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Polatuzumab vedotin, an antibody-drug conjugate containing monomethyl auristatin E, was associated with an incidence of grade ≥2 peripheral neuropathy (PN) of 55-72% in patients with indolent non-Hodgkin lymphoma in a phase II study, when dosed 1.8-2.4 mg/kg every 3 weeks until progression or for a maximum of 17 cycles. To quantify the correlation of conjugate exposure and treatment duration with PN risk, a time-to-event model was developed using data from phase I and II studies. The model suggested that PN risk increased with conjugate exposure and treatment cycles, and a trend for increased risk with body weight and albumin concentration. When capping the treatment duration to six to eight cycles, the risk ratio of a dose of 2.4 mg/kg vs. 1.8 mg/kg was ≥1.29; the predicted incidence of grade ≥2 PN at 1.8-2.4 mg/kg dose levels was 17.8-37.2%, which is comparable with other antimicrotubule agents for lymphoma treatment.

In impaction grafting of contained bone defects after revision joint arthroplasty the graft behaves as a friable aggregate and its resistance to complex forces depends on grading, normal load and compaction. Bone mills in current use produce a distribution of particle sizes more uniform than is desirable for maximising resistance to shear stresses. We have performed experiments in vitro using morsellised allograft bone from the femoral head which have shown that its mechanical properties improve with increasing normal load and with increasing shear strains (strain hardening). The mechanical strength also increases with increasing compaction energy, and with the addition of bioglass particles to make good the deficiency in small and very small fragments. Donor femoral heads may be milled while frozen without affecting the profile of the particle size. Osteoporotic femoral heads provide a similar grading of sizes, although fewer particles are obtained from each specimen. Our findings have implications for current practice and for the future development of materials and techniques.

We have reviewed the clinical and functional results of 21 centralizations for radial club hand in 17 patients, 21 to 31 (mean 27) years after operation. There were 13 associated pollicizations. Although the ulna was always short, no premature fusions of the distal ulnar epiphysis were found. Overall upper limb function was assessed by grip strengths and Moberg and Jebsen tests of manual dexterity and was satisfactory. This review emphasizes the important roles of centralization and pollicization in the surgical management of children with radial absence.

Effects of large (LA; 400 min/wk) and moderate (MA; 200 min/wk) amounts of endurance exercise in combination with weight training (3 d/wk) were compared with the effects of no exercise (C) in 23 obese females after a 12-wk, 3360-kJ/d very-low-energy diet (VLED). The LA group lost 6.5 kg more weight, mainly as fat (6.4 kg), than the C group (P < 0.05). No measurable differences were found among groups for decreases in resting metabolic rate (-729 to -1233 kJ/d; NS) or fat-free mass (-2.9 to -3.9 kg; NS). No improvements in aerobic capacity were achieved with the addition of exercise to a VLED (-0.079 to -0.037 L/min; NS). Strength indexes were improved (+16 to +5 kg; P < 0.05) or maintained with exercise (-3 kg; NS) whereas a loss (-9.3 kg; P < 0.05) or maintenance (+4.5 kg; NS) was found for VLED alone. Large amounts of endurance exercise in combination with weight training added to a VLED appear to improve weight and fat loss compared with a VLED alone.

Objectives. To identify patient-assessed health instruments specific to the knee and review evidence for reliability, validity and responsiveness. Methods. Instruments were identified through systematic searches of the literature. Information relating to instrument content, patient population, reliability, validity and responsiveness was extracted from published papers. Results. The 16 instruments that met the inclusion criteria varied in length from 4 to 42 items. The majority form a single index; six produce a profile of scores. Eight have been evaluated in patients with a variety of knee problems. All instruments have satisfactory internal or test–retest reliability. However, there is limited empirical support for the health domains of six instruments. Patients informed the development of items within just five instruments. Few authors gave explicit consideration to the size of expected relationships in tests of construct validity. Eleven instruments have evidence for responsiveness to changes in health. The minimally important difference was not determined for any of the instruments. Conclusions. In the absence of comparative evidence, the large number of patient-assessed instruments for knee problems makes instrument selection difficult. The Knee Injury and Osteoarthritis Outcome Score (KOOS), Knee Pain Scale and Oxford Knee Score have good evidence for reliability, content validity and construct validity. The KOOS and Oxford instruments also have evidence for responsiveness. The instruments have not been evaluated for all knee problems, and instrument appropriateness, including content relevance, must be assessed before application. The comparative evaluation of instruments is recommended.

We analyzed the presence of autonomic nerve fibers in the interface membranes (n = 9) surrounding aseptic loosened hip prostheses by immunohistochemistry. The study focused on the autonomic messengers neuropeptide Y (NPY), tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of noradrenaline (NA), and vasoactive intestinal polypeptide (VIP). Protein gene product (PGP) 9.5, a general marker of peripheral nerve fibers, was also analyzed to establish the neuronal character of the immunoreactive structures. PGP 9.5-positive and NPY-positive nerve fibers were identified in all 9 samples, and VIP-immunoreactive and TH-immunoreactive fibers were found in 7. There was a difference in the distribution of nerve fibers both between and within the samples. Among the neuropeptides analyzed, NPY was most abundant. NPY-positive and TH-positive fibers were predominantly found around the blood vessel walls forming varicose nerve terminals. VIP-positive fibers were mainly observed as thin varicose nerve terminals with no relationship to blood vessels. Autonomic neuropeptides exert not only vasoactive and immunoregulatory effects, but also have been found to have direct effects on bone tissue. Moreover, the autonomic nervous system has been strongly implicated in nociception and inflammation. Neuronal NPY, TH, and VIP in the interface membrane may prove to contribute to the pathologic mechanisms leading to aseptic loosening of hip prostheses.

The evidence from the 4 epidemiologic studies published before mid 1995, which have investigated the incidence of cancers in patients who have undergone joint implants, is conflicting. The results of the 2 earlier studies suggested a sustained increase in the risk of lymphoma and leukemia after total hip arthro- plasty. The results of the 2 more recent studies have not confirmed this, although in 1 study an increased risk was observed in the first year after implantation. The heterogeneity may be statistical in origin, but could also have a biologic explanation in the greater proportion of metal on metal prostheses used before 1973. All 4 studies used national data as the comparison. Here are presented the results of 2 matched cohort studies and a case control study set in North America and Scotland, and an overview of the 4 previous studies. Neither the results of the matched studies of patients operated on after 1973 nor the results of the latter 2 published studies suggest an increased risk of lymphoma or leukemia. If metal on metal articulations are reintroduced, careful surveillance is essential.

The incidence of skeletal tuberculosis in New Zealand as measured by both hospital morbidity and notification data has fallen since the introduction of chemotherapy to low levels comparable with other developed societies. The decline has been greatest in the 5-14 year age group and least in the over 65 group. Individual surgeons can now expect to see few cases in a practising lifetime. Effective chemotherapy is the key to successful treatment. Adequate biopsy is essential, but apart from the drainage of large abscesses the place of surgery in the early management of osteoarticular tuberculosis is discretionary. Early activity can usually be encouraged once chemotherapy is instituted, late reconstruction by joint arthroplasty being available if adequate function is not achieved.

A novel approach to the evaluation of the kinetics of drug removal by an extracorporal device (ECD), e.g., haemodialysis, haemofiltration, and haemoperfusion, is presented. The rate and extent of extracorporal drug removal (ECR) are determined by deconvolution. The proposed method is model independent in the sense that no specific models of corporal or extracorporal disposition are required. The estimation of various derived functions and parameters useful for describing ECR such as clearance and fractional drug removal are facilitated by the technique. The kinetics of cefsulodin elimination by haemodialysis in 3 patients were evaluated using the deconvolution approach. The results indicated that cefsulodin was dialyzable with approximately 50% of the drug in the body removed by haemodialysis over 3-4 h.

Hospital morbidity data from New Zealand, Western Australia, England and Wales and Scotland are reviewed. The incidence of osteomyelitis in childhood is greater in males than females, greater in European children in Australia and New Zealand than in Great Britain, and much greater in Aboriginal and New Zealand Maori children than in European children. A seasonal peak is present in late summer and autumn in both hemispheres. The reported incidence is generally declining, except in Western Australia. Local variations in incidence within New Zealand correlate with mean annual vapour pressure. The male/female sex ratio increases with age. Discussion centres on possible inferences from the data.

The effect of food on the rate and extent of absorption of tolbutamide in diabetic patients was studied by varying the time of drug administration in relation to the ingestion of a standard meal. Serum levels of tolbutamide, insulin and glucose and related bioavailability parameters were compared following the administration of a single dose of tolbutamide 0.5 g to diabetic patients 30 min prior to and immediately before a standardized meal. A placebo dosage form was also administered to determine baseline glucose and insulin response to the meal. The 700 calorie standard meal was composed of 41% carbohydrate, 18% protein, and 41% fat. Administration of the drug with the meal resulted in a 6% (statistically significant) decrease in the extent of absorption, as determined by measurement of the area under the tolbutamide serum level-time curve from zero to infinity. Serum levels of tolbutamide were also significantly higher 0.5 h after drug administration when the drug was taken with the meal. Except for these two minor effects, no other differences between the drug treatments were observed in any other parameters of tolbutamide absorption or in the postprandial glucose and insulin serum levels. Therefore, the small differences found were judged to be clinically meaningless. These findings demonstrate that administration of tolbutamide 0.5 g tablets 30 min prior to or with a standard meal results in equivalent therapeutic actions.

Staphylococcal colonization and infection were studied prospectively in infants, mothers and households after childbirth at home and in hospital. Infants were treated prophylactically with frequent applications of ‘Ster-zac’ hexachlorophane dusting powder. Some were treated in addition with ‘Naseptin’ nasal disinfectant cream.The incidence of staphylococcal sepsis in infants was much less than before the adoption of hexachlorophane prophylaxis. The sepsis rate was further reduced when ‘Naseptin’ was used in addition to hexachlorophane. Of the two prophylactic agents, hexachlorophane was the more convenient and probably the more effective. ‘Naseptin’ was difficult to employ correctly and unsuitable for routine use.The treatment of infants with disinfectants reduced nasal carriage markedly in infants and to a smaller extent in mothers. Both agents contributed to the reductions which persisted for some weeks after treatment ceased.Breast abscesses were almost entirely confined to mothers of infants who became nasal carriers by the second week of life.Staphylococcal colonization of infant's skin was greater when they wore impervious garments, probably because skin moisture increased.

1. Lysolecithin added in suitable doses to blood does not increase the red cell fragility in hypotonic saline, although the cells become spherical. The fragility of washed cells is slightly diminished by lysolecithin. The spherical cells produced by lysolecithin are essentially different from the spherocytes of congenital haemolytic anaemia. 2. After intravenous injection of lysolecithin into a rabbit, the fragility of the red cells remains raised for a much longer period than the spherical shape of the cells can be observed. 3. The effects of incubation of whole blood, and of plasma alone, on the morphology, volume, and fragility of the erythrocytes are contrasted. 4. The importance of the inhibiting action of plasma constituents on lysolecithin haemolysis is stressed. 5. The bearing of these experiments on some of the problems of haemolytic anaemia is discussed.

Plasma absorption studies were carried out on normal dogs and dogs with heart failure, with and without total lymph drainage from thoracic duct and right lymph ducts, after radioactive iodinated albumin (RISA) had been instilled into the lungs to explore a possible method for an indirect measurement of lung lymph flow. RISA entered plasma from the lungs mainly through the bloodstream. Its concentration in lung lymph correlated poorly with total lung lymph flow. More RISA entered the plasma than is normal in heart failure, implying an increased alveolar capillary permeability to protein in pulmonary oedema.

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Guidance by bacteriologists and changes in theatre and ward disciplines have greatly improved the results of urological surgery in recent years. The most noteworthy successes have been in treatment of chronic retention with renal failure, and in prevention of the bacteraemia which may occur following removal of the post-operative catheter or the passage of an instrument to dilate a stricture. It is hoped that safer urethral instrumentation may also reduce the incidence of chronic pyelonephritis.

Much cross-infection can be prevented by using chemical disinfectants to reduce the numbers of pathogens in sources such as superficial lesions and carrier sites, and by interrupting routes of spread. Examples are given to show the value of using disinfectants in the light of epidemiological knowledge.

SUMMARY The sources and routes of infection during continuous bladder drainage are discussed and illustrated. Twenty-nine male patients had continuous closed bladder drainage for periods of seven to seventy-seven days with an overall infection rate of 21 per cent. When accidental disruption of the closed circuit and repeated urethral instrumentation were avoided no patient became infected. Further improvements in the management of closed drainage are suggested. We wish to thank the consultant surgical staff of the United Bristol Hospitals, Southmead General Hospital and Frenchay Hospital, Bristol, for permission to investigate their patients. We are also grateful to Mr Ashton Miller for his help and advice during these studies.

Katz, A. M., Pearson, C. M., and Kennedy, J. J. (1963). Arthr. and Rheum., 6, 281. -(1965). Clin. Pharmacol. Ther., 6, 25. Kelly, M. (1964a). Med. J. Aust., 2, 541. (1964b). Lancet, 2, 474. Lansbury, J. (1958). Arthr. and Rheum., 1, 505. L?vgren, O., and Allander, E. (1964). Brit. med. J., 1, 118. Medical Research Council and Nuflield Foundation (1954). Ibid., 1, 1223. Mlchotte, L. J., and Wauters, M. (1964). Acta rheum, scand., 10, 273. Miehlke, K. (1965). Munch, med. Wschr., 107, 38. Norcross, B. M. (1963). Arthr. and Rheum., 6, 290. Percy, J. S., Stephenson, P., and Thompson, M. (1964). Ann. rheum. Dis., 23, 226. -and Thompson, P. (1963). 5th European Congress on Rheumatic Disease. Robecchi, A., Marrazzi, G., and Viara, M. (1964). Reumatismo, 16, 388. Robinson, R. G. (1965). Med. J. Aust., 1, 266. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A. (1957). Ann. rheum. Dis., 16, 118. Rothermich, N. O. (1963). Arthr. and Rheum., 6, 295. (1964). Proceedings of 8th Congress of Japan Rheumatism Associa tion (Okayama), p. 159 Rubens-Duval, A., and Villiaumey, J (1964). Rev. Rhum., 31, 204. Smyth, C. J. (1965). Arthr. and Rheum., 8, 921. Amoroso, C, and Velayos, E. (1964). Ibid., 7, 345. and Godfrey, R. (1964). Ibid., 7, 345. Velayos, E. E., and Amoroso, C. (1963a). Ibid., 6, 299. -(1963b). Acta rheum, scand., 9, 306. Suzman, M. M. (1964). Rhumatologie, 16, 423. Thompson, M. (1964). Ibid.. 16, 439. and Percy, J. S. (1966). Brit. med. J., 1, 80. Viara, M., and Marrazzi, G. (1964). Rhumatologie, 16, 429. Vignau, A I., Correa, E. T., Guasch, J. L., Schuster, A. C, Patri, A. M., Vaisman, S. B., and Mortimer, E. A. (1965). Arthr. and Rheum., 8, 501. Wanka, J., Jones, L. I., Wood, P. H. N., and Dixon, A. St. J. (1964). Ann. rheum. Dis., 23, 218. Ward, J. R. (1964). Excerpta Medica International Congress, No. 82, edited by S. Garattini and M. N. G. Dukes, p. 353. Amsterdam.

The ‘ascending and descending audiogram’ is a simple pure tone hearing test that exposes with a high degree of reliability those who are feigning bilateral deafness. The normal person has a marginally better pure tone audio-metric threshold when the stimuli are presented in descending levels of intensity, as compared to ascending intensities. The reverse situation applies with the malingerer where there usually is a 20-30dB difference between the audiometric graphs, with ascending levels of intensity indicating a better hearing threshold.

Summary A case of haematogenous osteomyelitis of the medial first metatarsal sesamoid is presented and the differential diagnosis discussed. Review of the literature suggests that the condition is rarely seen and tends to present in childhood and adolescence. This contrasts with metatarsal sesamoid osteomyelitis due to direct spread of infection, which occurs in the elderly as an important complication of the diabetic foot.

Postoperative chest infection was studied prospectively in 73 patients in order to evaluate standard laboratory methods of sputum examination and to relate the results to the patients' clinical state and to antibiotic therapy. When a culture medium selective for haemophilus was used in addition to unselective media, homogenisation of the specimen gave no advantage. Laboratory and clinical findings usually corresponded well. Profuse growths of Streptococcus pneumoniae or Haemophilus influenzae were clearly associated with clinical evidence of chest infection but other Gramnegative bacilli and Staphylococcus aureus much less so. Coliforms were more prominent after antibiotic therapy.

In a clinical and microbiological study of women with urinary frequency and dysuria (excluding those with bacterial cystitis), 41 patients were compared with 42 control subjects. No difference was found between patients and controls in the incidence of infection by Chlamydia trachomatis or other sexually transmitted organisms. The numbers of lactobacilli and other fastidious organisms in the urine of patients with either mild or severe symptoms were similar and did not differ from the numbers in the urine of control subjects. The numbers of leucocytes in urine were also similar in both patients and controls. Our findings support the view that the urethral syndrome is not caused by bacterial or chlamydial infection.

Albright in 1944 described a syndrome of hypercalcaemia in patients immobilized following fractures through bones affected with Paget's disease. This paper reports a further two cases in which this syndrome was considered the cause of hypercalcaemia with fatal outcome. Both patients had parathyroid adenomata. The literature is reviewed, and it is argued that no firm evidence for the existence of this syndrome has ever been put forward. The finding of hypercalcaemia in Paget's disease of bone should prompt an exhaustive search for its cause.

Acute exercise enhances fibrinolytic (FA), factor VIII coagulant and factor VIII ristocetin cofactor activities, and increases the concentration of factor VIII-related antigen. Little is known concerning the mechanisms of these changes. To investigate possible relationships between exercise-induced changes in blood lactate, 2,3-diphosphoglycerate (DPG), and the hemostatic variables, a branching multistage treadmill protocol was used to exercise male volunteers to a maximum effort. Blood samples were drawn before, immediately post-, and 8 min postexercise. All hemostatic variables were significantly (P less than 0.05) increased postexercise. Highest values for factor VIII coagulant, factor VIII-related antigens and factor VIII ristocetin cofactor were observed at 8 min postexercise. Significant (P less than 0.001) correlations were found postexercise for lactate with factor VIII coagulant (r = 0.64), while no association between pre-, post-, or 8 min postexercise. Postexercise lactate demonstrated a significant correlation (r = +0.81), which was strengthened by including the preexercise high-density lipoprotein (HDL) concentrations (r = +0.87). Consequently, the expected postexercise FA may be calculated from the observed values for postexercise lactate and preexercise HDL. The correlations of lactate with postexercise FA and with postexercise factor VIII coagulant may reflect a common stimulus for these exercise-induced changes.

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Biopsy material from the skeletal muscle (paraxials) of 21 patients with scoliosis was examined by light and electron microscopy. Virus-like particles, 17 nm in diameter with a crystalline structure, were identified in the skeletal muscle fibres of four patients. Associated changes in the sarcoplasm included swelling of mitochondria, presence of lipid droplets, and vesicular structures. Serological studies and culture for virus isolation gave negative results. An excess of lipid (predominantly in type 1 fibres) was noted in the skeletal muscle of several other cases. The significance of these findings is obscure, but the morphology of the paraxial muscles of patients with scoliosis and controls is currently being investigated in greater detail.