Impact of Covid-19 on farming systems in Europe through the lens of resilience thinking.

Context: Resilience is the ability to deal with shocks and stresses, including the unknown and previously unimaginable, such as the Covid-19 crisis. Objective: This paper assesses (i) how different farming systems were exposed to the crisis, (ii) which resilience capacities were revealed and (iii) how resilience was enabled or constrained by the farming systems' social and institutional environment. Methods: The 11 farming systems included have been analysed since 2017. This allows a comparison of pre-Covid-19 findings and the Covid-19 crisis. Pre-Covid findings are from the SURE-Farm systematic sustainability and resilience assessment. For Covid-19 a special data collection was carried out during the early stage of lockdowns. Results and conclusions: Our case studies found limited impact of Covid-19 on the production and delivery of food and other agricultural products. This was due to either little exposure or the agile activation of robustness capacities of the farming systems in combination with an enabling institutional environment. Revealed capacities were mainly based on already existing connectedness among farmers and more broadly in value chains. Across cases, the experience of the crisis triggered reflexivity about the operation of the farming systems. Recurring topics were the need for shorter chains, more fairness towards farmers, and less dependence on migrant workers. However, actors in the farming systems and the enabling environment generally focused on the immediate issues and gave little real consideration to long-term implications and challenges. Hence, adaptive or transformative capacities were much less on display than coping capacities. The comparison with pre-Covid findings mostly showed similarities. If challenges, such as shortage of labour, already loomed before, they persisted during the crisis. Furthermore, the eminent role of resilience attributes was confirmed. In cases with high connectedness and diversity we found that these system characteristics contributed significantly to dealing with the crisis. Also the focus on coping capacities was already visible before the crisis. We are not sure yet whether the focus on short-term robustness just reflects the higher visibility and urgency of shocks compared to slow processes that undermine or threaten important system functions, or whether they betray an imbalance in resilience capacities at the expense of adaptability and transformability. Significance: Our analysis indicates that if transformations are required, e.g. to respond to concerns about transnational value chains and future pandemics from zoonosis, the transformative capacity of many farming systems needs to be actively enhanced through an enabling environment.

Expanding the genotypic spectrum of Perrault syndrome.

Perrault syndrome is a rare autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) in both sexes and primary ovarian insufficiency in 46, XX karyotype females. Biallelic variants in five genes are reported to be causative: HSD17B4, HARS2, LARS2, CLPP and C10orf2. Here we present eight families affected by Perrault syndrome. In five families we identified novel or previously reported variants in HSD17B4, LARS2, CLPP and C10orf2. The proband from each family was whole exome sequenced and variants confirmed by Sanger sequencing. A female was compound heterozygous for a known, p.(Gly16Ser) and novel, p.(Val82Phe) variant in D-bifunctional protein (HSD17B4). A family was homozygous for mitochondrial leucyl aminocyl tRNA synthetase (mtLeuRS) (LARS2) p.(Thr522Asn), previously associated with Perrault syndrome. A further family was compound heterozygous for mtLeuRS, p.(Thr522Asn) and a novel variant, p.(Met117Ile). Affected individuals with LARS2 variants had low frequency SNHL, a feature previously described in Perrault syndrome. A female with significant neurological disability was compound heterozygous for p.(Arg323Gln) and p.(Asn399Ser) variants in Twinkle (C10orf2). A male was homozygous for a novel variant in CLPP, p.(Cys144Arg). In three families there were no putative pathogenic variants in these genes confirming additional disease-causing genes remain unidentified. We have expanded the spectrum of disease-causing variants associated with Perrault syndrome.

DMRTA2 (DMRT5) is mutated in a novel cortical brain malformation.

Lissencephaly is a phenotypically and genetically heterogeneous group of cortical brain malformations due to abnormal neuronal migration. The identification of many causative genes has increased the understanding of normal brain development. A consanguineous family was ascertained with three siblings affected by a severe prenatal neurodevelopmental disorder characterised by fronto-parietal pachygyria, agenesis of the corpus callosum and progressive severe microcephaly. Autozygosity mapping and exome sequencing identified a homozygous novel single base pair deletion, c.1197delT in DMRTA2, predicted to result in a frameshift variant p.(Pro400Leufs*33). DMRTA2 encodes doublesex and mab-3-related transcription factor a2, a transcription factor key to the development of the dorsal telencephalon. Data from murine and zebrafish knockout models are consistent with the variant of DMTRA2 (DMRT5) as responsible for the cortical brain phenotype. Our study suggests that loss of function of DMRTA2 leads to a novel disorder of cortical development.

A new taxonomy for describing and defining adherence to medications.

Interest in patient adherence has increased in recent years, with a growing literature that shows the pervasiveness of poor adherence to appropriately prescribed medications. However, four decades of adherence research has not resulted in uniformity in the terminology used to describe deviations from prescribed therapies. The aim of this review was to propose a new taxonomy, in which adherence to medications is conceptualized, based on behavioural and pharmacological science, and which will support quantifiable parameters. A systematic literature review was performed using MEDLINE, EMBASE, CINAHL, the Cochrane Library and PsycINFO from database inception to 1 April 2009. The objective was to identify the different conceptual approaches to adherence research. Definitions were analyzed according to time and methodological perspectives. A taxonomic approach was subsequently derived, evaluated and discussed with international experts. More than 10 different terms describing medication-taking behaviour were identified through the literature review, often with differing meanings. The conceptual foundation for a new, transparent taxonomy relies on three elements, which make a clear distinction between processes that describe actions through established routines ('Adherence to medications', 'Management of adherence') and the discipline that studies those processes ('Adherence-related sciences'). 'Adherence to medications' is the process by which patients take their medication as prescribed, further divided into three quantifiable phases: 'Initiation', 'Implementation' and 'Discontinuation'. In response to the proliferation of ambiguous or unquantifiable terms in the literature on medication adherence, this research has resulted in a new conceptual foundation for a transparent taxonomy. The terms and definitions are focused on promoting consistency and quantification in terminology and methods to aid in the conduct, analysis and interpretation of scientific studies of medication adherence.

Effects on blood pressure and cardiovascular risk of variations in patients' adherence to prescribed antihypertensive drugs: role of duration of drug action.

AIM: To determine the effects of imperfect adherence (i.e. occasionally missing prescribed doses), and the influence of rate of loss of antihypertensive effect during treatment interruption, on the predicted clinical effectiveness of antihypertensive drugs in reducing mean systolic blood pressure (SBP) and cardiovascular disease (CVD) risk. METHOD: The effects of imperfect adherence to antihypertensive treatment regimens were estimated using published patterns of missed doses, and taking into account the rate of loss of antihypertensive effect when doses are missed (loss of BP reduction in mmHg/day; the off-rate), which varies between drugs. Outcome measures were the predicted mean SBP reduction and CVD risk, determined from the Framingham Risk Equation for CVD. RESULTS: In patients taking 75% of prescribed doses (typical of clinical practice), only long-acting drugs with an off-rate of ∼1 mmHg/day were predicted to maintain almost the full mean SBP-lowering effect throughout the modelled period. In such patients, using shorter-acting drugs (e.g. an off-rate of ∼5-6 mmHg/day) was predicted to lead to a clinically relevant loss of mean SBP reduction of > 2 mmHg. This change also influenced the predicted CVD risk reduction; in patients with a baseline 10-year CVD risk of 27.0% and who were taking 75% of prescribed doses, a difference in off-rate from 1 to 5 mmHg/day led to a predicted 0.5% absolute increase in 10-year CVD risk. CONCLUSIONS: In patients who occasionally miss doses of antihypertensives, modest differences in the rate of loss of antihypertensive effect following treatment interruption may have a clinically relevant impact on SBP reduction and CVD risk. While clinicians must make every effort to counsel and encourage each of their patients to adhere to their prescribed medication, it may also be prudent to prescribe drugs with a low off-rate to mitigate the potential consequences of missing doses.

ADVIRC is caused by distinct mutations in BEST1 that alter pre-mRNA splicing.

Autosomal dominant vitreoretinochoroidopathy (ADVIRC), a retinal dystrophy often associated with glaucoma and cataract, forms part of a phenotypic spectrum of 'bestrophinopathies'. It has been shown previously that ADVIRC results from BEST1 mutations that cause exon skipping and lead to the production of shortened and internally deleted isoforms. This study describes a novel ADVIRC mutation and show that it disrupts an exonic splice enhancer (ESE) site, altering the binding of a splicing-associated SR protein. As with previous ADVIRC mutations, the novel c.704T-->C mutation in exon 6 altered normal splicing in an ex vivo splicing assay. Both this and another exon 6 ADVIRC-causing mutation (c.707G-->A) either weakened or abolished splicing in an ESE-dependent splice assay compared with a nearby exon 6 mutation associated with Best disease (c.703G-->C). Gel shift assays were undertaken with RNA oligonucleotides encompassing the ADVIRC and Best disease mutations with four of the most commonly investigated SR proteins. Although SC35, SRp40 and SRp55 proteins all bound to the wild-type and mutated sequences with similar intensities, there was increased binding of ASF/SF2 to the two ADVIRC-mutated sequences compared with the wild-type or Best disease-mutated sequences. The exon skipping seen for these two exon 6 ADVIRC mutations and their affinity for ASF/SF2 suggests that the region encompassing these mutations may form part of a CERES (composite exonic regulatory elements of splicing) site.

The electronic, 'paperless' medical office; has it arrived?

Modern information technology offers efficiencies in medical practice, with a reduction in secretarial time in maintaining, filing and retrieving the paper medical record. Electronic requesting of investigations allows tracking of outstanding results. Less storage space is required and telephone calls from pharmacies, pathology and medical imaging service providers to clarify the hand-written request are abolished. Voice recognition software reduces secretarial typing time per letter. These combined benefits can lead to significantly reduced costs and improved patient care. The paperless office is possible, but requires commitment and training of all staff; it is preferable but not absolutely essential that at least one member of the practice has an interest and some expertise in computers. More importantly, back-up from information technology providers and back-up of the electronic data are absolutely crucial and a paperless environment should not be considered without them.

Pneumocephalus with headache complicating labour epidural analgesia: should we still be using air?

Pneumocephalus is a rare complication of epidural block which typically occurs when the loss of resistance to air technique is used to identify the epidural space. We present a case of pneumocephalus with headache in a parturient following apparently uncomplicated labour epidural analgesia.

Commentary on "A Framework for Quantifying the Influence of Adherence and Dose Individualization".

Drugs that provide long durations of action after a last-taken dose are said to be "forgiving," as they allow the patient a degree of latitude in the timing of sequential doses. New research, by Assawasuwannakit et al.,(1) based on exemplary methods, enriches the pharmacometric analysis of forgiveness, which for several decades had been a simply descriptive reminder that the beneficial actions of some drugs can continue for hours or days after the disappearance of detectable drug.

Rate of increase in the plasma concentration of nifedipine as a major determinant of its hemodynamic effects in humans.

The relevance of the rate of increase in the plasma concentration of nifedipine for the drug's hemodynamic effect was investigated in healthy volunteers. Nifedipine was given intravenously according to two regimens, each designed to produce the same steady-state concentration, but attained gradually (within 5 to 7 hours) with one regimen and rapidly (within 3 minutes) with the other. The mean steady-state concentrations obtained were 31.7 +/- 5.2 (SD) ng/ml and 29.4 +/- 9.8 ng/ml, respectively (not significant). With the gradual regimen, heart rate was unchanged and diastolic blood pressure was lowered gradually by approximately 10 mm Hg. With the rapid regimen, heart rate increased immediately and remained elevated for the duration of the infusion, whereas diastolic blood pressure did not change significantly. At the end of the gradual-rise regimen, the infusion rate was increased tenfold for 10 minutes, promptly resulting in tachycardia and a paradoxical rise in diastolic blood pressure. These divergent hemodynamic responses of the gradual- and rapid-rise regimens could well be related to differences in baroreceptor activation. It is concluded that the hemodynamic response to nifedipine is influenced by the rate of increase of its concentration in plasma.

Role of patient compliance in clinical pharmacokinetics. A review of recent research.

Until 1986 to 1987, the estimation of patient compliance with prescribed drug regimens in ambulatory care relied on methods that were biased either by their subjectivity or by the improvement in compliance that commonly occurs during the day or two prior to a scheduled examination, so called 'white-coat compliance'. In 1986 to 1987, 2 objective methods were developed: electronic monitoring and low-dose, slow-turnover chemical markers (digoxin or phenobarbital [phenobarbitone]) incorporated into dosage forms. While neither method is without limitations, both have enabled major advances in the understanding of patients' compliance with dosage regimens and, thus, the spectrum of drug exposure in ambulatory care. The new methods have also triggered not only a revival of interest in patient compliance and its determinants, but also new statistical approaches to interpreting the clinical correlates of widely variable drug administration, and thus drug exposure, in drug trials. The marker methods prove dose ingestion during the 3 to 7 days prior to blood sampling, but do not reveal the timing of doses. The electronic monitoring methods, i.e. time and date-stamping microcircuitry incorporated into drug packages, provide a continuous record of timing of presumptive doses throughout periods of many months, but do not prove dose ingestion. The electronic record has been judged robust enough to detect certain types of investigator fraud, and to support modelling projections of the complete time course of the plasma drug concentration during a trial. Both marker and electronic methods show that the predominant errors are those of omission, i.e. delays or omissions of scheduled doses. Patient interviews, diaries, and counts of returned, untaken doses have been shown by both marker and electronic monitoring methods to consistently and substantially to overestimate compliance. Monitoring of plasma drug concentrations also overestimates compliance, because white-coat compliance is prevalent, and the pharmacokinetic turnover of most drugs is rapid enough that measured concentrations of drug in plasma reflect only drug administration during the period of white-coat compliance. Thus, compliance is a great deal poorer in clinical trials than has been revealed by the older methods. The long-standing underestimation of poor compliance in drug trials has many implications for the interpretation of drug trials, for optimal dose estimation, for the interpretation of failed drug therapy, and for accurate labelling of prescription drugs.

Comparative effects of calcium-channel blocking agents on left ventricular function during acute ischemia in dogs with and without congestive heart failure.

To examine the relative potencies of verapamil, nifedipine and diltiazem on left ventricular (LV) function under ischemic conditions, 20 conscious closed-chest dogs that had partial occlusion of their circumflex coronary arteries were studied. Myocardial blood flow was measured by microspheres, LV function by radionuclide angiography. Drug effects were compared at doses causing equal decreases in mean arterial pressure (MAP) and in coronary vascular resistance of the nonischemic zone. Global ejection fraction (EF) and EF of the ischemic region were significantly decreased by verapamil (p less than 0.002) and increased by nifedipine (p less than 0.001); diltiazem caused no significant changes. Verapamil significantly increased peak diastolic filling rate (p less than 0.001); nifedipine also increased diastolic filling rate but only at doses that markedly decreased MAP and coronary vascular resistance. Diltiazem was not significantly different from placebo. For doses causing an equal decrease in MAP, verapamil decreased heart rate (p less than 0.001), and diltiazem and nifedipine increased heart rate (p less than 0.05). Myocardial ischemic zone flow remained unchanged during placebo, verapamil, diltiazem or nifedipine infusion. To study the influence of heart failure on the hemodynamic effects of the calcium-channel blocking agents, 6 foxhounds underwent total occlusions of the left anterior descending coronary artery, resulting in myocardial infarction, volume loading to increase left atrial pressure and partial occlusion of the circumflex coronary artery. Verapamil depressed global left ventricular ejection fraction and increased left atrial pressure to as high as 40 to 45 mm Hg. In contrast, nifedipine decreased left atrial pressure and increased global EF.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantification of valve regurgitation by radionuclide angiography before and after valve replacement surgery.

Radionuclide gated cardiac blood pool imaging was used to quantify the severity of valve regurgitation in 20 patients, by calculating the ratio of left ventricular to right ventricular stroke counts (end-diastolic minus end-systolic counts in right and left ventricular regions of interest). This ratio (the stroke index ratio) was substantially higher in patients with aortic and mitral regurgitation (3.91 +/- 1.45) than in a control group of 10 patients without regurgitation (1.32 +/- 0.15), p less than 0.001. The stroke index ratio correlated closely (r = 0.947) with measurements of regurgitant fraction derived from simultaneous determinations of total and forward stroke volumes during cardiac catheterization. After aortic and mitral valve replacement in 18 patients, the stroke index ratio decreased from 4.03 +/- 1.46 to 1.38 +/- 0.23 (p less than 0.001), a value not significantly different from that observed in patients without regurgitation. All three patients with residual postoperative regurgitation had a stroke index ratio greater than 2 standard deviations above the mean values for the control group (greater than 1.62), whereas the remaining 15 patients, who had no evidence of regurgitation, had values within the normal range. Therefore, radionuclide gated blood pool scanning provides a noninvasive method of quantifying valve regurgitation and assessing the results of medical or surgical interventions.

Rapid method for estimating the risk of acutely controversial side effects of prescription drugs.

When controversy suddenly erupts about the risk of using a prescription drug, there is an urgent need for fast methods of risk estimation. Some unexpected side-effects of prescription drugs are indications for the prescribing of another kind of drug. If the risk of such a side-effect is high, it should be reflected in clustered prescribing of the side-effect-alleviating drug in sequence with the side-effect-causing drug. The risk of drug-attributable side-effects can be estimated by comparing average incidences of initial prescriptions for the side-effect-alleviating drug before, during, and long after the dispensing of the presumed side-effect-causing drug. We monitored computerized, complete drug dispensing records of anonymous outpatients for use of flunarizine, an anti-vertigo/anti-migraine drug that case reports had suggested causes mental depression and/or Parkinsonism. Among 1284 patients who eventually got flunarizine during a 31 month period, 1 in 7 was started on an anti-depressant before or long after flunarizine; only 1 in 82 might be said to have been started on an anti-depressant because of flunarizine. There was no evidence that anti-Parkinson drugs were started because of flunarizine, though the numbers are small. The analysis takes only a few days, and can help set bounds on risks of the subset of adverse drug reactions that are themselves indications for use of other drugs.

Spatial distribution of dopamine, methotrexate and antipyrine during continuous intracerebral microperfusion.

The spatial distributions of 3 model drugs, [14C]dopamine hydrochloride (DA), [3H]sodium methotrexate (MTX) and [14C]antipyrine (AP), were determined after 6 days continuous microperfusion of the diencephalon of rabbits. The basic pattern of distribution was the same for each drug: the tissue concentration, expressed as a function of the perfusate concentration, was maximal at the cannula tip, and declined sharply with radial distance from the tip. However, at any given distance, concentrations of radioisotopes derived from DA and MTX, both ionized, lipid-insoluble drugs, were one to two orders of magnitude higher than those derived from AP, a lipid-soluble drug. Although concentrations of isotopes derived from DA and MTX were in the same range, their distribution patterns were consistently different. The results demonstrate that intracerebrally microperfused drugs may have quantitatively different spatial distributions, related to their physicochemical characteristics and/or their binding and metabolism in brain tissue.

Incidence and determinants of sildenafil (dis)continuation: the Dutch cohort of sildenafil users.

Sildenafil utilization was prospectively evaluated among 153 men with a history of erectile dysfunction (ED)-prescription drug use prior to starting sildenafil and 164 men who were new starters of ED-prescription drugs. Further, some determinants of sildenafil discontinuation were identified. During a median follow-up period of 18 months 45% of all patients discontinued sildenafil treatment, regardless of earlier treatment history. However, patients with a history of drug treatment for ED were nearly eight times as likely to switch or re-start another ED-prescription drug after discontinuing sildenafil compared to previously untreated users. Age >60 y, diabetes medication, nitrate use, and use of incontinence pads (a proxy for disease/surgery in the pelvic region) were associated with an increased likelihood of discontinuing sildenafil. Although the introduction of sildenafil reduced the barrier to seek medical help for erectile problems, sildenafil treatment failure in previously untreated patients results in a high dropout rate from further ED drug treatment of any kind.

Comparative distribution of pilocarpine in ocular tissues of the rabbit during administration by eyedrop or by membrane-controlled delivery systems.

We compared the patterns of pilocarpine distribution in the rabbit eye during two regimens that were comparably efficacious in human clinical use: an administration of 2% pilocarpine nitrate eyedrops, every six hours, for four and eight days, and a continuous delivery of pilocarpine for as long as eight days, at 20 mug/hr, from a membrane-controlled delivery system in the inferior cul-de-sac. Pilocarpine labeled with radioactive carbon (14C) was used as a tracer. With administration of eyedrops, 14C levels in ocular tissues rose and fell within each six-hour interval between eyedrops, but with the delivery system, 14C levels remained constant over the two- to eight-day period. In each tissue, the 14C level within the first hour after the most recently administered eyedrop always exceeded the constant level maintained by the delivery system. Three to six hours after eyedrop administration, the 14C levels in cornea, iris, and sclera were approximately equal to those maintained by the delivery system. However, in lens, vitreous humor, and conjunctiva, the 14C levels were always two to five times higher with eyedrop administration than with the delivery system. Only aqueous humor showed a significantly lower 14C level with eyedrops than with the delivery system, occurring late in the interval between eyedrops. Compared to eyedrop administration, the membrane-controlled delivery system produced drug levels in ocular tissues that were constant rather than variable with time, and appreciably lower in tissues where the drug made no known contribution to the reduction of pressure.

Channelling of controlled release formulation of ketoprofen (Oscorel) in patients with history of gastrointestinal problems.

STUDY OBJECTIVE: The aim was to determine if a new controlled release formulation (Oscorel) of the non-steroidal anti-inflammatory drug (NSAID) ketoprofen has been preferentially prescribed in patients with prior history of gastro-intestinal disturbances. DESIGN: The study was a pharmacy records based comparison of the rates of prior prescribing of drugs indicated for peptic ulcer treatment in first recipients of Oscorel in 1989 versus recipients of other NSAID products. SETTING: A representative panel of Dutch community pharmacies serving approximately 425,000 people was used. MAIN RESULTS: Oscorel was launched in January 1989. Data on prescriptions dispensed in 1987-1988 to a total of 837 first users of Oscorel were analysed and compared with the dispensing history of a reference population including 30,787 patients who did not receive a prescription for Oscorel during 1989. Compared to the reference population, first users of Oscorel included a greater proportion of females, of patients 75 years and older, of heavy users of NSAIDs, and of patients switching among different NSAIDs. A total of 24.1% of first users of Oscorel had received peptic ulcer therapy in 1987-1988, versus 15.7% of the reference population. The rate ratio was 1.54, with 95% confidence interval of 1.36-1.74. Adjustment for stratifying variables caused only minor changes in the rate ratio, which remained stable on 1.5. CONCLUSIONS: Oscorel appears to have been channelled into use in patients with recognised risk factors for gastrointestinal toxicity. This preferential prescribing probably resulted from expectations and claims that this product has a lower risk of such toxicity.

Pharmacoeconomic consequences of variable patient compliance with prescribed drug regimens.

Variable compliance with prescribed drug regimens is a leading source of variability in drug response. Specifics differ by drug and disease. The role of variable compliance was clearly defined in 2 trials of lipid-lowering agents, cholestyramine and gemfibrozil, in which exceptionally careful measurements of compliance were made, which has not been done in later trials. Economic consequences of variable compliance are estimated by converting dose-dependent changes in absolute risk of incident coronary disease into the unicohort format, which designates how many patients must be treated to prevent, in a given time, a defined 'coronary event'. Two strong influences on the costs of treatment are: (i) the shape of the relation between drug intake and risk reduction; and (ii) the strength of the linkage between intake and prescription refills. The intake-effect relation for cholestyramine is linear, making compliance-neutral the cost to prevent 1 coronary event, provided that refills match intake. If refills exceed intake, treatment costs rise. The intake-effect relation for gemfibrozil is more typically nonlinear, so poorer compliers purchase and take the drug in amounts that have little benefit, increasing the cost to prevent 1 coronary event. If refills run at a higher rate than intake, costs increase still further. A key question for future study is: do policies that encourage timely refills increase compliance enough to offset their potential to waste money in the purchasing of an untaken drug?

Effect of the venereal diseases epidemic on the incidence of ectopic pregnancy -- implications for the evaluation of contraceptives.

This paper identifies a basis for quantifying the risk of ectopic pregnancy in pregnancy seekers and in users of the major means of contraception, with and without prior tubal infection. The doubling, in U.S. in recent years, of both numbers of ectopic pregnancies and the prevalence of nonsurgical sterility is correlated with the epidemic of gonorrhea and other sexually transmitted, salpingitis-producing diseases. The risk of ectopic pregnancy in women who have once had salpingitis is shown, on the basis of Weström's landmark prospective study and many retrospective studies, to be approximately 10-fold that of normal women. Fertilization-preventing contraceptives reduce uterine and ectopic pregnancies in the same proportion and in both categories of users--that is, in normal-risk and high-risk (post-salpingitis) women. Intrauterine contraceptives, however, markedly reduce uterine pregnancies, but have little effect on the incidence of ectopic pregnancy. Among IUD users, therefore, the incidence of ectopic pregnancy will be disproportionately great in relation to the fraction of high-risk women in the population of users. This disproportionate influence of prior salpingitis may confuse the comparative evaluation of contraceptive safety because the proportions of normal-risk and high-risk women probably vary widely, since public health data show extremely wide geographic differences in the incidence of gonorrhea -- the best known but not the only sexually transmitted, salpingitis-producing disease.