Transactions of the House of Delegates

Aspiration of vomitus is one of the leading causes of anesthetic deaths. These deaths can be prevented only by proper evaluation of the patient preoperatively and assuming that any patient dealt with in emergency has a full stomach until proven otherwise. Preliminary observations on the incidence of "silent regurgitation and aspiration" in a series of patients anesthetized for elective operation indicated that by obtaining a smooth induction and preventing any respiratory obstruction during anesthesia, regurgitation and aspiration can be minimized.     

PREVENTION OF CARDIAC ARREST—The Role of the Anesthesiologist

Many operating room deaths from “cardiac arrests” are potentially avoidable as well as potentially reversible. The incidence of these catastrophes may be substantially reduced by careful and adequate preoperative evaluation and preparation of the patient, by constant care and vigilance in the administration of anesthetic agents and adjuvants, and by close cooperation between members of the surgical team, with the safety of the patient being the first consideration at all times.     

INITIAL CARE OF ACUTE BACK INJURIES

The mechanism of injury to the back should be obtained with the utmost accuracy and set down in the history as a separate paragraph under that heading. This is usually best obtained by questioning and requestioning the patient during the course of the examination. A history of any previous back affections should also be obtained at the first visit.The detailed examination of the back is not complete without a general physical examination.X-ray studies should be done immediately in all cases in which the injury has been caused by direct violence or forceful indirect violence (as in “jackknife” injury).Terms such as “disc disease,” “ruptured intervertebral disc” and various others that convey a similar meaning should not be used as the initial diagnosis and should be withheld until such a diagnosis is definitely established.The plan of treatment may include a period in hospital or of rest at home, or it may be carried out with the patient ambulatory. Corsets and braces should be prescribed only when they are to serve a definite function and the same can be said of physiotherapy.     

MEASLES ENCEPHALITIS—A Successful Method of Treatment with Typhoid Vaccine

During a 12-year period 50 patients with measles encephalitis were treated with typhoid vaccine—45 of them not until they were in a vegetative state. There were no deaths in the treated cases. All except one were clinically normal after treatment was ended. Late in the series it became apparent that after the clinical normal is attained and the electroencephalogram becomes normal, treatment should still be continued until the cortex has been “challenged” repeatedly and the electroencephalogram shown to remain normal.The “shock” element in the treatment with typhoid vaccine was prevented by anticipating and circumventing the unfavorable reactions to the vaccine.It may take 20 to 50 treatments or more with typhoid vaccine to return a patient to normality. Each individual is different and responds in a different period of time.     

Cells derived from iPSC can be immunogenic — Yes or No?

The induced pluripotent stem cells (iPSCs), derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. However, our recent studies have found that even syngeneic iPSC-derived cells can be immunogenic in syngeneic hosts by using a teratoma transplantation model (Nature 474:212–215, 2011). Recently two research groups differentiated the iPSCs into different germ layers or cells, transplanted those cells to the syngeneic hosts, and evaluated the immunogenicity of those cells. Both of the two studies support our conclusions that some certain but not all tissues derived from iPSCs can be immunogenic, although they claimed either “negligible” or “lack of” immunogenicity in iPSC derivatives (Nature 494:100–104, 2013; Cell Stem Cell 12:407–412, 2013). To test the immunogenicity of clinically valuable cells differentiated from human iPSCs are emergently required for translation of iPSC technology to clinics.     

Editorial: Islet cell tumours of the pancreas.

This report documents a case of systemic lupus erythematosus in which the major presenting feature was pericarditis and in which the diagnosis was made after pericardiocentesis by the demonstration of typical LE cells in pericardial fluid stained with Wright''s stain. Review of the literature indicates that pericarditis in lupus is more common than is generally suspected, and when it is the initial manifestation it is often misdiagnosed as “benign viral pericarditis”.Screening for collagen disease should be a part of the work-up of any patient presenting with pericarditis, especially a woman. Occasionally lupus may be present even when the serologic tests have given negative results. Under such circumstances, or when the patient manifests an atypical or prolonged course, a diagnostic pericardiocentesis is in order, provided an effusion can be confirmed on scan. A search for LE cells should be included in the analysis of the aspirated fluid.     

Effects on Respiratory and Circulatory Dynamics

There are exceptions and variations to the general clinical rule that muscle relaxants depress respiration and have no effect on circulation.Variation may be attributed to differences in animal species, in individual response, in muscle affected, in drug used and in dose employed.Conclusions about muscle relaxants derived from animal experiments cannot always be assumed to apply to man.The “respiratory sparing” action of a muscle relaxant cannot be relied upon in any individual patient. Facilities for adequate artificial respiration must always be available when any dose of any muscle relaxant drug is administered.Muscle relaxants affect circulation by inhibition of parasympathetic and sympathetic ganglia, by anticholinesterase activity and by release of histamine.     

Relationship of drinking water quality (hardness-softness) to cardiovascular mortality in Newfoundland

The profile of mortality in Newfoundland was analysed for all deaths occurring in 1969 of persons 35 to 69 years of age, of whom the total was 1036. An exceptionally high cardiovascular mortality (793 deaths/100,000) was noted for St. John''s, the capital city of Newfoundland, a city which has an extremely soft drinking-water supply. This high rate corresponds to that observed in the “high mortality belt” reported for the east coast of the United States, and in conjunction with data from mainland Canada, extends the belt across the entire eastern aspect of North America. The proportion of cardiovascular deaths of men occurring outside the hospital was less within hard drinking-water areas in Newfoundland than in the soft water areas of the province. Thus, the statistics reported here of cardiovascular mortality confirm evidence reported elsewhere on “macro-geographic” variations in this disease(s) as well as “micro-geographic” regional variations which may be dependent upon local environmental factors.     

Clinical Diagnostic Process: An Analysis

An analysis of observations made during 1,307 diagnoses by a total of 28 clinicians (503 diagnoses in real life, and 804 on simulated patients) concerned primarily the interview of patients suffering from abdominal pain. Interviews ranged from 10 to 35 questions, and from “stereotyped” procedures, in which identical (and often irrelevant) questions were asked to each patient, to “adaptive” interviews, in which specific relevant questions were put to each patient. Senior clinicians tended to ask fewer, more relevant questions than their junior counterparts; and urgent cases were dealt with in a more adaptive fashion than routine cases in outpatients. Disappointingly, there was considerable difference between real-life and simulated situations. From these results it is suggested (a) that the “diagnostic process” does not exist, (b) that any automated diagnostic system must be flexible to accommodate the wishes of a variety of clinicians, and (c) that studies based on artificial clinical situations should be treated with extreme caution.     

CEREBRAL COMPLICATIONS INCURRED DURING PREGNANCY AND THE PUERPERIUM

In a statistical study of maternal mortality cases in Franklin County, Ohio, with a total of 170 deaths in a ten-year period (1948-1957), there were 36 fatal cases with cerebral complications of various types. Intracranial hemorrhage was the cause of death in 17 cases; subarachnoid hemorrhage in eight; intracerebral hemorrhage in eight and subdural hemorrhage in one case. There were nine cases of intracranial tumor with fatality. In a miscellaneous group of ten “cerebral deaths” infectious processes were the cause in eight cases, including tuberculous meningitis, purulent meningitis, brain abscess, acute (cerebromedullary) poliomyelitis, “viral” encephalitis, toxoplasmosis and tetanus.In a smaller clinical (nonfatal) group with cerebral complications occurring during pregnancy and the puerperium, two patients with subarachnoid hemorrhages made spontaneous recovery. A diagnosis of intracerebral hemorrhage was made in three instances, in two of which operation was done and evacuation of blood clots was accomplished. One patient recovered spontaneously from a minimal hemorrhage.Five other persons had cerebral thrombosis, three in the third month of pregnancy and two in the immediate puerperium. All recovered, with some residual deficits.Three patients with intracranial tumor were successfully treated surgically but with disappointing results ultimately (one case each of cerebellar medulloblastoma, cerebral astrocytoma and supratentorial meningioma).Only when the obstetrician, neurologist and the neurosurgeon are fully aware of the signs, symptoms, and many times the rapid course of these cerebral complications of pregnancy, can there be any material lowering of the morbidity and mortality. Emphasis should be placed on the early investigation of all neurological complaints during pregnancy and the puerperium, with immediate institution of an aggressive diagnostic and therapeutic regimen.     

Collective Intelligence Meets Medical Decision-Making: The Collective Outperforms the Best Radiologist

While collective intelligence (CI) is a powerful approach to increase decision accuracy, few attempts have been made to unlock its potential in medical decision-making. Here we investigated the performance of three well-known collective intelligence rules (“majority”, “quorum”, and “weighted quorum”) when applied to mammography screening. For any particular mammogram, these rules aggregate the independent assessments of multiple radiologists into a single decision (recall the patient for additional workup or not). We found that, compared to single radiologists, any of these CI-rules both increases true positives (i.e., recalls of patients with cancer) and decreases false positives (i.e., recalls of patients without cancer), thereby overcoming one of the fundamental limitations to decision accuracy that individual radiologists face. Importantly, we find that all CI-rules systematically outperform even the best-performing individual radiologist in the respective group. Our findings demonstrate that CI can be employed to improve mammography screening; similarly, CI may have the potential to improve medical decision-making in a much wider range of contexts, including many areas of diagnostic imaging and, more generally, diagnostic decisions that are based on the subjective interpretation of evidence.     

Benfluorex and Unexplained Valvular Heart Disease: A Case-Control Study

Background

Recent case reports suggest that benfluorex, a fenfluramine derivative used in the management of overweight diabetic patients and dyslipidemia, is associated with cardiac valve regurgitation.

Methods

We conducted a case-control study. Eligible patients were those admitted in the cardiology or the cardiac surgery units of our hospital between January, 1^st 2003 and June 30^th 2009, with mitral insufficiency diagnostic codes (ICD-10 I340 and I051). Patients with either a primary cause (degenerative, known rheumatic heart disease, infectious endocarditis, congenital, radiation-induced valvular disease, associated connective and/or vasculitis disease, trauma, tumor) or a secondary (functional) cause were considered as having an “explained” mitral regurgitation. Other patients were considered as having an “unexplained” mitral regurgitation and were included as cases. For each case, two controls were matched for gender and for the closest date of birth, among a list of patients with an “explained” mitral regurgitation. Drug exposures were assessed blindly regarding the case or control status, through contacts with patients, their family and/or their physicians.

Results

Out of the 682 eligible patients, 27 cases and 54 matched controls were identified. The use of benfluorex was reported in 22 patients: 19 of the 27 cases, versus 3 of the 54 controls, odds-ratio 17.1 (3.5 to 83), adjusted for body mass index, diabetes and dexfenfluramine use.

Conclusion

The use of benfluorex is associated with unexplained mitral regurgitation.     

PATHOLOGY AND THE PATHOLOGIST IN THE CANCER PROGRAM

Cancer as one of the most important human diseases does not present as formidable a problem as infectious disease did a century ago. The diversified cancer program, combining voluntary and governmental agencies in support of research, education and coordinated teamwork in the clinical care of the patient, presents a varied although unified approach to the problem that has never before been available for the study of any single human disease. Pathology, with its applied methods from the basic sciences, has a singular role in the scientific aspect of the cancer program. Representing a new specialty in medicine and embodying an inquiring approach to the study of human disease, pathology has a leading role to play. The pathologist, assuming the new role of “pathologist-physician” brings to the clinical care of the cancer patient the most precise methods of cancer diagnosis. The “pathologist-physician” should be a pivotal member of the “clinical team” in the immediate diagnosis, care and treatment of the cancer patient.     

Neonatal Respiratory Distress: Experience at The Hospital for Sick Children,Toronto, 1960-1961

Four hundred and thirty infants selectively referred to the Newborn Unit of The Hospital for Sick Children, Toronto, with the symptom of respiratory distress, were reviewed. There were 142 cases of the “idiopathic respiratory distress syndrome” (IRDS), of which 67 were fatal. The remainder included 100 cardiac (76 deaths), 63 extra-pulmonary (28 deaths) and 109 other specific pulmonary conditions (54 deaths). Of the 109, half were due to massive aspiration. Serial observations and radiographs led to correct clinical diagnosis in 85% of necropsy-proved cases of IRDS and in a comparable proportion of all other conditions. The incidence and mortality rate of IRDS were twice as high in males as in females. A significant number of premature infants have transient respiratory distress after birth, and diagnostic criteria for inclusion in any study should be defined in detail. This study emphasized the large contribution of disorders of the respiratory and cardiac systems to neonatal mortality and led to the formation of a special department for intensive care and research in these conditions.     

Accuracy of Predictions of Survival in Later Stages of Cancer

Though 83% of 168 cancer patients admitted for “terminal care” died within 12 weeks of admission predictions of the probable length of survival showed little relation to the actual length of survival. A total of 83% of all “errors” were in an “optimistic” direction, the patient being expected to survive longer than he actually did.No significant differences were found between the accuracy of predictions made at referral by general practitioners, by doctors at other hospitals, by hospice physicians on the day of admission, or by ward sisters and senior nurses at the same time. A week after admission predicted and actual survival correlated more closely but predictions were still optimistic.It is concluded that predictions of the length of time which a cancer patient who is at the end of active treatment can be expected to survive should be made and interpreted with the greatest caution.     

ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase,oral aspirin,both, or neither

Objective: To assess effects of intravenous streptokinase, one month of oral aspirin, or both, on long term survival after suspected acute myocardial infarction. Design: Randomised, “2×2 factorial,” placebo controlled trial. Setting: 417 hospitals in 16 countries. Subjects: 17 187 patients with suspected acute myocardial infarction randomised between March 1985 and December 1987. Follow up of vital status complete to at least 1 January 1990 for 95% of all patients and to mid-1997 for the 6213 patients in United Kingdom. Interventions: Intravenous streptokinase (1.5 MU in 1 hour) and oral aspirin (162 mg daily for 1 month) versus matching placebos. Main outcome measures: Mortality from all causes during up to 10 years’ follow up, with subgroup analyses based on 4 year follow up. Results: After randomisation, 1841 deaths were recorded in days 0-35, 991 from day 36 to end of year 1, 1478 in years 2-4, and 1230 in years 5-10. Allocation to streptokinase was associated with 29 (95% confidence interval 20 to 38) fewer deaths per 1000 patients during days 0-35. This early benefit persisted (death rate ratio 0.98 (0.92 to 1.04) for additional deaths between day 36 and end of year 10), so that there were 28 (14 to 42) and 23 (2 to 44) fewer deaths per 1000 patients treated with streptokinase after 4 years and 10 years respectively. There was no evidence that absolute survival benefit increased with prolonged follow up among any category of patient, including those presenting early after symptoms started or with anterior ST elevation. Nor did the early benefits seem to be lost in any category (including those aged over 70). Allocation to one month of aspirin was associated with 26 (16 to 35) fewer deaths per 1000 during first 35 days, with little further benefit or loss during subsequent years (death rate ratio 0.99 (0.93 to 1.06) between day 36 and end of year 10). The early benefit obtained with combination of streptokinase and one month of aspirin also seemed to persist long term. Conclusions: The early survival advantages produced by fibrinolytic therapy and one month of aspirin started in acute myocardial infarction seem to be maintained for at least 10 years.

Key messages

• Large randomised trials have shown that the survival benefits of intravenous fibrinolytic therapy for patients with acute myocardial infarction persist for at least one year, but there is relatively little information about longer term effects
• By contrast, this report from the ISIS-2 trial of intravenous streptokinase and of one month of oral aspirin includes nearly 4000 deaths between the start of year 2 and the end of year 10
• The early survival benefits of fibrinolytic therapy persist for at least 10 years after treatment and do not seem to increase or decrease with prolonged follow up in any category of patients, including elderly subjects
• The survival benefits of short term aspirin treatment in acute myocardial infarction also persist long term and are additional to those of fibrinolytic therapy, and other studies show that these benefits can be increased by continuing aspirin treatment for some years after myocardial infarction

     

Using Re-Sampling Methods in Mortality Studies

Traditional methods of computing standardized mortality ratios (SMR) in mortality studies rely upon a number of conventional statistical propositions to estimate confidence intervals for obtained values. Those propositions include a common but arbitrary choice of the confidence level and the assumption that observed number of deaths in the test sample is a purely random quantity. The latter assumption may not be fully justified for a series of periodic “overlapping” studies. We propose a new approach to evaluating the SMR, along with its confidence interval, based on a simple re-sampling technique. The proposed method is most straightforward and requires neither the use of above assumptions nor any rigorous technique, employed by modern re-sampling theory, for selection of a sample set. Instead, we include all possible samples that correspond to the specified time window of the study in the re-sampling analysis. As a result, directly obtained confidence intervals for repeated overlapping studies may be tighter than those yielded by conventional methods. The proposed method is illustrated by evaluating mortality due to a hypothetical risk factor in a life insurance cohort. With this method used, the SMR values can be forecast more precisely than when using the traditional approach. As a result, the appropriate risk assessment would have smaller uncertainties.     

The Preoperative Assessment of Multiple Valve Disease

Representative case histories are used to discuss the difficulties in preoperative assessment of patients with multiple valve disease and the dangers of correcting one lesion when two or more valves are seriously damaged. Errors fall into three broad categories: existing second valve disease (1) may not be suspected, (2) may be considered insignificant or (3) may be considered a consequence of the first.Recommendations are offered to minimize these errors. The four valves should be studied physiologically, no matter how “normal” the other three may appear to be clinically, whenever open-heart surgery is contemplated. In bivalvular disease angiographic methods are preferable to pressure studies, for data so obtained are not dependent on cardiac output. Mitral and tricuspid regurgitation can never be attributed with certainty to a more distal lesion but require direct examination at time of operation for assessment.     

Retention in care and connection to care among HIV-infected patients on antiretroviral therapy in Africa: estimation via a sampling-based approach

Introduction

Current estimates of retention among HIV-infected patients on antiretroviral therapy (ART) in Africa consider patients who are lost to follow-up (LTF) as well as those who die shortly after their last clinic visit to be no longer in care and to represent limitations in access to care. Yet many lost patients may have “silently” transferred and deaths shortly after the last clinic visit more likely represent limitations in clinical care rather than access to care after initial linkage.

Methods

We evaluated HIV-infected adults initiating ART from 1/1/2004 to 9/30/2007 at a clinic in rural Uganda. A representative sample of lost patients was tracked in the community to obtain updated information about care at other ART sites. Updated outcomes were incorporated with probability weights to obtain “corrected” estimates of retention for the entire clinic population. We used the competing risks approach to estimate “connection to care”—the percentage of patients accessing care over time (including those who died while in care).

Results

Among 3,628 patients, 829 became lost, 128 were tracked and in 111, updated information was obtained. Of 111, 79 (71%) were alive and 35/48 (73%) of patients interviewed in person were in care and on ART. Patient retention for the clinic population assuming lost patients were not in care was 82.3%, 68.9%, and 60.1% at 1, 2 and 3 years. Incorporating updated care information from the sample of lost patients increased estimates of patient retention to 85.8% to 90.9%, 78.9% to 86.2% and 75.8% to 84.7% at the same time points.

Conclusions

Accounting for “silent transfers” and early deaths increased estimates of patient retention and connection to care substantially. Deaths soon after the last clinic visit (potentially reflecting limitations in clinical effectiveness) and disconnection from care among patient who were alive each accounted for approximately half of failures of retention.     

On the proposed energy switch in photosynthesis

This paper analyzes the “energy switch” that has often been proposed to direct quanta absorbed by a given photosynthetic unit alternately to the site of one and then the other primary reaction. Such a device is essential to the Franck-Rosenberg theory, but not to the Duysens-Witt-Kok (DWK) model, which needs to assume only that the reactions occur in series. If there is no energy switch, an incident quantum absorbed at any time by any particular pigment molecule stands a chance of ending up in the reactive site of either primary reaction. The “separate packages” model is a special case of this general picture. Without an energy switch, a series model requires a storage device to insure that a quantum will not be wasted if it arrives at the site of one reaction while the photosynthetic unit is set up to perform the other. Such a storage device can be appended to the DWK model. Alternatively, this model can be augmented by an energy switch. This gives what is commonly known as the “spillover model,” a confusing name which we suggest be abandoned. As a clear-cut-though perhaps technically unfeasible-test of the energy switch hypothesis, we imagine a quantum injector, a hypothetical source of flashing light which delivers a single quantum to every photosynthetic unit with each flash. We aim this useful figment at an (equally hypothetical) photosynthetic system all of whose units are set up to perform the same primary reaction. If there is an energy switch, we can now prepare a “synchronous” photosynthetic apparatus in which each photosynthetic unit is undergoing the same reaction at the same time.