Territorywide Study of Early Coronavirus Disease Outbreak,Hong Kong,China

Initial cases of coronavirus disease in Hong Kong were imported from mainland China. A dramatic increase in case numbers was seen in February 2020. Most case-patients had no recent travel history, suggesting the presence of transmission chains in the local community. We collected demographic, clinical, and epidemiologic data from 50 patients, who accounted for 53.8% of total reported case-patients as of February 28, 2020. We performed whole-genome sequencing to determine phylogenetic relationship and transmission dynamics of severe acute respiratory syndrome coronavirus 2 infections. By using phylogenetic analysis, we attributed the community outbreak to 2 lineages; 1 harbored a common mutation, Orf3a-G251V, and accounted for 88.0% of the cases in our study. The estimated time to the most recent common ancestor of local coronavirus disease outbreak was December 24, 2019, with an evolutionary rate of 3.04 × 10⁻³ substitutions/site/year. The reproduction number was 1.84, indicating ongoing community spread.     

The status of women at one academic medical center. Breaking through the glass ceiling

Despite recent gains in admission to medical school and in obtaining junior faculty positions, women remain underrepresented at senior academic ranks and in leadership positions in medicine. This discrepancy has been interpreted as evidence of a "glass ceiling" that prevents all but a few exceptional women from gaining access to leadership positions. We analyzed data from Columbia University College of Physicians & Surgeons, New York, NY, for all faculty hired from 1969 through 1988 and found that the likelihood of promotion on the tenure track was 0.40 for women and 0.48 for men (ratio, 0.82; 95% confidence interval, 0.56 to 1.20); on the clinical track the likelihood of promotion was 0.75 for women and 0.72 for men (ratio, 1.04; 95% confidence interval, 0.56 to 1.94). Additional analysis of current faculty showed that in the academic year 1988-1989 the proportion of women at each tenure track rank at the College of Physicians & Surgeons equaled or exceeded the national proportion of women graduating from medical school, once allowance was made for the average time lag necessary to attain each rank. On the clinical track women were somewhat overrepresented, particularly at the junior rank. National data that describe medical school faculty, which combine tenure and clinical tracks, showed that in 1988 women were proportionately represented at each rank once the lead time from graduation was considered. We conclude that objective evidence shows that women can succeed and are succeeding in gaining promotions in academic medicine.     

Concurrent carboplatin and iodine-125 brachytherapy for recurrent glioblastoma multiforme

Toxicity and safety study of concurrent carboplatin chemotherapy and iodine-125 (I-125) brachytherapy. I-125 brachy therapy has an established albeit limited role in surgically accessible recurrent gliomas. Carboplatin has anti-tumoral; activity against gliomas and demonstrated sensitization of tumor to radiotherapy. In 15 patients (age range 30-77 years; median 53) with recurrent glioblastoma multiforme, stereotactically placed catheters were afterloaded with I-125 sources. A median 50 Gy minimum treatment volume dose was delivered during a 100 h period in conjunction with continuous infusion carboplatin (100 mg/m(2)/20 h x 5). Tumor volumes ranged from 13 to 63 cm(3) (median, 32 cm(3)). Early complications included: headache (n=7), transient exacerbations of pre existing neurologic deficits (n=5), seizures (n=2), nausea/vomiting (n=2), myelosuppression (n=2) and a catheter site wound CSF leak (n=1). Late complications included: steroid dependency (n=10), carcinomatous meningitis in association with hydrocephalus (n=1) and radiation-induced necrosis requiring reoperation (n=6). All patients were evaluable with a median survival of 10 months. In 12 patients, best clinical and neuroradiographic response was stable disease all of whom died of recurrent tumor (local recurrence in 11; CSF dissemination in 1). In 3 patients best response was either complete (n=2) or partial (n=1) all of whom are alive with a median follow-up of 31 months. I-125 brachytherapy with concurrent carboplatin chemotherapy is associated with an acceptable level of toxicity, has anti-tumoral activity and warrants further investigation in carefully selected patients with recurrent gliomas.     

Heel pain in children. Diagnosis and treatment

Heel pain in children is common, and its evaluation is challenging. Medical history and physical examination may be unrevealing owing to children's limited communication skills. Often, advanced laboratory and imaging studies are required to make an accurate diagnosis. The most common causes of heel pain in children are apophysitis, enthesopathy, and overuse syndromes such as tendinitis. Juvenile rheumatoid arthritis is relatively uncommon. In very active children, occult fractures must also be evaluated. Pain unrelated to activity may indicate tumors, infection, or congenital problems. In general, heel pain in children is treated nonoperatively. For fractures in particular, children are less likely than adults to receive surgical treatment.     

Cardiorespiratory variables and sensation during stimulation of the left vagus in patients with epilepsy

We studied physiological and sensory effects of left cervical vagal stimulation in six adult patients receiving this stimulation as adjunctive therapy for intractable epilepsy. Stimulus strength varied among subjects from 0.1 to 2.1 microCoulomb (microC) per pulse, delivered in trains of 30-45 s at frequencies from 20 to 30 Hz; these stimulation parameters were standard in a North American study. The stimulation produced no systematic changes in ECG, arterial pressure, breathing frequency tidal volume or end-expiratory volume. Five subjects experienced hoarseness during stimulation. Three subjects with high stimulus strength (0.9-2.1 microC) recalled shortness of breath during stimulation when exercising; these sensations were seldom present during stimulation at rest. No subjects reported the thoracic burning sensation or cough previously reported with chemical stimulation of pulmonary C fibers. Four of six subjects (all those receiving stimuli at or above 0.6 microC) experienced a substantial reduction in monthly seizure occurrence at the settings used in our studies. Although animal models of epilepsy suggest that C fibers are the most important fibers mediating the anti-seizure effect of vagal stimulation, our present findings suggest that the therapeutic stimulus activated A fibers (evidenced by laryngeal effects) but was not strong enough to activate B or C fibers.     

Co-occurrence of mood and personality disorders: a report from the Collaborative Longitudinal Personality Disorders Study (CLPS)

The purpose of this study was to examine the relationship of subtypes and particular clinical features of mood disorders to co-occurrence with specific personality disorders. Five hundred and seventy-one subjects recruited for the Collaborative Longitudinal Personality Disorders Study (CLPS) were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I) and the Diagnostic Interview for DSM-IV Personality Disorders (DIPD-IV). Percent co-occurrence rates for current and lifetime mood disorders with personality disorders were calculated. Logistic regression analyses examined the effects of clinical characteristics of depressive disorders (e.g., age at onset, recurrence, symptom severity, double depression, and atypical features) on personality disorder co-occurrence. In comparison with other DSM-IV personality disorders, avoidant, borderline, and dependent personality disorders (PDs) were most specifically associated with mood disorders, particularly depressive disorders. Severity and recurrence of major depressive disorder and comorbid dysthymic disorder predicted co-occurrence with borderline and to a lesser extent research criteria depressive personality disorders. The results are consistent with the view that a mood disorder with an insidious onset and recurrence, chronicity, and progression in severity leads to a personality disorder diagnosis in young adults.     

A phase I trial of continuous-infusion cyclophosphamide in refractory cancer patients

Summary Cyclophosphamide demonstrates enhanced tumoricidal activity with decreased bone marrow toxicity when given on a divided-dose schedule in certain animal models. A total of 22 patients presenting with refractory metastatic cancer were treated in a phase I trial of continuous infusion of cyclophosphamide over 96 h. Granulocytopenia of <500/l that lasted for > 14 days or thrombocytopenia of <25,000/l that lasted for > 14 days was the target dose-limiting toxicity in the absence of nonhematologic grade 4 toxicity. The maximal tolerated dose was 7 g/m². Three patients died. Of 21 evaluable patients, 9 responded, including 8/9 who had experienced disease progression during prior oxazaphosphorine-containing combination chemotherapy. Clinically meaningful responses were observed in patients who had demonstrated clinical resistance to an oxazaphosphorine drug given at lower doses.Supported in part by U.S. Public Health Service grant P01CA-38493 and by a grant from the Mather's Foundation. Two of the authors (J. P. E. and A. D. E.) are recipients of Career Development awards from the American Cancer Society, and one (T. C. S.) is a recipient of a Faculty Development Award from the Pharmaceutical Manufacturer's Association Foundation     

Hemoglobin and albumin adducts of benzene oxide among workers exposed to high levels of benzene

Benzene oxide (BO) reacts with cysteinyl residues in hemoglobin (Hb) and albumin (Alb) to form protein adducts (BO-Hb and BO-Alb), which are presumed to be specific biomarkers of exposure to benzene. We analyzed BO-Hb in 43 exposed workers and 42 unexposed controls, and BO-Alb in a subsample consisting of 19 workers and 19 controls from Shanghai, China, as part of a larger cross-sectional study of benzene biomarkers. The adducts were analyzed by gas chromatography-mass spectrometry following reaction of the protein with trifluoroacetic anhydride and methanesulfonic acid. When subjects were divided into controls (n = 42) and workers exposed to < or =31 (n = 21) and >31 p.p.m. (n = 22) benzene, median BO-Hb levels were 32.0, 46.7 and 129 pmol/g globin, respectively (correlation with exposure: Spearman r = 0.67, P < 0.0001). To our knowledge, these results represent the first observation in humans that BO-Hb levels are significantly correlated with benzene exposure. Median BO-Alb levels in these 3 groups were 103 (n = 19), 351 (n = 7) and 2010 (n = 12) pmol/g Alb, respectively, also reflecting a significant correlation with exposure (Spearman r = 0.90, P < 0.0001). The blood dose of BO predicted from both Hb and Alb adducts was very similar. These results clearly affirm the use of both Hb and Alb adducts of BO as biomarkers of exposure to high levels of benzene. As part of our investigation of the background levels of BO-Hb and BO-Alb found in unexposed persons, we analyzed recombinant human Hb and Alb for BO adducts. Significant levels of both BO-Hb (19.7 pmol/g) and BO-Alb (41.9 pmol/g) were detected, suggesting that portions of the observed background adducts reflect an artifact of the assay, while other portions are indicative of either unknown exposures or endogenous production of adducts.      

Increased aneusomy and long arm deletion of chromosomes 5 and 7 in the lymphocytes of Chinese workers exposed to benzene

Two of the most common cytogenetic changes in therapy- and chemical- related leukemia are the loss and long (q) arm deletion of chromosomes 5 and 7. The detection of these aberrations in lymphocytes of individuals exposed to potential leukemogens may serve as useful biomarkers of increased leukemia risk. We have used a novel fluorescence in situ hybridization (FISH) procedure to determine if specific aberrations in chromosomes 1, 5 and 7 occur at an elevated rate in the blood cells of workers exposed to benzene. Forty-three healthy workers exposed to a wide range of benzene concentrations (median 31 p.p.m., 8 h time-weighted average) and 44 unexposed controls from Shanghai were studied. Whole blood was cultured and metaphase spreads were harvested at 72 h. Benzene exposure was associated with increases in the rates of monosomy 5 and 7 but not monosomy 1 (P < 0.001, P < 0.0001 and P = 0.94, respectively) and with increases in trisomy and tetrasomy frequencies of all three chromosomes. Long arm deletion of chromosomes 5 and 7 was increased in a dose-dependent fashion (P = 0.014 and P < 0.0001) up to 3.5-fold in the exposed workers. These results demonstrate that leukemia-specific changes in chromosomes 5 and 7 can be detected by FISH in the peripheral blood of otherwise healthy benzene-exposed workers. We suggest that aberrations in chromosomes 5 and 7 may be useful biomarkers of early biological effect for benzene exposure.      

Neuropsychological functioning in end-stage renal disease.

AIMS: To compare the neuropsychological functioning and behaviour of children with non-syndromic end-stage renal disease (ESRD) and sibling controls. METHODS: The study was carried out at two tertiary care paediatric teaching hospitals, in Halifax and Vancouver, Canada. Children with ESRD were on a renal transplant waiting list and either pending dialysis or on dialysis therapy. Twenty two patient-sibling pairs were evaluated. Neuropsychological assessments consisting of measures of intelligence, academic achievement, memory, and motor abilities were carried out. Maternal ratings of behaviour and self-report rating of self-esteem were collected. RESULTS: The Verbal, Performance, and Full Scale IQs of patients with ESRD were significantly lower than the IQs of the sibling controls. The mean differences were 8.6, 11.7, and 10.9 points, respectively. ESRD patients also had significantly more difficulty on measures of fine motor coordination and ability to copy geometric designs than sibling controls. There were no differences between groups on measures of academic achievement, memory, behaviour, or self-esteem. CONCLUSIONS: Although children with ESRD exhibited mild deficits on measures of intelligence and some measures of motor abilities, their neuropsychological outcome was more favourable than earlier reports indicated.