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Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to describe the in vivo situation, which can affect downstream development decisions. Implementing in vitro - in vivo - in silico strategies throughout the drug development process is effective in identifying and mitigating risks while speeding up their development. Risdiplam (EVRYSDI®) - an orally bioavailable, small molecule approved by the U.S. Food and Drug Administration and more recently by the European Medicines Agency for the treatment of patients {greater than or equal to}2 months of age with spinal muscular atrophy (SMA), is presented here as a case study. Risdiplam is a low turnover compound whose metabolism is mediated through a non-cytochrome P450 enzymatic pathway. Four main challenges of risdiplam are discussed: predicting in vivo hepatic clearance, determining in vitro metabolites with regard to metabolites in safety testing guidelines, elucidating enzymes responsible for clearance, and estimating potential drug-drug interactions. A combination of in vitro and in vivo results was successfully extrapolated and used to develop a robust physiologically based pharmacokinetic model of risdiplam. These results were verified through early clinical studies, further strengthening the understanding of the ADME properties of risdiplam in humans. These approaches can be applied to other compounds with similar ADME profiles, which may be difficult to investigate using standard methods. Significance Statement Risdiplam is the first approved, small molecule, survival of motor neuron 2 mRNA splicing modifier for the treatment of spinal muscular atrophy. The approach taken to characterize the absorption, distribution, metabolism and excretion (ADME) properties of risdiplam during clinical development incorporated in vitro-in vivo-in silico techniques, which may be applicable to other small molecules with challenging ADME. These strategies may be useful in improving the speed at which future drug molecules can be developed.

ObjectiveTo examine vaccine uptake, hesitancy and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination.DesignCross-sectional survey.SettingTen Australian health services.Participants4683 patients (3560 cancer, 842 diabetes and 281 multiple sclerosis) receiving care at the health services participated in the 42-item survey, between June 30 to October 5, 2021.Main outcome measuresSociodemographic and disease-related characteristics, COVID-19 vaccine uptake, and the scores of three validated scales which measured vaccine hesitancy and vaccine-related beliefs generally and specific to the participants’ disease, including the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale. Multivariable logistic regression was used to determine the associations between scale scores and vaccine uptake.ResultsOf all participants, 81.5% reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas (all pConclusionsDisease-specific concerns impact COVID-19 vaccine-related behaviours and beliefs in people with serious and/or chronic health conditions. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.Trial registrationACTRN12621001467820

Small molecules that present complex absorption, distribution, metabolism, and elimination (ADME) properties can be challenging to investigate as potential therapeutics. Acquiring data through standard methods can yield results that are insufficient to describe the in vivo situation, which can affect downstream development decisions. Implementing in vitro-in vivo-in silico strategies throughout the drug development process is effective in identifying and mitigating risks while speeding up their development. Risdiplam (Evrysdi)-an orally bioavailable, small molecule approved by the US Food and Drug Administration and more recently by the European Medicines Agency for the treatment of patients ≥2 months of age with spinal muscular atrophy-is presented here as a case study. Risdiplam is a low-turnover compound whose metabolism is mediated through a non-cytochrome P450 enzymatic pathway. Four main challenges of risdiplam are discussed: predicting in vivo hepatic clearance, determining in vitro metabolites with regard to metabolites in safety testing guidelines, elucidating enzymes responsible for clearance, and estimating potential drug-drug interactions. A combination of in vitro and in vivo results was successfully extrapolated and used to develop a robust physiologically based pharmacokinetic model of risdiplam. These results were verified through early clinical studies, further strengthening the understanding of the ADME properties of risdiplam in humans. These approaches can be applied to other compounds with similar ADME profiles, which may be difficult to investigate using standard methods. SIGNIFICANCE STATEMENT: Risdiplam is the first approved, small-molecule

Since 2000, federal regulations have affirmed that patients have a right to a complete copy of their health records from their physicians and hospitals. Today, providers across the nation use electronic health records and electronic information exchange for health care, and patients are choosing digital health apps to help them manage their own health and health information. Some doctors and health systems have voiced concern about whether they may transmit a patient’s data upon the patient’s request to the patient or the patient’s health app. This hesitation impedes shared information and care coordination with patients. It impairs patients’ ability to use the state-of-the-art digital health tools they choose to track and manage their health. It undermines the ability of patients’ family caregivers to monitor health and to work remotely to provide care by using the nearly unique capabilities of health apps on people’s smartphones. This paper explains that sharing data electronically with patients and patients’ third-party apps is legally consistent under the Health Insurance Portability and Accountability Act (HIPAA) with routine electronic data sharing with other doctors for treatment or with insurers for reimbursement. The paper explains and illustrates basic principles and scenarios around sharing with patients, including patients’ third-party apps. Doctors routinely and legally share health data electronically under HIPAA whether or not their organizations retain HIPAA responsibility. Sharing with patients and patients’ third-party apps is no different and should be just as routine.

UNSTRUCTURED Since 2000, federal regulations have affirmed that patients have a right to a complete copy of their health records from their physicians and hospitals. Today, providers across the nation use electronic health records and electronic information exchange for health care, and patients are choosing digital health apps to help them manage their own health and health information. Some doctors and health systems have voiced concern about whether they may transmit a patient’s data upon the patient’s request to the patient or the patient’s health app. This hesitation impedes shared information and care coordination with patients. It impairs patients’ ability to use the state-of-the-art digital health tools they choose to track and manage their health. It undermines the ability of patients’ family caregivers to monitor health and to work remotely to provide care by using the nearly unique capabilities of health apps on people’s smartphones. This paper explains that sharing data electronically with patients and patients’ third-party apps is legally consistent under the Health Insurance Portability and Accountability Act (HIPAA) with routine electronic data sharing with other doctors for treatment or with insurers for reimbursement. The paper explains and illustrates basic principles and scenarios around sharing with patients, including patients’ third-party apps. Doctors routinely and legally share health data electronically under HIPAA whether or not their organizations retain HIPAA responsibility. Sharing with patients and patients’ third-party apps is no different and should be just as routine.

Background Health systems have recently started to activate patient-facing application programming interfaces (APIs) to facilitate patient access to health data and other interactions. Objective This study sought to ascertain health systems’ understanding, strategies, governance, and organizational infrastructure around patient-facing APIs, as well as their business drivers and barriers, to facilitate national learning, policy, and progress toward adoption. Methods We performed a content analysis of semistructured interviews with a convenience sample of 10 health systems known to be leading adopters of health technology, having either implemented or planning to implement patient-facing APIs. Results Of the 10 health systems, eight had operational patient-facing APIs, with organizational strategy driven most by federal policy, the emergence of Health Records on iPhone, and feelings of ethical obligation. The two priority use cases identified were enablement of a patient’s longitudinal health record and digital interactions with the health system. The themes most frequently cited as barriers to the increased use of patient-facing APIs were security concerns, an immature app ecosystem that does not currently offer superior functionality compared with widely adopted electronic health record (EHR)–tethered portals, a lack of business drivers, EHR vendor hesitation toward data sharing, and immature technology and standards. Conclusions Our findings reveal heterogeneity in health system understanding and approaches to the implementation and use of patient-facing APIs. Ongoing study, targeted policy interventions, and sharing of best practices appear necessary to achieve successful national implementation.

Objective: To describe the characteristics of patients presenting to an Emergency Department (ED) following overdoses; to identify risk factors for intensive care unit (ICU) admission among these patients; and to identify the rate of mortality and repeat overdose presentations over four years. Methods: Adult patients presenting to ED following drug overdose during 2014 were included. Data were collected from medical notes and hospital databases. Results: During the study period, 654 patients presented to ED 800 times following overdose. Seventy-eight (9.8%) resulted in ICU admission, and 59 (7.4%) required intubation; 57.2% had no history of overdose presentations, and 72.9% involved patients with known psychiatric illness. Overdose of atypical antipsychotics (AAP), age and history of prior overdose independently predicted ICU admission. A third of patients ( n = 196, 30%) had subsequent presentations to ED following overdose, in the four years from their index presentation, with an all-cause four-year mortality of 3.4% ( n = 22). Conclusion: A history of overdose, use of AAP and older age were risk factors for ICU admission following ED presentations. Over a third of patients had repeat overdose presentation in the four-year follow-up with a mortality of 3.4%.

BACKGROUND Health systems have recently started to activate patient-facing application programming interfaces (APIs) to facilitate patient access to health data and other interactions. OBJECTIVE This study sought to ascertain health systems’ understanding, strategies, governance, and organizational infrastructure around patient-facing APIs, as well as their business drivers and barriers, to facilitate national learning, policy, and progress toward adoption. METHODS We performed a content analysis of semistructured interviews with a convenience sample of 10 health systems known to be leading adopters of health technology, having either implemented or planning to implement patient-facing APIs. RESULTS Of the 10 health systems, eight had operational patient-facing APIs, with organizational strategy driven most by federal policy, the emergence of Health Records on iPhone, and feelings of ethical obligation. The two priority use cases identified were enablement of a patient’s longitudinal health record and digital interactions with the health system. The themes most frequently cited as barriers to the increased use of patient-facing APIs were security concerns, an immature app ecosystem that does not currently offer superior functionality compared with widely adopted electronic health record (EHR)–tethered portals, a lack of business drivers, EHR vendor hesitation toward data sharing, and immature technology and standards. CONCLUSIONS Our findings reveal heterogeneity in health system understanding and approaches to the implementation and use of patient-facing APIs. Ongoing study, targeted policy interventions, and sharing of best practices appear necessary to achieve successful national implementation.

Scaling of projects from inception to establishment within the healthcare system is rarely formally reported. The Victorian Stroke Telemedicine (VST) programme provided a very useful opportunity to describe how rural hospitals in Victoria were able to access a network of Melbourne-based neurologists via telemedicine. The VST programme was initially piloted at one site in 2010 and has gradually expanded as a state-wide regional service operating with 16 hospitals in 2017. The aim of this paper is to summarise the factors that facilitated the state-wide transition of the VST programme. A naturalistic case-study was used and data were obtained from programme documents, e.g. minutes of governance committees, including the steering committee, the management committee and six working groups; operational and evaluation documentation, interviews and research field-notes taken by project staff. Thematic analysis was undertaken, with results presented in narrative form to provide a summary of the lived experience of developing and scaling the VST programme. The main success factors were attaining funding from various sources, identifying a clinical need and evidence-based solution, engaging stakeholders and facilitating co-design, including embedding the programme within policy, iterative evaluation including performing financial sustainability modelling, and conducting dissemination activities of the interim results, including promotion of early successes.

In brief: Sixty-three students aged 7 to 12 years (32 boys, 31 girls) were assessed for coronary heart disease (CHD) risk factors, including family history of CHD, blood pressure, VO2 max, serum lipids, body composition, and history of diabetes mellitus and cigarette smoking. Forty-two percent of the children had one risk factor, and 12% and 3% had two and three risk factors, respectively. This information was used to encourage school administrators and faculty to modify the physical education program, teach health and fitness concepts in the classroom, and develop a rehabilitation program for children at risk.

Purpose Selumetinib (AZD6244, ARRY-142886), an oral mitogen activated kinase 1/2 inhibitor, is in clinical development for the treatment of a variety of different tumor types. Herein, we report a study that determined the distribution, metabolism, and excretion of selumetinib in healthy male volunteers. Methods In this open-label, single-center, Phase I clinical trial, 6 subjects received a single 75-mg dose of [ 14 C]-selumetinib. Blood and excreta samples were collected for pharmacokinetic and radiometric analyses. Tolerability monitoring was performed throughout the study. Findings The C max of plasma selumetinib was 1520 ng/mL at 1 hour postdose and declined with a t 1/2 of 13.7 hours. Over a 216-hour postdose collection period, total dose recovery was 93% of the radioactive dose, with 59% recovered from feces and 33% from urine. Circulating drug-related material was primarily associated with plasma, with minimal distribution into red blood cells. Selumetinib was the major circulating drug-related component and accounted for 40% of the plasma radioactivity (mean of AUC 0–72h pool). The major circulating metabolite (M2; accounting for 22% of the plasma radioactivity) resulted from multiple biotransformation pathways, including loss of the ethanediol moiety in combination with glucuronidation. A further 6 circulating metabolites were identified, each accounting for between 2% and 7% of plasma radioactivity. Selumetinib was a minor component in urine, accounting for ≤1% of the dose. M2 was the most abundant metabolite in urine, accounting for 10% of the dose, and there were 5 other metabolites accounting for between 1% and 10% of the dose. In feces, selumetinib accounted for a mean of 19% of the dose. Also present were 7 metabolites accounting for between 1% and 9% of the dose. The majority of the dose was recovered as metabolites, indicating that the liver is the major route of drug elimination. There were no tolerability concerns. Implications The findings from this study will inform the label and will contribute to the understanding of the clinical pharmacology of selumetinib. ClinicalTrials.gov identifier: NCT01931761.

Short radius laterals, where a drilling tool is able to make a right turn in a cased wellbore and then penetrate some distance out into a formation, is an attractive technology for enhanced oil recovery for both existing and new field developments. Lateral holes with different geometries can penetrate untapped compartments, thin or by-passed pay, less permeable oil zones that cannot be sufficiently drained by conventional processes, and extend the effective radius of a well while reducing skin effects. A commonly referenced technology is radial jet drilling, where a specialized shoe is deployed in the well, a casing cutter cuts a hole through the pipe, and then a nozzle with high-pressure cutting jets is deployed on a hose at the end of coiled tubing. The technology has yet to become common in the United States, despite tens of thousands of candidate wells that could benefit from such a restimulation. Problems with jet drilling systems include: uncertainty in distance and direction of emplaced laterals; low available power to front-facing cutting jets, as most of the power has to be directed to rear-facing jets to keep the nozzle on the formation; and difficulties cutting hard formations and when encountering hard clasts. The objective of this study was to evaluate a newly developed technology for production enhancement from low-permeability reserves that utilizes a purely mechanical drilling string deployed on coiled tubing that is able to make a right-angle turn in a wellbore and drill a ~1.5 in. diameter lateral 30 ft or more into a reservoir. To study the technology, two wells were selected and stimulated. A simulation study for one of the field test sites, Millman field, a Grayburg/San Andres field in the Permian Basin, New Mexico, allowed a sensitivity study for optimization of lateral emplacements, optimal number of laterals per level, and allowed prediction of the impact of the recompletions. The prediction of lateral efficiency showed that the four emplaced laterals gave the best overall efficiency for enhancing oil production with 28.5% predicted incremental production in previously stimulated zones, and a 33.3% increase for previously unstimulated zones. Diagnostic techniques for monitoring lateral direction and placement based on small, chip-based gyroscope and accelerometer chips were developed and field-tested, verifying lateral emplacement during the field tests. The first test well saw ~40% increase in oil rate with emplacement of 12 laterals in three intervals. The second test well saw a 47% increase in production after 15 laterals targeted a previously untapped zone. This paper presents, discusses, and validates the drilling technology, the simulation models and results, the sensor development, and field-testing of those three technologies at two wells, with the emplacement of 27 total laterals with lengths of up to 32 ft.

The harvesting of noble fir (Abies procera) for the production of Christmas wreaths and related products has been a mainstay of the nontimber forest products industry in the Pacific Northwest (PNW) for decades. Although noble fir is the single most important bough product harvested in the PNW, little or no work has been published concerning the estimation of the weight of harvestable boughs from standing trees. The model presented in this article was designed specifically for use in predicting the weight of harvestable boughs from standing trees. A total of 322 noble fir were selected on the west side of the Cascades of Washington and Oregon. The stands and sites for sampling were chosen to represent a wide range of environmental and stand conditions. Sample trees were selected at fixed distances along systematical located lines at each selected site. Circular plots with a 20-ft radius centered at each sample tree were established to provide data on competition. Regression analysis was used to estimate the final model. Variables included in the final model were total tree height, merchantable bough height, dbh2, age at dbh, whorl age for each merchantable whorl, and the associated number of boughs for each whorl as well as the total number of trees within a 20-foot radius of the plot tree. In addition, an intercept shifter (0,1) to designate noble fir stands located north and South of the Marion/Clackamas County line in Oregon (South = 0, North = 1) was included in the model. The overall model was significant at the 0.0001 level with an adjusted R2 of 0.77 West. J. Appl. For. 20(1):44–49.

Bottom water coning has a detrimental impact on the performance of steam assisted gravity drainage (SAGD) causing reduced oil mobility around the producer. It, also, leads to higher steam to oil ratio (SOR). Produced water chlorides concentration can be used as an indication and quantification tool for bottom water coning analysis. The chlorides material balance for bottom water coning analysis depends upon connate water saturation and the concentrations of chlorides in connate water, bottom water and produced water along with the water cut of produced emulsion. Most oil sands are water wet but wettability changes with high steam temperatures and almost all the connate water is drained because of steaming. The safe produced water chlorides concentration, at which no bottom water is produced, depends mainly upon connate water saturation and its chlorides concentration besides water cut and oil saturation. Therefore, careful sampling and laboratory procedures for connate water chlorides measurement is vital in bottom water coning analysis. The mechanical extraction device (referred to as the plunger) was developed mainly to facilitate the recovery of heavy oil and bitumen samples from oil sands cores. In this study, the plunger technology is employed in order to recover water samples to enable measure connate water chlorides PPM (concentration in parts per million). The measured connate water chlorides are also corrected for drilling fluid invasion. A new material balance for bottom water coning analysis is established based on different connate water and bottom water chlorides concentrations and drainage patterns of connate water and oil saturations. The new material balance is used to determine the safe chlorides concentration and applied to bottom water coning analysis in the field application at Leismer SAGD project. Since, the earlier study assumed the same chlorides concentrations of bottom water and connate water, the new measurement technique of chlorides concentration of connate water has led to a better material balance calculation for bottom water coning and data analysis. The new material balance has led to a lower safe chlorides limit. It has, also, helped better optimization of steam chamber pressure and steam injection strategy to avoid negative impacts of bottom water conning to enhance oil production and lower SOR at Leismer.

PF-184298 ((S)-2,3-dichloro-N-isobutyl-N-pyrrolidin-3-ylbenzamide) and PF-4776548 ((3-(4-fluoro-2-methoxy-benzyl)-7-hydroxy-8,9-dihydro-3H,7H-pyrrolo[2,3-c][1,7]naphthyridin-6-one)) are novel compounds which were selected to progress to human studies. Discordant human pharmacokinetic predictions arose from pre-clinical in vivo studies in rat and dog, and from human in vitro studies, resulting in a clearance prediction range of 3 to >20 mL min⁻¹ kg⁻¹ for PF-184298, and 5 to >20 mL min⁻¹ kg⁻¹ for PF-4776548. A package of work to investigate the discordance for PF-184298 is described. Although ultimately complementary to the human pharmacokinetic data in characterising the disposition of PF-184298 in humans, these data did not provide any further confidence in pharmacokinetic prediction. A fit for purpose human pharmacokinetic study was conducted for each compound, with an oral pharmacologically active dose for PF-184298, and an intravenous and oral microdose for PF-4776548. This provided a relatively low cost, clear decision making approach, resulting in the termination of PF-4776548 and further progression of PF-184298. A retrospective analysis of the data showed that, if the tools had been available at the time, the pharmacokinetics of PF-184298 in human could have been predicted from a population based simulation tool in combination with physicochemical properties and in vitro human intrinsic clearance.

Beaked whales have been over-represented in whale strandings that have occurred at similar times and places of some naval exercises in the northern hemisphere. Although whale strandings are common, it is unusual to find beaked whales stranded in such large numbers. Consequently, the environmental management of naval exercises requires mitigation measures to avoid potential impact on beaked whales. This requires some knowledge of beaked whale distributions and behavior, but little is known about beaked whales, less than for all other whales. Beaked whales are small whales that inhabit deep water. They are particularly elusive and rarely seen at sea. Much of what little is known about them results from the few that have been washed ashore. Visual surveying has proved to be generally ineffective. Beaked whale vocalizations are, however, sufficiently distinctive to allow passive acoustic detection and classification [1]. The sounds are sufficiently distinctive to distinguish them from those of other toothed whales, though these distinctions are subtle. All toothed whales produce echolocation clicks or pulses with a small number of cycles and most energy at ultrasonic frequencies. Beaked whale clicks can be distinguished by the frequency range, duration and number of cycles but other species have clicks that are close in one or other of the characteristics.

Serotonin syndrome is a predictable consequence of excess serotonergic agonism of the central nervous system receptors as well as peripheral serotonergic receptors.1 The clinical manifestations of the syndrome range from barely noticeable to fatal features. In serotonin synthesis, ingested tryptophan crosses the blood-brain barrier and enters neurones where it is hydrolysed and decarboxylated to serotonin. The serotonin is stored in vesicles and released into the synaptic cleft with resultant depolarisation of the presynaptic neurones. 2,3 Removal of serotonin from the cleft is via reuptake pumps and it is either repackaged or degraded by monoamine oxidase (MAO). Monoamine oxidase has two isoforms: MAO-A which metabolises serotonin, and MAO-B which metabolises catecholamines. 4 Theoretically, damage to vascular endothelium is associated with a decrease in MAO-A activity, hence a reduction in the capacity to metabolise serotonin with a resultant increase in levels of serotonin. This lesson reports the case of serotonin syndrome in a 71 -year-old man secondary to fluoxetine believed to be precipitated by radiation-induced vasculopathy.

REFERENCES 1. Wajchenberg BL, Mendonca BB et. al; Ectopic ACTH syndrome. Endocrine review 15:752-787 2. Bhansali A, Walia R et. Al; Ectopic Cushing`s syndrome: experience from a tertiary care centre. Indian J Med Res 129, January 2009, p33-41 3. Kondo T, Matsuyama R et al; A cae of ectopic ACTH producing pancraetic NET with multiple liver metastasis. Endocrine Journal, 2009, p1-8 4. Pascual-Le Tallec L, Dulmet E et al. Identification of genes associated with the corticotroph pnenotype in bronchial carcinoid tumours. J Clin Endocrinol Metab 2002; 87:5015 5. White A, Ray DW et al. Cushing`s syndrome due to phaeochromocytoma secreting the precursors of adrenocorticotropin. J Clin Endocrinol Metab 2000; 85:4771 TREATMENT POST-OP COURSE

Previous experiments from this laboratory demonstrated that oral administration of D-penicillamine (DPA) throughout gestation produced significant teratogenic effects and low copper concentrations in both maternal and fetal tissues in a dose-related manner. To test the hypothesis that the teratogenicity of DPA was due to induced copper deficiency, Sprague-Dawley rats were fed throughout gestation complete, purified diets containing 5 (control), 50, or 100 micrograms/g (supplemental) copper. One-half of the rats in each group received DPA at 0.83% of the diet. On day 21 of gestation, fetuses were removed and examined for gross malformations. Selected maternal and fetal tissues were analyzed for copper, zinc, iron and manganese. Animals fed the drug and supplemental copper had a very low incidence of fetal resorption (4%) and malformation (4%) compared to a high frequency of resorption (23%) and malformation (21%) in drug-fed nonsupplemented animals. There were no consistent differences in tissue iron, zinc or manganese levels among the groups. Tissue copper concentrations were lowest in the drug-fed, nonsupplemented group; those of the group fed DPA and supplemental copper were higher, but did not reach control values. Thus, there was a correlation between tissue copper levels and the frequency of malformations, supporting our hypothesis that DPA teratogenicity is due at least in part to induced copper deficiency.

The teratogenicity of D-penicillamine was studied using the Sprague-Dawley rat. Fetuses from rats fed diets containing 0.83% D-penicillamine during pregnancy had a high incidence of malformations. Maternal and fetal tissue copper levels were significantly lower in the D-penicillamine group than in controls, suggesting that the teratogenicity of the drug may be due in part to the induction of copper deficiency by its chelating properties.

One undertakes a study of the law of abortion with a sense of irony. Abortion is very personal to the woman considering it. Laws on abortion, however, and studying the laws of abortion, separate the act and the choice from their very bases in each woman's experience. With this abstraction, each abortion becomes either legal or illegal, depending upon the law of the country where the woman lives, and becomes an instrument of a state's demographic policies, or its health policies, or its policies on crime, or its policies on women's rights. A note on the law of abortion in the Union of Soviet Socialist Republics (U.S.S.R.) and the People's Republic of China (P.R.C.) cannot completely resolve this disparity between personal reality and abstract law and policy. It must analyze the laws on abortion, with legal criteria, even while undertaking to determine how those laws affect women personally.'

The teratogenicity of D-penicillamine (DP) (dimethyl cysteine) was studied using the Sprague-Dawley rat. D-Penicillamine was fed during pregnancy at a level of 0 (control), 0.17, 0.83, or 1.66% of the diet. The frequency of resorptions, and the frequency and severity of malformations, increased with increasing levels of the drug. Maternal and fetal tissue copper levels were significantly lower in the DP groups than in controls, with the levels decreasing in a dose-related manner. Maternal and fetal zinc levels were lower in the 1.6% DP group than in controls. Maternal liver iron concentration was higher in the drug-fed rats than in controls, increasing in a dose-related manner. Fetal iron concentration was not consistently affected by the drug. Maternal and fetal manganese, calcium, and magnesium concentrations were similar among all groups. These results suggest that the teratogenicity of D-penicillamine may be due in part to induction of copper deficiency and, at high dose levels, zinc deficiency, caused by its chelating properties.