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The U.S. Preventive Services Task Force and several medical professional associations have published guidelines recommending that all women be counseled around the time of menopause about the benefits and risks of estrogen replacement therapy (ERT) so that they may make an informed decision about its use. Despite the proliferation of ERT counseling guidelines, little is known about whether these guidelines are being followed. There were 1,500 female members (aged 40 to 69) of a Northeastern U.S. Independent Practice Association--model Health Maintenance Organization who were surveyed, and 51 percent reported that a health care provider had talked with them about the benefits and risks of ERT. In multivariate analyses, a woman's demographic characteristics (age, race, income), stage of menopause, severity of menopausal symptoms, and body weight were the major correlates of receipt of ERT counseling. Women at greater risk for osteoporosis or heart disease were no more likely to be counseled, although those with diagnosed osteoporosis were. What appear to be selective ERT counseling practices will need to be modified if the goal of providing universal ERT counseling to midlife women is to be attained. [ABSTRACT FROM AUTHOR]

Reports the case of a patient on chronic hemodialysis who developed N-acetylprocainamide intoxication. Medical history of the patient; Superiority of hemoperfusion over hemodialysis in treating the intoxication; Complexity of acetylprocainamide pharmacokinetics in patients on chronic hemodialysis; Removal of N-acetylprocainamide from plasma by hemoperfusion and hemodialysis.

Background: Child maltreatment and child protective service (CPS) involvement negatively impacts families, and disproportionately impact families of color. Urban neighborhood greenspace is associated with improved mental health and decreased community violence, however correlations between greenspace and CPS involvement have not been evaluated., Objective: To examine the association between greenspace and CPS involvement., Methods: This is a secondary analysis of City of Philadelphia CPS report data from 2008 to 2018. Logistic regression was used to determine associations between greenspace and 3 CPS outcomes (substantiated reports, cases accepted for CPS services, and foster care placements) at the census block level, adjusting for sociodemographic information and area deprivation index, a composite measure combining education, employment, housing, and poverty characteristics at the census block group level. 13,336 census blocks were included, which had key exposure, covariate, and outcome data, and had a child population of at least 1., Results: 66,043 CPS reports were included. In the adjusted model, compared to blocks with >30 % greenspace, blocks with <10 % greenspace had 1.52 times the odds of a substantiated report (95 % CI 1.30-1.76, p < 0.001) and 1.52 times the odds of a case accepted for CPS services (95 % CI 1.30-1.77, p < 0.001). Blocks with less greenspace had increased odds of foster care placement than blocks with >30 % greenspace, however the correlation was less strong., Conclusion: Increased density of neighborhood greenspace is associated with decreased risk of substantiated child maltreatment and cases accepted for CPS services, suggesting that greenspace may confer protection against CPS involvement., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

We describe the discovery of a thioester-containing glucocorticoid receptor modulator (GRM) payload and the corresponding antibody-drug conjugate (ADC). Payload 6 was designed for rapid hepatic inactivation to minimize systemic exposure of nonconjugated GRM. Mouse PK indicated that 6 is cleared 10-fold more rapidly than a first-generation GRM payload, resulting in 10-fold lower exposure and 3-fold decrease in Cmax. The anti-mTNF conjugate ADC5 fully inhibited inflammation in mouse contact hypersensitivity with minimal effects on corticosterone, a biomarker for systemic GRM effects, at doses up to and including 100 mg/kg. Concomitant inhibition of P1NP suggests potential delivery to cells involved in the remodeling of bone, which may be a consequence of TNF-targeting or bystander payload effects. Furthermore, ADC5 fully suppressed inflammation in collagen-induced arthritis mouse model after one 10 mg/kg dose for 21 days. The properties of the anti-hTNF conjugate were suitable for liquid formulation and may enable subcutaneous dosing.

Urban living limits access to nature yet spending time in nature is crucial for human health and well-being. To overcome this, urban planners and policymakers are actively looking for different ways to conserve and create more urban nature through parks, street trees, and other greening strategies. However, research shows that in most cities, these greening efforts are not equitably distributed, nor are they equal in terms of their quality or benefits they provide. Creating more equitable access to urban nature is a challenge and a priority in the next decade, and so is improving the quality of urban nature and associated benefits for urbanites. To address this challenge and contribute at both practical and conceptual levels, we propose a new Local Restorative Nature (LRN) index for geospatially assessing the "restorative quality" of urban nature that can support mental well-being. To contextualize the LRN index, we map the distribution of restorative nature in relation to social vulnerability in Vancouver, Canada. The novel LRN index provides critical insights showing that many neighborhoods with vulnerable populations in Vancouver have less exposure to restorative nature to support mental health and highlights where to strategically prioritize urban greening investment in areas that need it the most. The LRN index is scalable and can be used by urban planners in other cities and contexts to improve equitable distribution of restorative nature and better support urbanites' well-being., (© 2023. Crown.)

Maleimide chemistry is widely used in antibody-drug conjugate (ADC) generation to connect drugs to antibodies through a succinimide linker. The resulting ADC is prone to payload loss via a reverse Michael reaction, leading to premature drug release in vivo . Complete succinimide hydrolysis is an effective strategy to overcome the instability of ADC. However, we discovered through previous work that hydrolysed succinimide rings can close again in a liquid formulation during storage and under thermal stress conditions. In this work, a set of maleimide linkers with hydrolysis-prone groups were designed. The corresponding ADCs were prepared and subjected to thermal stress conditions. The extent of succinimide hydrolysis and drug release was measured, and ADC properties such as SEC, DAR, pI and clog  P of linkers were calculated. Our results demonstrated that even though all these groups increased the hydrolysis rate, they have different impacts on maintaining the hydrolysed succinimide ring in an open conformation and ADC stability in a liquid formulation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Side chains of natural occurring amino acids vary greatly in terms of charge state, polarity, size and hydrophobicity. Using a linear synthetic route, two amino acids were sequentially coupled to a potent glucocorticoid receptor modulator (GRM) to afford a library of dipeptide-GRM linker payloads with a range of in silico properties. The linker payloads were conjugated to a mouse anti-TNF antibody through interchain disulfide Cys. Impact of various dipeptide linkers on ADC physical properties, including solubility, hydrophobicity, and aggregation were evaluated and the in silico properties pI, Log  P and tPSA of the linker drugs used to correlate with these properties. ADCs were screened in a GRE luciferase reporter assay to compare their in vitro efficacy. Data identified Ala-Ala as a superior dipeptide linker that allowed a maximum drug load of 10 while affording ADCs with low aggregation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Stable attachment of drug-linkers to the antibody is a critical requirement, and for maleimide conjugation to cysteine, it is achieved by ring hydrolysis of the succinimide ring. During ADC profiling in our in-house property screening funnel, we discovered that the succinimide ring open form is in equilibrium with the ring closed succinimide. Bromoacetamide (BrAc) was identified as the optimal replacement, as it affords stable attachment of the drug-linker to the antibody while completely removing the undesired ring open-closed equilibrium. Additionally, BrAc also offers multiple benefits over maleimide, especially with respect to homogeneity of the ADC structure. In combination with a short, hydrophilic linker and phosphate prodrug on the payload, this afforded a stable ADC (ABBV-154) with the desired properties to enable long-term stability to facilitate subcutaneous self-administration.

To facilitate subcutaneous dosing, biotherapeutics need to exhibit properties that enable high-concentration formulation and long-term stability in the formulation buffer. For antibody-drug conjugates (ADCs), the introduction of drug-linkers can lead to increased hydrophobicity and higher levels of aggregation, which are both detrimental to the properties required for subcutaneous dosing. Herein we show how the physicochemical properties of ADCs could be controlled through the drug-linker chemistry in combination with prodrug chemistry of the payload, and how optimization of these combinations could afford ADCs with significantly improved solution stability. Key to achieving this optimization is the use of an accelerated stress test performed in a minimal formulation buffer.

Using a convergent synthetic route to enable multiple points of diversity, a series of glucocorticoid receptor modulators (GRM) were profiled for potency, selectivity, and drug-like properties in vitro . Despite covering a large range of diversity, profiling the nonconjugated small molecule was suboptimal and they were conjugated to a mouse antitumor necrosis factor (TNF) antibody using the MP-Ala-Ala linker. Screening of the resulting antibody drug conjugates (ADCs) provided a better assessment of efficacy and physical properties, reinforcing the need to conduct structure-activity relationship studies on the complete ADC. DAR4 ADCs were screened in an acute mouse contact hypersensitivity model measuring biomarkers to ensure a sufficient therapeutic window. In a chronic mouse arthritis model, mouse anti-TNF GRM ADCs were efficacious after a single dose of 10 mg/kg i.p. for over 30 days. Data on the unconjugated payloads and mouse surrogate anti-TNF ADCs identified payload 17 which was conjugated to a human anti-TNF antibody and advanced to the clinic as ABBV-3373.

Glucocorticoid receptor modulators (GRM) are the first-line treatment for many immune diseases, but unwanted side effects restrict chronic dosing. However, targeted delivery of a GRM payload via an immunology antibody-drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. We initiated our α-TNF-GRM ADC project focusing on identifying the optimal payload and a linker that afforded stable attachment to both the payload and antibody, resulting in the identification of the synthetically accessible maleimide-Gly-Ala-Ala linker. DAR 4 purified ADCs were shown to be more efficacious in a mouse contact hypersensitivity model than the parent α-TNF antibody. Analysis of P1NP and corticosterone biomarkers showed there was a sufficient therapeutic window between efficacy and unwanted effects. In a chronic mouse arthritis model, α-TNF-GRM ADCs were more efficacious than both the parent α-TNF mAb and an isotype control bearing the same GRM payload.

Purpose The current Joint Committee on Infant Hearing guidelines recommend that infants with syndromes or craniofacial abnormalities (CFAs) who pass the universal newborn hearing screening (UNHS) undergo audiological assessment by 9 months of age. However, emerging research suggests that children with these risk factors are at increased risk of early hearing loss despite passing UNHS. To establish whether earlier diagnostic audiological assessment is warranted for all infants with a syndrome or CFA, regardless of screening outcome, this study compared audiological outcomes of those who passed UNHS and those who referred. Method A retrospective analysis was performed on infants with a syndrome or CFA born between July 1, 2012, and June 30, 2017 who participated in Queensland, Australia's state-wide UNHS program. Results Permanent childhood hearing loss (PCHL) yield was higher among infants who referred on newborn hearing screening (51.20%) than in those who passed. Nonetheless, 27.47% of infants who passed were subsequently diagnosed with hearing loss (4.45% PCHL, 23.02% transient conductive), but PCHL was generally milder in this cohort. After microtia/atresia, the most common PCHL etiologies were Trisomy 21, other syndromes, and cleft palate. Of the other syndromes, Pierre Robin sequence featured prominently among infants who passed the hearing screen and were subsequently diagnosed with PCHL, whereas there was a broader mix of other syndromes that caused PCHL in infants who referred on screening. Conclusion Children identified with a syndrome or CFA benefit from early diagnostic audiological assessment, regardless of their newborn hearing screening outcome.

This article contains four data tables: 1 and 2: A content analysis framework for evaluating the degree to which urban resilience plans emphasize issues of justice and equity in plan content, and associated point rubric for scoring criteria; 3. The raw numerical data collected for a plan evaluation where we deployed this framework to analyze a sample of 31 strategies from the "100 Resilient Cities - Pioneered by the Rockefeller Foundation" (100RC) initiative; and, 4. Inter-rater reliability scores for this plan evaluation. This dataset accompanies a 2019 article submitted to the journal World Development titled: Just urban futures? Exploring equity in "100 Resilient Cities".

Objective: We performed an open-label Phase I/II trial to evaluate the safety and tolerability of vagus nerve stimulation (VNS) in patients with treatment-resistant fibromyalgia (FM) as well as to determine preliminary measures of efficacy in these patients., Methods: Of 14 patients implanted with the VNS stimulator, 12 patients completed the initial 3-month study of VNS; 11 patients returned for follow-up visits 5, 8, and 11 months after start of stimulation. Therapeutic efficacy was assessed with a composite measure requiring improvement in pain, overall wellness, and physical function. Loss of both pain and tenderness criteria for the diagnosis of FM was added as a secondary outcome measure because of results found at the end of 3 months of stimulation., Results: Side effects were similar to those reported in patients treated with VNS for epilepsy or depression and, in addition, dry mouth and fatigue were reported. Two patients did not tolerate stimulation. At 3 months, five patients had attained efficacy criteria; of these, two patients no longer met widespread pain or tenderness criteria for the diagnosis of FM. The therapeutic effect seemed to increase over time in that additional participants attained both criteria at 11 months., Conclusions: Side effects and tolerability were similar to those found in disorders currently treated with VNS. Preliminary outcome measures suggested that VNS may be a useful adjunct treatment for FM patients resistant to conventional therapeutic management, but further research is required to better understand its actual role in the treatment of FM., (Wiley Periodicals, Inc.)

Automated semipreparative LC/MS systems are now well established commercially and commonly used for purification of early stage drug discovery compounds. A number of vendors have instruments on the market that are capable of reliably purifying compounds with good water/acetonitrile solubility. However, these systems often fail when the sample has poor solubility, extreme polarity, and/or poor ionization. Even in cases when substantial optimization has been done prior to purification, a certain percent of failures to recover the desired product is unavoidable. In the past, when the majority of samples run on LC/MS semipreparative systems were large combinatorial libraries, some losses in this high throughput mode were acceptable. However, now that more chemistry laboratories are making smaller more focused libraries with higher purity requirements, reliability and recovery are more crucial. This paper describes modifications made to customize an MS-triggered semipreparative LC/MS system in order to ensure improved reliability and recovery of products from traditional medicinal chemistry as well as combinatorial libraries.

Introduction: We evaluated polysomnograms of chronic fatigue syndrome (CFS) patients with and without fibromyalgia to determine whether patients in either group had elevated rates of sleep-disturbed breathing (obstructive sleep apnea or upper airway resistance syndrome) or periodic leg movement disorder. We also determined whether feelings of unrefreshing sleep were associated with differences in sleep architecture from normal., Methods: We compared sleep structures and subjective scores on visual analog scales for sleepiness and fatigue in CFS patients with or without coexisting fibromyalgia (n = 12 and 14, respectively) with 26 healthy subjects. None had current major depressive disorder, and all were studied at the same menstrual phase., Results: CFS patients had significant differences in polysomnograpic findings from healthy controls and felt sleepier and more fatigued than controls after a night's sleep. CFS patients as a group had less total sleep time, lower sleep efficiency, and less rapid eye movement sleep than controls. A possible explanation for the unrefreshing quality of sleep in CFS patients was revealed by stratification of patients into those who reported more or less sleepiness after a night's sleep (a.m. sleepier or a.m. less sleepy, respectively). Those in the sleepier group reported that sleep did not improve their symptoms and had poorer sleep efficiencies and shorter runs of sleep than both controls and patients in the less sleepy group; patients in the less sleepy group reported reduced fatigue and pain after sleep and had relatively normal sleep structures. This difference in sleep effects was due primarily to a decrease in the length of periods of uninterrupted sleep in the a.m. sleepier group., Conclusion: CFS patients had significant differences in polysomnographic findings from healthy controls and felt sleepier and more fatigued than controls after a night's sleep. This difference was due neither to diagnosable sleep disorders nor to coexisting fibromyalgia but primarily to a decrease in the length of periods of uninterrupted sleep in the patients with more sleepiness in the morning than on the night before. This sleep disruption may explain the overwhelming fatigue, report of unrefreshing sleep, and pain in this subgroup of patients.

Objective: To examine the independent impact of major depression and hostility on mortality rate at 6 months and 12 months after discharge from the hospital in patients with a myocardial infarction., Method: Three hundred thirty-one patients were prospectively evaluated for depression with a modified version of the National Institute of Mental Health Diagnostic Interview Schedule for major depressive episode. The Cook Medley Hostility Scale data were analyzed by chi(2) procedures for nominal and categoric data, and Student t test was used for continuous data types., Results: Depression was a significant predictor of death at 12 months (P =. 04) but not at 6 months (P =.08). Hostility was not found to be a predictor of death at 6 months or 12 months., Conclusions: Major depression in patients hospitalized after myocardial infarction is a significant univariable predictor of death at 12 months, although it was not a statistically significant predictor after adjusting for other variables. Hostility is not a predictor of death. Prospective studies are needed to determine the impact of aggressive treatment of depression on post-myocardial infarction survival.

Long-term potentiation (LTP) is a use-dependent form of synaptic plasticity that is of great interest as a cellular mechanism that may contribute to memory storage. It is the sustained phase of population excitatory postsynaptic potential induced by high-frequency stimulation (HFS). HFS can also induce short-term potentiation (STP), a decremental potentiation lasting approximately 15 min. It has been unclear whether STP is simply a reversible form of LTP elicited by subthreshold stimuli or whether it is an independently expressed form of synaptic plasticity. We have attempted to clarify the relationship between LTP and STP in the extracellular recording technique in area CA1 of the adult rat hippocampal slice preparation to test four predictions of the hypothesis that LTP and STP are expressed via the same mechanism. First, occluding LTP expression should block STP expression. Saturating LTP under six different conditions, however, did not occlude STP expression. Second, occluding STP expression should occlude LTP expression. The partial or full occlusion of STP by two maneuvers (increasing the stimulus intensity used for HFS or applying 3-isobutyl-1-methylxanthine), however, did not occlude LTP expression. Third, LTP increases and decreases paired-pulse facilitation (PPF), and STP should have the same effect. STP did not change PFF, however. The first three results, then, suggest that STP and LTP are expressed via different mechanisms. Fourth, STP should be maximal near the LTP induction threshold, and then decrease above it. Surprisingly, STP was maximal at or very close to the LTP induction threshold, but it did not decrease above this threshold. This relationship suggests the possibility that STP and LTP share an induction step(s). What is the function of the independently expressed STP? We find that LTP can be induced by two HFSs, each of which is subthreshold for LTP, if the second is given during STP from the first. This suggests that STP can temporarily lower the LTP induction threshold. Three lines of evidence, then, suggest that STP and LTP may be expressed via different mechanisms; however, the proximity of STP saturation to LTP induction suggests that they may share an induction step(s). STP may also have the very important function of temporarily lowering the LTP induction threshold. Finally, these data suggestion caution in interpreting LTP data obtained <20-30 min after HFS, because they may be contaminated by STP, which appears to have different underlying mechanisms.

Because of ontogenic influences on the pathophysiologic mechanisms of brain injury in the perinatal brain, and in particular, the incomplete development of adenosine receptor systems, we investigated the potential for adenosine to provide cerebro-protection in a well established newborn rat model of hypoxia-ischemia. Fifteen litters of postnatal d 7 animals were subjected to unilateral carotid ligation and exposure to hypoxia (8% oxygen) for 3 h. Immediately after hypoxia-ischemia, animals received either the adenosine deaminase inhibitor deoxycoformycin (DCF; 2.5 mg/kg intraperitoneally) or the adenosine uptake inhibitor propentofylline (PPF; 10 mg/kg intraperitoneally); paired littermates received an equivalent volume of normal saline. On postnatal d 14, injury or protection was assessed by differences in hemispheric weights, morphometric determinations of infarct area, and histopathologic analyses. DCF resulted in a 34% (p = 0.02) and 31% (p = 0.03) reduction in hemispheric weight disparities and infarct area, respectively; for PPF, these reductions were 46% (p = 0.03) and 32% (p = 0.04), respectively. Light microscopic examinations of striatum, thalamus, hippocampus, and cortex revealed that both drugs significantly improved histologic scores as well. Measurements in six separate litters indicated that neither drug significantly reduced core body temperature for at least 6 h postadministration. These findings indicate that potentiation of endogenous adenosine levels in the perinatal brain can significantly ameliorate brain injury. Each of these treatment strategies was effective even when administered after the hypoxic-ischemic insult. Thus, further investigations of adenosinergic therapies are warranted in this and other perinatal models of cerebral ischemia to elucidate in detail their potential for clinical application.

Background: Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant disease with protean clinical manifestations, ranging from asymptomatic to that of severe heart failure or sudden death. There is no known parameter in individuals with hypertrophic cardiomyopathy (HCM) that predicts a specific clinical event. This is particularly troublesome for premature sudden death that frequently occurs in young athletes without prior symptoms. Recent identification of mutations in the beta myosin heavy chain (beta MHC) gene that co-segregate with the inheritance of the disease provides an opportunity to determine whether certain mutations are more likely to induce a particular clinical event. In this study we analyzed the genotype and phenotype of individuals from two unrelated families with HCM in which the affected individuals have the same missense mutation in exon 13 (G1208A) of the coding sequence for beta MHC., Methods: Individuals from two unrelated families with the diagnosis of FHCM were screened by history, physical examination, electrocardiography, and two dimensional echocardiography. After extraction of DNA from the blood of these individuals, the exon 13 of the beta MHC gene was amplified by polymerase chain reaction (PCR), and the PCR product was digested with Ddel restriction endonuclease. The digestion products were separated by gel electrophoresis and identified by ethidium bromide staining., Results: We studied 54 individuals from the two families, 21 were affected with HCM of which eleven died prematurely, eight from sudden cardiac death. While most of the nine affected individuals studied had septal hypertrophy, three had concentric hypertrophy and six, left ventricular outflow tract obstruction. Onset of symptoms was in the second decade of life. Electrophoretic separation of the digested DNA (exon 13) from unaffected individuals provided two fragments of 84 and 70 bp in size, as expected. In contrast, DNA from individuals affected with HCM showed four fragments of 84 bp, 70 bp, 52 bp and 32 bp indicating they inherited the mutation. In only one 10 year old male was the mutation present without evidence of HCM which gives an overall penetrance of 86%., Conclusions: The missense mutation in exon 13 of the beta MHC gene in individuals with FHCM is associated with high penetrance, highly variable expressivity, severe disease, early in onset and a high incidence of premature sudden death. Based on these results we recommend individuals from families with HCM be screened for this missense mutation and if positive, be counselled to avoid combative sports, as it is these activities that often precipitate sudden death.

It has been reported that under normal conditions, mixed venous blood gases have approximated arterial samples; however, during cardiac arrest or severe cardiogenic shock, marked differences between arterial and venous blood gases have been noted. To further assess the relationships between arterial and mixed venous blood gases and cardiac index, a study population was chosen consisting of patients with less severe states of cardiac impairment. The differences between arterial and mixed venous PCO2s and pHs were compared with cardiac indexes (CI) of 44 patients in an intensive care unit with arterial lines and Swan-Ganz catheters in place. Twenty-six patients with normal CIs (2.6 to 4.1 L/min/m2) had a mean difference in mixed venous-arterial PCO2 (delta PCO2) of 4.88 +/- 0.40 mm Hg. In patients with low CIs (< 2.6), the delta PCO2 was 7.44 +/- 0.63 mm Hg (P = .001). The difference of mixed venous and arterial pH (delta pH) was 0.027 +/- 0.004 pH units for patients with normal CIs and 0.04 +/- 0.003 pH units for those with low CIs (P < .002). When the CIs of all patients were plotted against the delta PCO2s, there was an inverse linear relationship wherein delta PCO2 increased as CI decreased (r = -.47, P = .0011). There is an inverse relationship between delta PCO2 and CI that has not been previously described. An elevated delta PCO2 may be a marker of a low cardiac index.

A newborn black boy had two facial blisters at birth that progressed to bullous lesions over the trunk, genitals, extremities, and oral and tracheal mucosa. A biopsy specimen demonstrated a subepidermal bulla with mixed eosinophilic and neutrophilic, inflammatory infiltrate. Direct immunofluorescence showed linear IgA, IgG, and C3 depositions along the basement membrane zone, consistent with a diagnosis of childhood linear IgA bullous dermatosis (chronic bullous dermatosis of childhood). The skin disease was controlled with combined prednisone and dapsone. This is the youngest reported patient with the disease. Linear IgA bullous dermatosis should be considered in the differential diagnosis of blistering diseases of the newborn, and immunofluorescence should be performed on a skin biopsy specimen.

The Askin tumor is one of a group of small round cell tumors and is found mainly in the thoraco-pulmonary region of children and young adults. The treatment of the patient and the differentiation of this tumor from other small round cell tumors, especially Ewing's sarcoma and neuroblastoma by light microscopy, immunohistochemical methods, and electron microscopy is discussed.

We report a case of a head and neck melanoma fulfilling the criteria for spontaneous regression of the primary tumor. The melanoma originated within a pretragal nevus. Histological examination of the surgical specimen revealed regressive changes within the nevus but no demonstrable melanoma. This brings to a total of 14 the number of patients with documented regression of a primary melanoma.

A retrospective evaluation of the effect of renal and respiratory failure on mortality in our surgical intensive care unit was undertaken. The coexistence of combined renal and respiratory failure had a synergistic adverse effect on survival. Combined pulmonary and kidney failure appeared to develop simultaneously. A subset of patients with severe prerenal azotemia but without uremia had the highest mortality. These results are not consistent with the simple combination of single systems failure but rather suggest that renal and respiratory failure are makers of a generalized underlying defect.