Spinal navigation for minimally invasive thoracic and lumbosacral spine fixation: implications for radiation exposure, operative time, and accuracy of pedicle screw placement.

PURPOSE: Navigation is emerging as a useful adjunct in percutaneous, minimally invasive spinal surgery (MIS). The aim of this study was to compare C-Arm navigated, O-Arm navigated and conventional 2D-fluoroscopy assisted MIS thoracic and lumbosacral spine fixation techniques in terms of operating time, radiation exposure and accuracy of pedicle screw (PS) placement. METHODS: Retrospective observational study of 152 consecutive adults who underwent MIS fixations for spinal instability: 96 2D-fluoroscopy assisted, 39 3D-C-Arm navigated and 27 using O-Arm navigated. RESULTS: O-Arm navigation significantly reduced PS misplacement (1.23%, p) compared to 3D-C-Arm navigation (7.29%, p = 0.0082) and 2D-fluoro guided placement (5.16%, p = 0379). 3D-C-Arm navigation was associated with lower procedural radiation exposure of the patient (0.4 mSv) than O-Arm navigation (3.24 mSv) or 2D-fluoro guidance (1.5 mSv). Operative time was comparable between three modalities. CONCLUSIONS: O-Arm navigation provides greater accuracy of percutaneous instrumentation placement with an acceptable procedural radiation dose delivered to the patients and comparable operative times. These slides can be retrieved under Electronic Supplementary material.

Time trends in breast cancer and menopause hormone therapy use in New Zealand.

OBJECTIVE: The publication of preliminary findings from the Women's Health Initiative (WHI) Study in 2002 suggested an increased risk of breast cancer among users of menopause hormone therapy (MHT). This resulted world-wide in a rapid and significant decline in the use of hormone therapy. It was later claimed that breast cancer incidence rates had fallen as a result of lower rates of hormone therapy use. Our aim was to investigate whether there was an association between changes in the use of hormone therapy and rates of breast cancer diagnosis in New Zealand subsequent to the publication of the WHI. METHOD: Validated prescription usage data along with breast cancer screening and cancer registration data were accessed. Time trends extending for 8 years after the publication of the WHI were assessed. RESULTS: The use of hormone therapy for managing menopausal symptoms fell by about 70% following the controversy about its safety. Breast cancer registration rates among women aged 50-59 years had started to fall in advance of this change in prescribing. Changes in other age groups appear to coincide with changes in the screening eligibility for the national breast screening program rather than use of hormone therapy. CONCLUSION: The time trend analysis does not support an association between changes in hormone therapy use and the incidence rate of breast cancer.

Natural course of cannabis use disorders.

BACKGROUND: Despite its importance as a public health concern, relatively little is known about the natural course of cannabis use disorders (CUDs). The primary objective of this research was to provide descriptive data on the onset, recovery and recurrence functions of CUDs during the high-risk periods of adolescence, emerging adulthood and young adulthood based on data from a large prospective community sample. METHOD: Probands (n = 816) from the Oregon Adolescent Depression Project (OADP) participated in four diagnostic assessments (T1-T4) between the ages of 16 and 30 years, during which current and past CUDs were assessed. RESULTS: The weighted lifetime prevalence of CUDs was 19.1% with an average onset age of 18.6 years. Although gender was not significantly related to the age of initial CUD onset, men were more likely to be diagnosed with a lifetime CUD. Of those diagnosed with a CUD episode, 81.8% eventually achieved recovery during the study period. Women achieved recovery significantly more quickly than men. The recurrence rate (27.7%) was relatively modest, and most likely to occur within the first 36 months following the offset of the first CUD episode. CUD recurrence was uncommon after 72 months of remission and recovery. CONCLUSIONS: CUDs are relatively common, affecting about one out of five persons in the OADP sample prior to the age of 30 years. Eventual recovery from index CUD episodes is the norm, although about 30% of those with a CUD exhibit a generally persistent pattern of problematic use extending 7 years or longer.

Selective AKR1C3 inhibitors do not recapitulate the anti-leukaemic activities of the pan-AKR1C inhibitor medroxyprogesterone acetate.

BACKGROUND: We and others have identified the aldo-keto reductase AKR1C3 as a potential drug target in prostate cancer, breast cancer and leukaemia. As a consequence, significant effort is being invested in the development of AKR1C3-selective inhibitors. METHODS: We report the screening of an in-house drug library to identify known drugs that selectively inhibit AKR1C3 over the closely related isoforms AKR1C1, 1C2 and 1C4. This screen initially identified tetracycline as a potential AKR1C3-selective inhibitor. However, mass spectrometry and nuclear magnetic resonance studies identified that the active agent was a novel breakdown product (4-methyl(de-dimethylamine)-tetracycline (4-MDDT)). RESULTS: We demonstrate that, although 4-MDDT enters AML cells and inhibits their AKR1C3 activity, it does not recapitulate the anti-leukaemic actions of the pan-AKR1C inhibitor medroxyprogesterone acetate (MPA). Screens of the NCI diversity set and an independently curated small-molecule library identified several additional AKR1C3-selective inhibitors, none of which had the expected anti-leukaemic activity. However, a pan AKR1C, also identified in the NCI diversity set faithfully recapitulated the actions of MPA. CONCLUSIONS: In summary, we have identified a novel tetracycline-derived product that provides an excellent lead structure with proven drug-like qualities for the development of AKR1C3 inhibitors. However, our findings suggest that, at least in leukaemia, selective inhibition of AKR1C3 is insufficient to elicit an anticancer effect and that multiple AKR1C inhibition may be required.

Ethnic differences in the severity and clinical management of type 2 diabetes at time of diagnosis: A cohort study in the UK Clinical Practice Research Datalink.

AIMS: To characterize ethnic differences in the severity and clinical management of type 2 diabetes at initial diagnosis. METHODS: An observational cohort study of 179,886 people with incident type 2 diabetes between 2004 and 2017 in the Clinical Practice Research Datalink was undertaken; 63.4% of the cohort were of white ethnicity, 3.9% south Asian, and 1.6% black. Ethnic differences in clinical profile at diagnosis, consultation rates, and risk factor recording were derived from linear and logistic regression. Cox-proportional hazards regression was used to determine ethnic differences in time to initiation of therapeutic and non-therapeutic management following diagnosis. All analyses adjusted for age, sex, deprivation, and clustering by practice. RESULTS: In the 12 months prior to diagnosis, non-white groups had fewer consultations compared to white groups, but risk factor recording was better than or equivalent to white groups for 9/10 risk factors for south Asian groups and 8/10 risk factors for black groups (p < 0.002). Blood pressure, BMI, cholesterol, eGFR, and CVD risk levels were more favourable in non-white groups, and prevalence of macrovascular disease was significantly lower (p < 0.003). Time to initiation of antidiabetic treatment and first risk assessment was faster in non-white groups relative to white groups, while time to risk factor measurement and diabetes review was slower. CONCLUSIONS: We find limited evidence of systematic ethnic inequalities around the time of type 2 diabetes diagnosis. Ethnic disparities in downstream consequences may relate to genetic risk factors, or manifest later in the care pathway, potentially in relation to long-term risk factor control.

Auditory sequence: confusion of patterns other than speech or music.

Accurate perception of temporal order is essential for many auditory tasks. Yet the temporal pattern of four successive sounds (for example, hisses, buzzes, and tones) could not be recognized even when the duration of each sound was considerably longer than either the average phoneme in normal discourse or the notes of melodies. Although each of the stimuli was perceived, their order remained frustratingly elusive.

Effect of Intravenous Administration of Cobalt Chloride to Horses on Clinical and Hemodynamic Variables.

BACKGROUND: Cobalt chloride (CoCl2 ) is administered to racehorses to enhance performance. The purpose of this study was to evaluate the clinical, cardiovascular, and endocrine effects of parenterally administered CoCl2 . OBJECTIVES: To describe the effects of weekly intravenous doses of CoCl2 on Standardbred horses. ANIMALS: Five, healthy Standardbred mares. METHODS: Prospective, randomized, experimental dose-escalation pilot. Five Standardbred mares were assigned to receive 1 of 5 doses of CoCl2 (4, 2, 1, 0.5, or 0.25 mg/kg) weekly IV for 5 weeks. Physical examination, blood pressure, cardiac output, and electrocardiography (ECG) were evaluated for 4 hours after administration of the first and fifth doses. Blood and urine samples were collected for evaluation of cobalt concentration, CBC and clinical chemistry, and hormone concentrations. RESULTS: All mares displayed pawing, nostril flaring, muscle tremors, and straining after CoCl2 infusion. Mares receiving 4, 2, or 1 mg/kg doses developed tachycardia after dosing (HR 60-126 bpm). Ventricular tachycardia was noted for 10 minutes after administration of the 4 mg/kg dose. Increases in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) occurred after administration of all doses (4, 2, 1, 0.5, and 0.25 mg/kg). Profound hypertension was observed after the 4 mg/kg dose (SAP/DAP, MAP [mmHg] = 291-300/163-213, 218-279). Hemodynamics normalized by 1-2 hours after administration. ACTH and cortisol concentrations increased within 30 minutes of administration of all CoCl2 doses, and cardiac troponin I concentration increased after administration of the 4 and 2 mg/kg doses. CONCLUSIONS AND CLINICAL IMPORTANCE: The degree of hypertension and arrhythmia observed after IV CoCl2 administration raises animal welfare and human safety concerns.

Myocardial infarction risk and hormone replacement: differences between products.

OBJECTIVES: To establish the risk of myocardial infarction (MI) in users of hormone replacement therapy (HRT) compared with non-users and to compare the risk between different HRT regimens. METHODS: A population-based cohort and case-control study, and a case-control study nested within a cohort of HRT users, using the UK General Practice Research Database. Differences between HRT regimen, mode of administration and duration and recency of use were examined whilst adjusting for confounding. RESULTS: In the cohort and case-control study, 4537 cases of MI were identified in 2.62 million observed women years, cases were age-matched to 27,220 controls. In both studies, current and past HRT use were associated with reduced risk estimates for MI compared with no prior use. MIs were less likely to be fatal amongst women who had used HRT than amongst never users (OR(adj) 0.58; 95% CI 0.45-0.75). No difference in risk was seen between current and past use, oral and transdermal HRT or between different regimens (p>0.44). In the nested study, no difference was found in the association with MI risk between different oestrogen-progestogen combinations or between different combinations and tibolone. Unopposed oestrogen use was not associated with a decrease in risk compared with combined HRT. CONCLUSIONS: These results are consistent with previous observational studies in supporting the hypothesis that use of postmenopausal HRT is associated with a decrease in risk of acute myocardial infarction (AMI). Case fatality differed between HRT users and non-users, suggesting a protective effect of HRT. This study does not demonstrate a difference between regimens.

Simvastatin did not prevent nor restore ovariectomy-induced bone loss in adult rats.

Current published results on whether statins have beneficial effects on bone metabolism have been conflicting so far. In order to further investigate if statins were promising candidates for the treatment for osteoporosis, we conducted a study in which rats were ovariectomized (OVX) at 6 months of age, allowed to lose bone for 60 days and followed by oral administration of simvastatin at the dose levels of 0.3-10 mg/kg/d for 60 days. PGE2 (6 mg/kg) was used as a positive control. Study endpoints included bone histomorphometry on the proximal tibial metaphysis (PTM) and the tibial diaphysis (TX), dual-energy X-ray absorptiometry on the right femur and micro computed tomography (ICT) on the 5th lumbar vertebra (LV). After 120 days of OVX, cancellous bone lost by 80% in the PTM and 18% in the LV accompanied by increased bone formation and resorption. Simvastatin at all dose levels did not affect bone volume, bone formation rate and bone erosion surface when compared to 120 day ovariectomized animals at all bone sites studied. By contrast, PGE2 restored cancellous and cortical bone area to sham control levels. In conclusion, this study demonstrated that unlike PGE2, oral administration of simvastatin did not have effects on cancellous or cortical bone formation and resorption; and consequently was not able to prevent further bone loss or restore bone mass in the osteopenic, OVX rats.

Decreased dose of radiation to dogs during acquisition of elbow radiographs using draped shielding.

Protective lead equivalent shielding of patients is not routinely used in veterinary radiology. The goal of this study was to determine whether the use of lead equivalent shielding results in a significant reduction in dose of radiation to dogs during acquisition of elbow radiographs. The authors measured radiation doses in the primary beam and over and under protective lead equivalent shielding that was placed at the level of the eyes, body and gonads during acquisition of elbow radiographs using 0.01 mSv sensitivity dosimetry badges. Shielding consisted of 0.5 mm lead equivalent aprons and thyroid shields placed over bodies and eyes, respectively. All badges in the primary beam-detected radiation. Shielding significantly decreased the dose of radiation with significantly less scatter and tube leakage radiation detected under compared with over shielding (P=0.0001). The dose of radiation detected over shielding was significantly greater than zero (P=0.0001), while that under shielding did not differ significantly from zero (P=0.09). Based on these results, the authors recommend protective shielding be used on veterinary patients during radiography.

Acute areflexic paralysis. Association with hyperalimentation and hypophosphatemia.

Acute areflexic paralysis associated with diffuse sensory loss, cranial nerve paisies, and respiratory insufficiency occurred in two patients who developed hypophosphatemia during hyperalimentation. Prompt recovery followed replacement of serum phosphorus in both cases. An electromyogram performed on one patient revealed only decreased insertional activity. A muscle biopsy specimen from the same patient showed minor, nonspecific neurogenic changes.

Quality of life in multiple sclerosis. Comparison with inflammatory bowel disease and rheumatoid arthritis.

Multiple sclerosis (MS) and other chronic illnesses can drastically decrease quality of life (QOL), but there has been little systematic study of QOL in patients with chronic medical diseases. We analyzed QOL in 68 patients with MS, 164 patients with inflammatory bowel disease, and 75 patients with rheumatoid arthritis. The previously validated test instrument was a standardized interview consisting of 41 questions clustered in four subscales: functional and economic scale, social and recreational scale, affect and life in general scale, and medical problems scale. Patients were included in the study if they had a definite medical diagnosis and disease duration of 10 years or longer. In the patients with MS, Kurtzke's Expanded Disability Status Scale correlated strongly only with the medical problems score. Of Kurtzke's Functional System Scales, only the visual Functional System Scores was correlated with total QOL and subscale scores, suggesting that vision is strongly related to QOL. Duration of MS was unrelated to QOL scores. There were significant differences between patients with MS, inflammatory bowel disease, and rheumatoid arthritis on the subscale and total QOL scores. Results suggested that QOL was best in the inflammatory bowel disease group and worst in the MS group. Numerous statistically significant differences on individual questions were evident, suggesting that unique clinical profiles differentially characterize these diseases. Assessments of QOL are a meaningful addition to impairment scales, such as Kurtzke's Expanded Disability Status Scale. Furthermore, QOL scores may meaningfully measure the impact of a chronic medical disease, such as MS, compare the impacts of different diseases, and assess the effects of therapeutic intervention.

Vanilloids. 1. Analogs of capsaicin with antinociceptive and antiinflammatory activity.

As part of a program to establish structure-activity relationships for vanilloids, analogs of the pungent principle capsaicin, the alkyl chain portion of the parent structure (and related compounds derived from homovanillic acid) was varied. In antinociceptive and antiinflammatory assays (rat and mouse hot plate and croton oil-inflamed mouse ear), compounds with widely varying alkyl chain structures were active. Short-chain compounds were active by systemic administration in the assays mentioned above but they retained the high pungency and acute toxicity characteristic of capsaicin. In contrast, the long chain cis-unsaturates, NE-19550 (vanillyloleamide) and NE-28345 (oleylhomovanillamide), were orally active, less pungent, and less acutely toxic than capsaicin. The potential of these compounds as antiinflammatory/analgesic agents is discussed in light of recent data on the mechanism of action of vanilloids on sensory nerve fibers.

New cyclooxygenase-2/5-lipoxygenase inhibitors. 1. 7-tert-buty1-2,3-dihydro-3,3-dimethylbenzofuran derivatives as gastrointestinal safe antiinflammatory and analgesic agents: discovery and variation of the 5-keto substituent.

A series of 5-keto-substituted 7-tert-buty1-2,3-dihydro-3,3- dimethylbenzofurans (DHDMBFs) were prepared and evaluated as potential nonsteroidal antiinflammatory and analgesic agents. Interest in this class of compounds arose when a DHDMBF was found to be an active metabolite of the di-tert-butylphenol antiinflammatory agent tebufelone. We have now found that a variety of 5-keto-substituted DHDMBFs have good in vivo antiinflammatory and analgesic activity after oral administration. These compounds inhibit both cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) in vitro. The cyclooxygenase inhibition was found to be selective for the cyclooxygenase-2 isoform, and this combination of COX-2/5-LOX inhibition may be responsible for the gastrointestinal safety of compounds such as 30.

Evaluating adverse cardiovascular effects of drug treatment for benign prostatic hyperplasia (BPH): methodological considerations.

When studying the effects of drug exposure in diseases with a long asymptomatic clinical course, exposure classification may be biased by the gradually developing "visibility" of the disease. Benign prostatic hyperplasia (BPH) is such a disease. We found that cardiovascular morbidity is two times more prevalent in patients starting drug treatment for BPH when compared to age-matched population controls. This resulted in a difference of cardiovascular prognostic factors between the exposed and non-exposed. This feature can jeopardize the validity of non-randomized comparisons of drug effects. Moreover, the existence of non-treatment strategies, disease under-reporting, and an elderly population with a high baseline risk of experiencing (cardiovascular) outcome events were encountered as methodological problems. When studying adverse cardiovascular effects in patients using BPH products in a non-randomized fashion, an important question is whether we can measure in the database all relevant prognostic factors and use the information for statistical adjustment. This question is an important challenge to observational research and once again stresses the need for control of possible biases in choosing an appropriate study design.

Impact of diagnosis-related groups' prospective payment on utilization of medical intensive care.

We examined the financial impact of diagnosis-related groups (DRGs) payment for Medicare patients receiving medical intensive care and looked for any change in the type of patients admitted to the medical intensive care unit (MICU) after one year's experience with DRGs. During 1984, payment for 267 Medicare patients receiving medical intensive care at a large, multispecialty referral hospital was calculated to be $2.6 million below cost, representing an average loss per discharge of $9,794. For those who died (42 percent), the average payment per case was $11,418 below the average per discharge cost. In 1985, 241 Medicare patients treated in the MICU showed an average loss per discharge of $14,113, which rose to $20,271 for those who expired (39.4 percent). There was no significant difference in mortality between the two groups and in type of patients per DRG assignment (p = 0.56 and p = 0.88, respectively) by Chi-squared test. Despite the 1984 DRG experience, there was no change in admission practices or utilization of MICU beds during 1985. Appropriate management responses are needed from both the Federal government and the medical profession for better utilization of MICU resources.

Suicide on the London Underground System.

Over the past 50 years there has been an increase in the numbers of people jumping/falling in front of trains on the London Underground system. Case-fatality rates have fallen from 70% in the 1950s to 55% today. The proportion certified as suicide has fallen while the proportions certified as accidents or open verdicts have risen. There is unusual clustering of events at some stations which are adjacent to psychiatric units. The hypothesis that ease of access to London Underground stations may sometimes be a determinant of suicide is investigated.

Carcinoma of the small intestine associated with transmural ileitis (Crohn's disease).

A case of adenocarcinoma of the small bowel arising in pre-existing transmural ileitis (Crohn's disease) is reported and 28 previously reported cases are reviewed. Carcinoma associated with transmural enteritis occurs more often in the distal ileum, in younger patients, and in more males than expected from published data on carcinoma not associated with transmural enteritis. If the patient has had exclusion procedures, the carcinoma has been found to arise in the excluded bowel segment.

Why we should eliminate the due date: a truth in jest.

We currently use flawed calculations to set a woman's due date based on menstrual periods to determine gestational age. We use the estimated gestational age to make management decisions based on our patients' individual needs. This principle is in contrast to our patients' use of dating to set an estimated date of confinement. This date is seen as a very specific point in time. Patients and their families plan on that date and become distressed when the expected date is not met. Given that many patients are induced electively, that many will have their delivery dates changed, and that many will have delivery dates adjusted for medical reasons, and most importantly given that dating is inaccurate and unreliable, we propose eliminating the due date. We propose giving patients a calculated assigned week of delivery at 32 weeks. An assigned week of delivery allows for individualization of obstetric care based on the needs of our patients, their support systems, and hospital staffing. We believe an assigned week of delivery will improve obstetric practice and patient satisfaction.