of cabergoline they had achieved at the end of week 5. At the end of 13 weeks, the group of 37 patients achieved additional significant improvements in mean ADL and mean motor scores in the "on" and "off" periods. The percent time "off" decreased by 31%.(ABSTRACT TRUNCATED AT 250 WORDS)

Multicenter phase II efficacy trial of toremifene in tamoxifen-refractory patients with advanced breast cancer.

PURPOSE: To explore further the efficacy of high-dose toremifene in patients with advanced breast cancer who had failed to respond to tamoxifen or whose disease had progressed on tamoxifen. PATIENTS AND METHODS: One hundred two perimenopausal or postmenopausal women with metastatic breast cancer refractory to tamoxifen were entered onto a phase II clinical trial of toremifene at a dose of 200 mg/d. The study patients consisted of 28 primarily refractory patients; 43 patients who had relapsed after a prior tamoxifen response; and 31 patients who had relapsed while receiving adjuvant tamoxifen. This was a heavily pretreated group of patients, with 65% having failed chemotherapeutic attempts and 72% having failed two or more hormonal therapies. Forty-nine percent of patients had visceral dominant disease. RESULTS: The objective response rate was 5% (95% confidence interval [CI], 3% to 7%). The median time to treatment failure (TTF) was 10.9 months for the five responders. An additional 23% of patients had stable disease for a median TTF of 7.8 months, whereas the patients who experienced treatment failure had a median TTF of 2.1 months. Whether those patients with stable disease derived clinical benefit or simply had slow progression in an intrinsically indolent disease presentation is uncertain. Common toxicities were generally mild and similar to those encountered with tamoxifen. CONCLUSION: We conclude that there is major cross-resistance between tamoxifen and toremifene and that only occasional tamoxifen-refractory patients will have objective responses to toremifene.

Conditional rate derivation in the presence of intervening variables using a Markov chain.

When conducting inferential and epidemiologic studies, researchers are often interested in the distribution of time until the occurrence of some specified event, a form of incidence calculation. Furthermore, this interest often extends to the effects of intervening factors on this distribution. In this paper we impose the assumption that the phenomena being investigated are governed by a stationary Markov chain and review how one may estimate the above distribution. We then introduce and relate two different methods of investigating the effects of intervening factors. In particular, we show how an investigator may evaluate the effect of potential intervention programs. Finally, we demonstrate the proposed methodology using data from a population study.

PIP: In an effort to determine whether a prespecified response occurs more frequently among those persons who exhibit a certain risk, biological and epidemiological investigations often assess the relationship between risk factors (e.g., personal or demographic variables) and response factors (e.g., development of disease). Researchers frequently will investigate more than the initial risk and response; they will consider intervening variables. 2 ways of incorporating intervening variables--as either subsequent or antecedent factors--are investigated in this discussion. Noting that traditional epidemiological approaches to both methods of intervening variable analysis frequently exert an unreasonable large data demand, it is shown how a Markov chain (MC) may be used to significantly reduce the data requirements. It is assumed that the underlying process is a stationary (time homogeneous) MC. Formal analytic definitions of both types (antecedent and subsequent) of intervening variable analyses are presented, and a relationship is derived between them. It is shown how researchers may conduct both analyses, as well as the ordinary (nonintervening variable) analysis, using functions of the MC transition matrix. All analyses demand only sufficient data either to estimate the transition matrix or to modify an existing matrix; none requires the subgroup specific data required by traditional epidemiologic approaches (e.g., direct incidence measures). To illustrate these concepts, a numerical example is presented using a MC from a study of induced abortion. The MC was submitted to formal goodness of fit tests to verify the Markov property (Shachtman et al.). Alternatively, depending on the application the researcher may prefer to employ structural assumption validation, accept the model as a reasonable approximation to the empirical process under study, or "internally" validate the property by examining functions of the transition matrix and seeing if these functions replicate equivalent empirical distribution functions derived directly from the underlying data. Possibly the most important aspect of this approach is that by developing stochastic models, e.g., Markov chain models, and using these conditional rates, researchers may perform intervening variable analyses as parameterizations of the model used in the nonintervening variable analysis. This permits them to circumvent the estimation of independent distributions for each of the subgroups defined by the intervening variables, offering the potential for a large reduction in data requirements.

Effect of an infection surveillance and control program on the accuracy of retrospective chart review.

The primary analyses of the SENIC Project (Study on the Efficacy of Nosocomial Infection Control) will test the association between the presence of infection surveillance and control programs (ISCPs) and changes in nosocomial infection rates (NIRs) as measured by retrospective chart review (RCR). If the establishment of an ISCP affects the quality or completeness of information important for diagnosing infection by RCR, the analyses could be biased (i.e., there could be an increased chance of a Type I or Type II error). To determine whether this type of "ISCP effect" on the accuracy of RCR is likely to occur, the authors carried out a prospective intervention study in one hospital where 1) nosocomial infections among a pre-ISCP cohort of patients were detected by prospective data collection (PDC), 2) the hospital's first ISCP was instituted, and 3) infections were identically studied by PDC exactly two years later. Several months after the end of the second PDC, a team of trained chart reviewers read the medical records of the patients in both study cohorts and abstracted all clinical data bits used for diagnosing nosocomial infection. By a nonparametric matched correlation analysis, no significant change was found in the amount of relevant clinical information recorded in the medical records, and sensitivity and specificity did not change significantly. The authors conclude that, if an ISCP effect on RCR accuracy is present at all, it must be small.

The interactive effects of induced abortion, inter-pregnancy interval and contraceptive use on subsequent pregnancy outcome.

Prior induced abortion and outcome of the next pregnancy are investigated, allowing for two intervening and potentially confounding variables: 1) length of interval between the termination of the first pregnancy and the conception of the next (inter-pregnancy interval) and 2) the utilization of contraception during this interval. Results show that non-contracepting (susceptibility) intervals which immediately precede a subsequent pregnancy are significantly shorter following an induced abortion than those following a spontaneous abortion or delivery. A life table analysis of all susceptibility intervals confirmed this finding. To investigate outcome of subsequent pregnancy as influenced by preceding pregnancy outcome, inter-pregnancy interval and contraceptive use in the interval, a categorical linear model has been developed. Among non-contraceptors, the model indicates no differences in proportions of succeeding adverse outcomes (spontaneous abortion or low birth weight) regardless of inter-pregnancy interval and whether or not the preceding pregnancy had been terminated by an induced abortion. For the contraceptive users, however, proportions of adverse outcomes increased with length of inter-pregnancy interval, and, within each interval category, proportion of adverse outcomes was higher when the preceding pregnancy had terminated in an induced abortion.