Post-operative volumes following endoscopic surgery for non-functioning pituitary macroadenomas are predictive of further intervention, but not endocrine outcomes.

BACKGROUND: Transsphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown. METHODS: Data from patients who underwent endoscopic TSS for a NFPMA (2009-2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes. RESULTS: Of 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (p = 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm3, p = 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm3, p = 0.004). CONCLUSION: Pre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.

Recurrent Superior Mesenteric Artery Stent Fracture.

Ostial stenosis of the superior mesenteric artery (SMA) is usually a benign finding due to the significant collateralization inherent with visceral vessels. There is a subset of patients, however, with significant atherosclerotic disease leading to in situ thrombosis and subsequent mesenteric ischemia requiring intervention. Over the last 20 years, management of mesenteric ischemia-acute or chronic-has transitioned from an open embolectomy or bypass to an endovascular-first approach involving angioplasty and stenting. We are reporting a unique case of recurrent SMA stent fracture with imaging demonstrating diaphragmatic compression of the SMA during the respiratory cycle, subsequent management, and recommendations for future intervention.

Causal models for estimating the effects of weight gain on mortality.

Suppose, in contrast to the fact, in 1950, we had put the cohort of 18-year-old non-smoking American men on a stringent mandatory diet that guaranteed that no one would ever weigh more than their baseline weight established at the age of 18 years. How would the counterfactual mortality of these 18 year olds have compared to their actual observed mortality through 2007? We describe in detail how this counterfactual contrast could be estimated from longitudinal epidemiologic data similar to that stored in the electronic medical records of a large health maintenance organization (HMO) by applying g-estimation to a novel of structural nested model (SNM). Our analytic approach differs from any alternative approach in that, in the absence of model misspecification, it can successfully adjust for (i) measured time-varying confounders such as exercise, hypertension and diabetes that are simultaneously intermediate variables on the causal pathway from weight gain to death and determinants of future weight gain, (ii) unmeasured confounding by undiagnosed preclinical disease (that is, reverse causation) that can cause both poor weight gain and premature mortality (provided an upper bound can be specified for the maximum length of time a subject may suffer from a subclinical illness severe enough to affect his weight without the illness becomes clinically manifest) and (iii) the presence of particular identifiable subgroups, such as those suffering from serious renal, liver, pulmonary and/or cardiac disease, in whom confounding by unmeasured prognostic factors is so severe as to render useless any attempt at direct analytic adjustment. However, (ii) and (iii) limit the ability to empirically test whether the SNM is misspecified. The other two g-methods--the parametric g-computation algorithm and inverse probability of treatment weighted estimation of marginal structural models--can adjust for potential bias due to (i) but not due to (ii) or (iii).

Matrix remodeling associated 5 expression in trunk and limb during avian development.

Matrix remodeling associated 5 (MXRA5) is an extracellular protein that is upregulated in several cancers, but little is known regarding its spatial and temporal localization in the developing embryo. The present study was undertaken to investigate MXRA5 transcript expression in the trunk and limb of the embryonic chick to provide groundwork for future investigation of its developmental function. In situ hybridization utilizing digoxigenin-labeled sense control and experimental antisense probes was performed in paraffin sections of chick embryos from Hamburger and Hamilton (HH) stages 18-38. MXRA5 expression was initially low and restricted in extent at the earliest stages examined, but expression increased in strength and tissue distribution with developmental age. Transcripts were largely found in cells of mesodermal origin, including gut associated mesenchyme, tendon and ligament rudiments, intervertebral discs, dermal papillae of feather buds, heart valve precursors and leaflets, as well as in appendicular joint primordia. The present study has provided initial information on MXRA5 gene expression in the trunk and limb of early to mid-stage avian embryos. Results show that MXRA5 was expressed most strongly at sites undergoing change and remodeling of the extracellular matrix during transition of embryonic tissues into the functional adult morphology.

Differences in radial expansion force among inferior vena cava filter models support documented perforation rates.

OBJECTIVE: Inferior vena cava (IVC) filters are used in patients at risk for pulmonary embolism who cannot be anticoagulated. Unfortunately, these filters are not without risk, and complications include perforation, migration, and filter fracture. The most prevalent complication is filter perforation of the IVC, with incidence varying among filter models. To our knowledge, the mechanical properties of IVC filters have not been evaluated and are not readily available through the manufacturer. This study sought to determine whether differences in mechanical properties are similar to differences in documented perforation rates. METHODS: The radial expansion forces of Greenfield (Boston Scientific, Marlborough, Mass), Cook Celect (Cook Medical, Bloomington, Ind), and Cook Platinum filters were analyzed with three replicates per group. The intrinsic force exerted by the filter on the measuring device was collected in real time during controlled expansion. Replicates were averaged and significance was determined by calculating analysis of covariance using SAS software (SAS Institute, Cary, NC). RESULTS: Each filter model generated a significantly different radial expansion force (P < .001), and force was distributed at significantly different rates (P < .001) during expansion. The largest radial expansion force at minimal caval diameter was seen in the Cook Platinum filter, followed by the Cook Celect and Greenfield filters. Radial force dispersion during expansion was greatest in the Cook Celect, followed by the Cook Platinum and Greenfield filters. CONCLUSIONS: Differences in radial expansion forces among IVC filter models are consistent with documented perforation rates. Cook Celect IVC filters have a higher incidence of perforation compared with Greenfield filters when they are left in place for >90 days. Evaluation of Cook Celect filters yielded a significantly higher radial expansion force at minimum caval diameter, with greater force dispersion during expansion.

Oxygen tension directs the differentiation pathway of human cytotrophoblast cells.

During placental development, human cytotrophoblast cells can differentiate to either villous syncytiotrophoblast cells or invasive extravillous trophoblast cells. We hypothesize that oxygen tension plays a critical role in determining the pathway of cytotrophoblast differentiation. A highly purified preparation of cytotrophoblast cells from human third trimester placenta was cultured for 5 days in either 20% or 1% oxygen tension. The cells incubated at 20% oxygen formed a syncytium as determined by immunohistochemistry using an anti-desmosomal protein antibody that identifies cell membranes. In addition, the mRNA was markedly induced for syncytin, a glycoprotein shown to be essential for syncytiotrophoblast formation, and for human placental lactogen (hPL), which is a specific marker for syncytiotrophoblast cells. In contrast, the cell incubated at 1% oxygen tension did not fuse by morphologic analysis and did not express syncytin or hPL mRNA. However, these cells expressed abundant amounts of HLA-G, a specific marker for extravillous trophoblast cells, which was not seen in cells incubated at 20% oxygen tension. These results suggest that low oxygen tension directs differentiation along the extravillous trophoblast cell pathway while greater oxygen tension directs differentiation along the villous trophoblast cell pathway.

Multiple robustness in factorized likelihood models.

We consider inference under a nonparametric or semiparametric model with likelihood that factorizes as the product of two or more variation-independent factors. We are interested in a finite-dimensional parameter that depends on only one of the likelihood factors and whose estimation requires the auxiliary estimation of one or several nuisance functions. We investigate general structures conducive to the construction of so-called multiply robust estimating functions, whose computation requires postulating several dimension-reducing models but which have mean zero at the true parameter value provided one of these models is correct.

Instrumental variables as bias amplifiers with general outcome and confounding.

Drawing causal inference with observational studies is the central pillar of many disciplines. One sufficient condition for identifying the causal effect is that the treatment-outcome relationship is unconfounded conditional on the observed covariates. It is often believed that the more covariates we condition on, the more plausible this unconfoundedness assumption is. This belief has had a huge impact on practical causal inference, suggesting that we should adjust for all pretreatment covariates. However, when there is unmeasured confounding between the treatment and outcome, estimators adjusting for some pretreatment covariate might have greater bias than estimators without adjusting for this covariate. This kind of covariate is called a bias amplifier, and includes instrumental variables that are independent of the confounder, and affect the outcome only through the treatment. Previously, theoretical results for this phenomenon have been established only for linear models. We fill in this gap in the literature by providing a general theory, showing that this phenomenon happens under a wide class of models satisfying certain monotonicity assumptions. We further show that when the treatment follows an additive or multiplicative model conditional on the instrumental variable and the confounder, these monotonicity assumptions can be interpreted as the signs of the arrows of the causal diagrams.

Impact of a person-centred dementia care training programme on hospital staff attitudes, role efficacy and perceptions of caring for people with dementia: A repeated measures study.

BACKGROUND: People with dementia occupy up to one quarter of acute hospital beds. However, the quality of care delivered to this patient group is of national concern. Staff working in acute hospitals report lack of knowledge, skills and confidence in caring for people with dementia. There is limited evidence about the most effective approaches to supporting acute hospital staff to deliver more person-centred care. OBJECTIVES: This study aimed to evaluate the efficacy of a specialist training programme for acute hospital staff regarding improving attitudes, satisfaction and feelings of caring efficacy, in provision of care to people with dementia. DESIGN: A repeated measures design, with measures completed immediately prior to commencing training (T1), after completion of Foundation level training (T2: 4-6 weeks post-baseline), and following Intermediate level training (T3: 3-4 months post-baseline). SETTING: One NHS Trust in the North of England, UK. PARTICIPANTS: 40 acute hospital staff working in clinical roles, the majority of whom (90%) were nurses. METHODS: All participants received the 3.5 day Person-centred Care Training for Acute Hospitals (PCTAH) programme, comprised of two levels, Foundation (0.5 day) and Intermediate (3 days), delivered over a 3-4 months period. Staff demographics and previous exposure to dementia training were collected via a questionnaire. Staff attitudes were measured using the Approaches to Dementia Questionnaire (ADQ), satisfaction in caring for people with dementia was captured using the Staff Experiences of Working with Demented Residents questionnaire (SEWDR) and perceived caring efficacy was measured using the Caring Efficacy Scale (CES). RESULTS: The training programme was effective in producing a significant positive change on all three outcome measures following intermediate training compared to baseline. A significant positive effect was found on the ADQ between baseline and after completion of Foundation level training, but not for either of the other measures. CONCLUSIONS: Training acute hospital staff in Intermediate level person-centred dementia care is effective in producing significant improvements in attitudes towards and satisfaction in caring for people with dementia and feelings of caring efficacy. Foundation level training is effective in changing attitudes but does not seem to be sufficient to bring about change in satisfaction or caring efficacy.

Depressed thyroid indexes associated with occupational exposure to inorganic lead.

The finding of low values for serum thyroxine and estimated free thyroxine in seven of 12 workers referred because of elevated blood lead levels (greater than 40 mg/L) prompted further investigation. In a cross-sectional study of workers at a small foundry, both measurements were found to regress negatively with blood lead level. In 12 of 47 subjects, both indexes were in the hypothyroid range. Serum thyrotropin and triiodothyronine levels in patients and study subjects with low indexes were all normal. Physical examinations failed to demonstrate the classic features of hypothyroidism. These data are compatible with a central depression of the thyroid axis or an alteration in thyroxine metabolism or binding to proteins. Irrespective of mechanism, the association between low thyroid indexes and elevated lead levels merits attention because of the large number of workers exposed to lead and the similarities between the clinical features of adult lead poisoning and hypothyroidism.

Management of Acute Lower Gastrointestinal Bleeding: Principles and Current Practice in the United Kingdom.

Acute lower gastrointestinal bleeding (ALGIB) is a common cause for hospital admission that results in significant morbidity and mortality. The major objectives of all involved in the management of ALGBI patients are to reduce mortality and the need for major surgery. A secondary objective is to prevent unnecessary hospital admission for patients presenting with bleeding that is not life-threatening. The management of ALGBI has evolved over last decade with the changing modalities of diagnostic facilities. On review of the published literature, there is paucity of randomised control trials in relation to the diagnostic tools and management of ALGBI. The aim of this review is to summarise the principles and current methods available for the diagnosis and treatment of ALGIB and based on the available evidence and the current practice in the United Kingdom, outline an algorithm for the management of ALGIB.

A real-time audit of radiation therapy in a regional cancer center.

PURPOSE: To report the development, structure, and implementation of a real-time clinical radiotherapy audit of the practice of radiation oncology in a regional cancer center. METHODS AND MATERIALS: Radiotherapy treatment plans were audited by a real-time peer-review process over an 8-year period (1989-1996). The overall goal of the audit was to establish a process for quality assurance (QA) of radiotherapy planning and prescription for individual patients. A parallel process was developed to audit the implementation of intervention-specific radiotherapy treatment policies. RESULTS: A total of 3052 treatment plans were audited. Of these, 124 (4.1%) were not approved by the audit due to apparent errors in radiation planning. The majority of the nonapproved plans (79%) were modified prior to initiating treatment; the audit provided important clinical feedback about individual patient care in these instances. Most of the remaining nonapproved plans were deviations from normal practice due to patient-specific considerations. A further 110 (3.6% of all audited plans) were not approved by the audit due to deviations from radiotherapy treatment policy. A minority of these plans (22%) were modified prior to initiating treatment and the remainder provided important feedback for continuous quality improvement of treatment policies. CONCLUSION: A real-time audit of radiotherapy practice in a regional cancer center setting proved feasible and provided important direct and indirect patient benefits.

The antipyretic effect of tilorone hydrochloride in the cat.

1 The antipyretic activity of tilorone hydrochloride was studied in conscious, unrestrained cats provided with implanted jugular venous catheters, third cerebral ventricular (i.c.v.) cannulae and retroperitoneal thermocouples. 2 In afebrile animals, 10 mg/kg i.v. or 1 mg i.c.v. tilorone hydrochloride did not alter body temperature, but 20 mg/kg i.v. or 2 to 5 mg i.c.v. caused hypothermia and various behavioural responses. 3 Non-hypothermogenic doses of tilorone (i.v. or i.c.v.) antagonized hyperthermic responses to leucocytic pyrogen (i.v. or i.c.v.), bacterial pyrogen (i.c.v.) and sodium arachidonate (i.c.v.) but did not antagonize prostaglandin E1 (i.c.v.). 4 These results indicate that tilorone has an antipyretic action within the central nervous system that is distinct from its hypothermogenic action. Although there is no published evidence to indicate that tilorone can inhibit prostaglandin synthesis peripherally, its ability to reduce hyperthermic responses to arachidonate suggests that it can inhibit prostaglandin synthesis within the brain.

Implications of comorbidity and ascertainment bias for identifying disease genes.

Comorbidity, the co-occurrence of disorders, is frequently observed to occur at higher rates in clinically ascertained samples than in population-based samples. An explanation for this finding is that subjects suffering from multiple illnesses are more likely to seek medical care and receive a diagnostic evaluation. We refer to the component of the comorbidity between illnesses due to such ascertainment bias as "spurious comorbidity." When spurious comorbidity is present, an apparent association between a candidate locus and the phenotype of interest may actually be attributable to an association between the locus and a comorbid phenotype. This phenomenon, which we call "spurious comorbidity bias," could thus produce misleading association findings. In this article, we describe this phenomenon and demonstrate that it may produce marked bias in the conclusions of family-based association studies. Because of the extremely high rates of comorbidity among psychiatric disorders in clinical samples, this problem may be particularly salient for genetic studies of neuropsychiatric disorders. We conclude that ascertainment bias may contribute to the frequent difficulty in replicating candidate gene study findings in psychiatry. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:817-822, 2000.

Estimation of ventilatory capacity in subjects with unacceptable lung function tests.

Based on pulmonary function data collected annually for six years on 540 Vermont granite workers, FEV1 in survey 1 was estimated by extrapolating back from subsequent measurements. The extrapolation method was found to fit the observed data of subjects with reproducible initial values very well (R2 = 0.87). Extrapolated FEV1s for workers unable to perform an adequate pulmonary function test according to the standards of the American Thoracic Society were compared to extrapolated values in the rest of the cohort. After adjusting for confounding, subjects with test failure in survey 1 had a lower extrapolated FEV1 than the rest of the cohort (p = 0.07). The mean extrapolated FEV1 of the 71 workers with an initial test failure was only 95% of a predicted value derived from the group with reproducible data, and the per cent predicted decreased from 98% to 71% as the number of test failures in the follow-up surveys increased (p = 0.0004). The American Thoracic Society and the Epidemiology Standardization Project currently recommend that test failures be excluded from the analysis of epidemiological data. Our findings suggest that alternative strategies for handling non-reproducible lung function may need to be explored in order to avoid selection bias.

Identifiability, exchangeability, and epidemiological confounding.

Non-identifiability of parameters is a well-recognized problem in classical statistics, and Bayesian statisticians have long recognized the importance of exchangeability assumptions in making statistical inferences. A seemingly unrelated problem in epidemiology is that of confounding: bias in estimation of the effects of an exposure on disease risk, due to inherent differences in risk between exposed and unexposed individuals. Using a simple deterministic model for exposure effects, a logical connection is drawn between the concepts of identifiability, exchangeability, and confounding. This connection allows one to view the problem of confounding as arising from problems of identifiability, and reveals the exchangeability assumptions that are implicit in confounder control methods. It also provides further justification for confounder definitions based on comparability of exposure groups, as opposed to collapsibility-based definitions.

The behaviour of common measures of association used to assess a vaccination programme under complex disease transmission patterns--a computer simulation study of malaria vaccines.

Case-control studies have been evoked as important alternatives to randomized clinical trials in the evaluation of infectious disease interventions. Using computer simulations, we compare the behaviour of common measures of association derived from case-control studies in the context of a malaria vaccine programme administered under complex transmission conditions. Several simplifying assumptions of previous workers have been relaxed and the simulated conditions are endemic rather than epidemic. The common estimators of association used in case-control studies remain unbiased only in limited circumstances. The term dependent happenings, first defined by Ross in 1916, is resurrected. Since the number of people becoming infected is dependent on the number of people already infected, control programmes in infectious diseases produce direct as well as indirect effects. Three different study designs with different pairs of comparison populations are defined. The choice of comparison population can be used to differentiate direct from indirect effects. In order to clarify the direct effects of a vaccination programme the comparison groups must be subjected to identical transmission intensities. In contrast, the referent group must remain unaffected by consequences of the intervention to determine indirect effects.

Alternatives in midtrimester abortion induction.

To develop objective criteria for the individualization of patient management, the results of a series of investigations of 1764 midtrimester pregnancy terminations are examined. These include intraamniotic instillation of hypertonic saline or prostaglandin F2 alpha, intramuscular 15(S)15-methyl prostaglandin F2 alpha, and intravaginal prostaglandin E2. Laminaria and intravenous oxytocin augmentation have also been used. The relative advantages and disadvantages of these techniques are evaluated in terms of safety, efficacy, and acceptability. The effects of parity and length of gestation are considered. Before 20 weeks' gestation, vaginal prostaglandin E2 is believed superior to the other techniques by most criteria, and intraamniotic saline is the authors' method of choice in amore advanced pregnancies.

Ripening of the term cervix with laminaria.

Laminaria tents were used to ripen the cervix in cases where induction of labor was indicated and the Bishop score was less than or equal to 5. Induction of labor was significantly more successful in these cases as compared with a matched control group where the cervix had not been ripened.

Maternal serum and amniotic fluid alpha-fetoprotein as a marker of acute fetal distress in a midtrimester abortion model.

Maternal serum (MS) and amniotic fluid (AF) alpha-fetoprotein (alpha-FP) levels were serially determined in 18 cases of elective midtrimester abortion. Prostaglandin F2alpha (PGF2alpha) and 20% NaCl were used as the abortifacients in 2 groups of 9 patients, respectively. The time from instillation to abortion (IAT) was accurately recorded in all cases. A marked 260-600% increase in MS alpha-FP occurred prior to fetal demise in both groups. Amniotic fluid alpha-FP content remained largely unchanged for the first 6 hours following intraamniotic prostaglandin injection. A 50% INCREASE WAS OBSERVED IN THE AF alpha-FP content in the group with 20% NaCl-induced abortion (after an initial dilutionary drop). The results of this investigation confirm the value of alpha-FP in MS as a marker of impending fetal demise. This rise is not caused by a prior alpha-FP change in the AF. The data suggest a major fetomaternal transplacental route for alpha-FP.