Introduction of paediatric laparoscopic cholecystectomy in Scotland: a national review of incidence, outcomes and training implications.

BACKGROUND: We present a national data series to determine the incidence, outcomes and training opportunities for laparoscopic cholecystectomy among children <16yrs in Scotland as performed by paediatric surgeons. METHODS: A retrospective cohort study was performed reviewing laparoscopic cholecystectomy performed at the three children's hospitals in Scotland. Using the National Records Scotland Database mid-year population estimates; age and sex specific annual incidence rates of laparoscopic cholecystectomy were calculated between 1998-2015. Trends in the observed case mix were tested using univariate linear regression and students t-test. RESULTS: Between 1998-2015; 141 paediatric laparoscopic cholecystectomies were performed. The annual rate of cholecystectomy increased from 0.10/100,000 to 0.88/100,000 (p = 0.069). Sex specific incidences were identified; 0.00-0.90/100,000 (p = 0.098) in girls and 0.20-0.86/100,000 in boys (p = 0.28). Cholecystectomy was more frequent in girls (63%; p = 0.04). No major complications, defined as common bile duct injury or mortality were identified. Overall; 75% of cases were performed by consultants (n = 17 consultants, median = 5 cases, p < 0.05) and 25% by trainees. CONCLUSION: We have demonstrated that despite a low national case load (8 laparoscopic cholecystectomies per year) paediatric surgeons have been able to perform laparoscopic cholecystectomy safely without major morbidity.

Medical Journey of Patients with Mild Cognitive Impairment and Mild Alzheimer's Disease Dementia: A Cross-sectional Survey of Patients, Care Partners, and Neurologists.

BACKGROUND: Alzheimer's disease (AD) is a progressive, neurodegenerative disease presenting along a continuum ranging from asymptomatic disease to mild cognitive impairment (MCI), followed by dementia characterized as mild, moderate, or severe. OBJECTIVES: To better understand the medical journey of patients with all-cause MCI or mild AD dementia from the perspective of patients, care partners, and physicians. DESIGN: Cross-sectional study. SETTING: Online surveys in the United States between February 4, 2021, and March 1, 2021. PARTICIPANTS: 103 patients with all-cause MCI or mild AD dementia and 150 care partners participated in this survey. 301 physicians (75 of whom were neurologists) completed a survey. MEASUREMENTS: The surveys included questions regarding attitudes, experiences, and behaviors related to diagnosis and management of MCI and mild AD dementia. For the patient and care partner surveys, questions regarding healthcare received for MCI and mild AD dementia were only asked of care partners. RESULTS: Most patients (73%) had a similar medical journey. The majority (64%) initially consulted a primary care physician on average 15 months after symptom onset, with symptoms primarily consisting of forgetfulness and short-term memory loss. About half (51%) of patients in the typical medical journey were diagnosed by a neurologist. Upon diagnosis, most neurologists reported having discussions with patients and care partners about the potential causes of MCI or mild AD dementia (83%); of these physicians, 83% explained the effect other conditions have on the risk of the diagnoses and symptom progression. Neurologists (52%) consider themselves the coordinator of care for patients with MCI or mild AD dementia. Amongst patients and care partners, about one-third (35%) perceive the neurologists to be the coordinating physician. CONCLUSIONS: Neurologists commonly diagnose MCI and mild AD dementia but are typically not the first point of contact in the medical journey, and patients do not consult with a physician for over a year after symptom onset. Neurologists play a key role in the medical journey for patients and care partners, and could help ensure earlier diagnosis and treatment, and improve clinical outcomes by coordinating MCI and mild AD dementia care and collaborating with primary care physicians.

Ability of radial arterial palpation and observation of the pulse oximetry trace to estimate non-invasive systolic pressure in healthy volunteers and in women undergoing spinal anaesthesia for elective caesarean section.

We assessed the ability of palpating the radial arterial pulse and observing the oximeter trace to estimate the automated non-invasive systolic pressure reading in 20 healthy female volunteers and 20 parturients undergoing spinal anaesthesia for elective caesarean section. Using real-time values of cuff pressure during inflation/deflation, the pressure was recorded when the manually palpated radial arterial pulse or pulse oximeter waveform disappeared and reappeared. The actual measured systolic pressure was noted and the results compared using Bland-Altman analysis. In the volunteers, the bias/precision for radial arterial palpation was -12.9/22.1 mmHg (inflation) and -9.7/16.7 mmHg (deflation), and for oximetry 29.5/18.8 mmHg (inflation) and -20.7/21.7 mmHg (deflation). In the parturients, the bias/precision was -19.0/47.6 mmHg (inflation) and -15.5/51.0 mmHg (deflation) for arterial palpation, and 22.6/16.1 mmHg (inflation) and -14.2/19.9 mmHg (deflation) for oximetry. Our results suggest that neither method is accurate at estimating the non-invasive systolic pressure, with all except oximetry (inflation) underestimating it by approximately 10-20 mmHg and with poor precision.

O(6)-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib.

We evaluated the pharmacodynamic effects of the O(6)-methylguanine-DNA methyltransferase (MGMT) inactivator lomeguatrib (LM) on patients with melanoma in two clinical trials. Patients received temozolomide (TMZ) for 5 days either alone or with LM for 5, 10 or 14 days. Peripheral blood mononuclear cells (PBMCs) were isolated before treatment and during cycle 1. Where available, tumour biopsies were obtained after the last drug dose in cycle 1. Samples were assayed for MGMT activity, total MGMT protein, and O(6)-methylguanine (O(6)-meG) and N7-methylguanine levels in DNA. MGMT was completely inactivated in PBMC from patients receiving LM, but detectable in those on TMZ alone. Tumours biopsied on the last day of treatment showed complete inactivation of MGMT but there was recovery of activity in tumours sampled later. Significantly more O(6)-meG was present in the PBMC DNA of LM/TMZ patients than those on TMZ alone. LM/TMZ leads to greater MGMT inactivation, and higher levels of O(6)-meG than TMZ alone. Early recovery of MGMT activity in tumours suggested that more protracted dosing with LM is required. Extended dosing of LM completely inactivated PBMC MGMT, and resulted in persistent levels of O(6)-meG in PBMC DNA during treatment.

Thromboelastography (TEG®) demonstrates that tinzaparin 4500 international units has no detectable anticoagulant activity after caesarean section.

BACKGROUND: Low molecular weight heparin is routinely used for thromboprophylaxis in pregnancy and the puerperium. Consensus guidelines recommend waiting 10-12h after administration of a thromboprophylactic dose of low molecular weight heparin before performing a neuraxial block or removing an epidural catheter. Thromboelastography (TEG®) has been reported to be sensitive to the effects of enoxaparin 4h after administration. The purpose of this study was to use TEG to examine coagulation changes in the first 10h after a thromboprophylactic dose of tinzaparin in an attempt to ratify the current consensus guidelines about timing of neuraxial blockade and epidural catheter removal. METHODS: Twenty-four women who had undergone caesarean delivery and were classified as low or intermediate risk of thrombosis were recruited. Blood samples were taken before subcutaneous administration of tinzaparin 4500IU, and at 4, 8 and 10h post-dose. Standard TEG analyses were performed using plain and heparinase cuvettes and samples were also sent for laboratory anti-Xa assay. Thromboelastograph profiles were analysed for a low molecular weight heparin effect. RESULTS: Analysis revealed no significant differences in R time, K time, alpha angle or maximum amplitude between plain and heparinase samples at any time point. Apart from a small statistically significant (P=0.033) decrease in maximum amplitude of 2.8% (95% CI 0.3 to 5.4%) at 4h, there were no significant changes in coagulation for any TEG parameter. Anti-Xa levels were virtually undetectable in all patients over the 10h period (median 0.00U/mL; range 0.00-0.13U/mL). CONCLUSION: A thromboprophylactic dose of tinzaparin 4500IU had little detectable effect on coagulation as assessed by TEG and anti-Xa assay. These findings support consensus guidelines which state that it is acceptable to perform neuraxial blockade or remove an epidural catheter 10-12h after a thromboprophylactic dose of tinzaparin. Rather than suggesting a lack of anticoagulant activity, the findings indicate that TEG may not have the sensitivity to detect a tinzaparin effect when this dose is used in this patient group.

Acute colonic pseudo-obstruction in a child taking trihexyphenidyl for drooling: Prescribers beware.

Colonic pseudo-obstruction (Ogilvie's Syndrome) in children is relatively uncommon. We report an unusual case of colonic pseudo-obstruction in an 8-year-old child with cerebral palsy and long-term hypomotility issues being treated for drooling with the anticholinergic medication trihexyphenidyl. He presented as an emergency with severe abdominal distension, abdominal tenderness and vomiting. An emergency laparotomy revealed colonic dilatation and a defunctioning ileostomy was created. To our knowledge, this is the first case reporting colonic pseudo-obstruction as a possible complication of treatment with trihexyphenidyl. We suggest prescribers should exercise caution when prescribing trihexyphenidyl in patients with long-term intestinal hypomotility issues.

The outcome of pregnancy following renal transplantation--the experience of a single center.

Many centers still recommend avoidance of pregnancy after renal transplantation because of fears for the safety of both mother and fetus. These fears are in part based on a lack of information concerning the effects of newer immunosuppressive drugs such as cyclosporine on the course and outcome of pregnancy. The present study examines the experience of first pregnancies following renal transplantation in a single center, with emphasis on the role of CsA. Data on the first pregnancies of 22 women transplanted between 1977 and 1988 were studied. The mean age of patients at the time of transplant was 23.4 +/- 3.1 years and interval from transplant to pregnancy was 34.5 +/- 24.5 months (range 1-75 months). Twelve patients received CsA alone or in combination with other immunosuppressives, while the remaining 10 patients received azathioprine and prednisone. Mean serum creatinine fell progressively during pregnancy in both CsA- and azathioprine-treated mothers. Mean CsA dose rose during pregnancy while mean CsA blood concentration fell during the 2nd trimester (P = 0.042). The gestation period ranged from 27 to 40 weeks (35.5 +/- 3.3) with 14 pregnancies ending prematurely prior to 37 weeks. Thirteen deliveries occurred by Caesarian section. Hypertension complicated 10 pregnancies. Birth weight correlated directly with both maternal weight gain (r = 0.57; P less than 0.02) and gestational age (r = 0.9; P less than 0.01). Ten of 23 offspring were below the 10th percentile for weight. Mean birth weight ranged from 0.72 to 3.7 kg (2.3 +/- 0.84 kg). The mean birth weight and gestational age of children born to mothers taking CsA were lower than those in azathioprine treated mothers but these differences were not statistically significant. Successful pregnancy is possible following renal transplantation, although there is a high rate of prematurity, low birth weight, and intrauterine growth retardation. CsA dose requirements may be increased. Maternal risks including hypertension require that such pregnancies be handled by a multidisciplinary team approach.

Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.

The majority of fatal acute myocardial infarctions occur in the elderly. Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Antithrombin, Protein C, Protein S. and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women > or = 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p < or = 0.001), and TFPI was higher in older men (p < or = 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen. plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment F1-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and internal carotid artery stenosis, p trend < or = 0.01; and carotid wall thickness, p trend < or = 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen; the fibrinolytic marker plasmin-antiplasmin complex; LDL-cholesterol; and carotid wall thickness (R2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age, and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endothelial damage.

Post-mortem findings in fetal and neonatal congenital diaphragmatic hernia.

Analyses of survival data of neonates born with congenital diaphragmatic hernia (CDH) can be misleading. There is a hidden mortality only apparent when fetuses with CDH are included in the analysis. A retrospective review of all post mortems with a diagnosis of CDH in the West of Scotland over a 10-year period was carried out. Congenital anomalies were identified and heart and lung weights were compared with controls (infants dying of non-cardiorespiratory causes). 70 Pm reports were studied. Major congenital anomalies were present in 53% (18/ 47 live born, 19/23 not live born). Neural tube defects, cardiac and chromosomal anomalies were the most common. Antenatal detection rate was 17% in live-born infants. In infants dying within the first week of life lung weights showed severe pulmonary hypoplasia, but heart weights were within the normal range. Detailed antenatal scanning needs to be considered if the detection rate for CDH is to improve in this region.

Subcuticular skin closure using a 'blunt' needle.

Recognising the desirability of avoiding the use of sharp needles, especially for wound closure, this study was undertaken to determine whether it was technically feasible to perform a subcuticular skin closure with a 'blunt' Ethiguard needle (Ethicon Ltd). A total of 108 skin incisions was closed in 40 patients. In each case it was found that the needle successfully penetrated the subcuticular layers allowing the use of a standard subcuticular closure technique with the advantage of reduced risk of skin or glove puncture.

A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer.

BACKGROUND: Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan in patients with metastatic colorectal cancer and assessed the safety, toxicity and clinical pharmacology of combination treatment. PATIENTS AND METHODS: Patients with metastatic colorectal cancer received lomeguatrib (10-80 mg PO) on days 1-5 with irinotecan (250-350 mg/m(2) IV) on day 4 of a 21-day cycle. RESULTS: Twenty-four patients, pre-treated with a median of 2 lines of chemotherapy, received 104 cycles of treatment. The MTD was defined as 80 mg/day lomeguatrib with 300 mg/m(2) irinotecan. The main toxicities observed were neutropaenia and diarrhoea. Lomeguatrib of 80 mg/day produced complete MGMT depletion in all available peripheral blood mononuclear cells (PBMCs) and paired tumour biopsies (one patient). There was no pharmacokinetic interaction between the drugs. In 22 patients assessable for tumour response, one achieved a partial response and 16 had stable disease. CONCLUSION: This study defined a tolerable dose of irinotecan in combination with lomeguatrib in patients with metastatic colorectal cancer. Combination treatment gave a similar response rate to irinotecan monotherapy in this heavily pre-treated patient group.

The hidden mortality of congenital diaphragmatic hernia: a 20-year review.

AIMS: The true mortality associated with congenital diaphragmatic hernia (CDH) is hidden because survival analyses do not include fetuses with CDH. A retrospective review of all postmortems (PMs) with a diagnosis of CDH over a 20-year period was carried out to highlight this hidden mortality and also measure the nature and number of associated anomalies. METHODS: Postmortem case record details were reviewed for the period January 1986 to December 2005. Data were collected on live birth, stillbirth, therapeutic abortion, and spontaneous abortion. RESULTS: There was a decline in the annual number of PMs during the period of the study. The median for the four 5-year intervals being 609 (570-657), 528 (488-565), 515 (413-537), and 373 (357-388). A total of 130 PMs were identified, which included a diagnosis of CDH; 97 (75%) were left sided, 22 (17%) were right sided, and 11 (8%) were bilateral. There were 69 live births, 46 therapeutic abortions, 10 stillbirths, and 5 intrauterine deaths; 22% were right sided/bilateral in the live and therapeutic abortion groups, whereas 53% were right sided/bilateral in the latter 2 groups. Of 130, 82 (63%) had major associated anomalies, and 50% of these had at least 1 further major anomaly. The commonest categories of anomalies were cardiac (30), gastrointestinal/abdominal wall defect (28), and neural tube defects (25). CONCLUSIONS: The true incidence of CDH is considerably higher than that seen in neonatal surgical practice. The decline in number of PMs in our region will exacerbate the underestimation of the true incidence. There is a higher incidence of right-sided/bilateral hernias and more than one major anomaly in those who die in utero.

Morphology of human suprarenal glands: a parameter for comparison.

Forty suprarenal glands were studied, 20 being dissected from aborted fetuses of 9 to 36 weeks' gestation and 20 obtained from human cadavers of ages 1 day to 60 years. All the specimens were from a Northern India population. The side and shape of each suprarenal gland was noted and documented. The length, breadth, thickness and volume of each gland were measured and tabulated in terms of age. The mean length, breadth and thickness in fetuses of 9-36 weeks were found to be 1.4 cm, 1 cm and 0.45 cm respectively. In the postnatal age group the measurements were 4.5 cm, 2.08 cm and 0.66 cm respectively. The commonest shape of the suprarenal glands on left side was semilunar but on the right side it was highly variable: triangular, tetrahedral, inverted Y or V shaped. On comparison of the gross measurements with available ultrasound and CT scan data it was found that both the length and thickness in the population studied were greater than reported in the literature. A knowledge of these variations is very important in diagnosis of abnormalities of the suprarenal gland, of which tumoral enlargement is rather common.

Antibody-probed conformational transitions in the protease domain of human factor IX upon calcium binding and zymogen activation: putative high-affinity Ca(2+)-binding site in the protease domain.

The Fab fragment of a monoclonal antibody (mAb) reactive to the N-terminal half (residues 180-310) of the protease domain of human factor IX has been previously shown to inhibit the binding of factor IXa to its cofactor, factor VIIIa. These data suggested that this segment of factor IXa may participate in binding to factor VIIIa. We now report that the binding rate (kon) of the mAb is 3-fold higher in the presence of Ca2+ than in its absence for both factors IX and IXa; the half-maximal effect was observed at approximately 300 microM Ca2+. Furthermore, the off rate (koff) of the mAb is 10-fold higher for factor IXa than for factor IX with or without Ca2+. Moreover, like the kon for mAb binding, the incorporation of dansyl-Glu-Gly-Arg chloromethyl ketone (dEGR-CK) into factor IXa was approximately 3 times faster in the presence of Ca2+ than in its absence. Since steric factors govern the kon and the strength of noncovalent interactions governs the koff, the data indicate that the region of factor IX at residues 180-310 undergoes two separate conformational changes before expression of its biologic activity: one upon Ca2+ binding and the other upon zymogen activation. Furthermore, the dEGF-CK incorporation data suggest that both conformational changes also affect the active site residues. Analyses of the known three-dimensional structures of serine proteases indicate that in human factor IX a high-affinity Ca(2+)-binding site may be formed by the carboxyl groups of glutamates 235 and 245 and by the main chain carbonyl oxygens of residues 237 and 240. In support of this conclusion, a synthetic peptide including residues 231-265 was shown to bind Ca2+ with a Kd of approximately 500 microM. This peptide also bound to the mAb, although with approximately 500-fold reduced affinity. Moreover, like factor IX, the peptide bound to the mAb more strongly (approximately 3-fold) in the presence of Ca2+ than in its absence. Thus, it appears that a part of the epitope for the mAb described above is contained in the proposed Ca(2+)-binding site in the protease domain of human factor IX. This proposed site is analogous to the Ca(2+)-binding site in trypsin and elastase, and it may be involved in binding factor IXa to factor VIIIa.

Congenital colonic atresia: should primary anastomosis always be the goal?

We report 4 cases of the rare condition, congenital colonic atresia, presenting over 9 years. Two patients had dilated loops of bowel noted on routine ante-natal ultrasound. Three had primary anastomosis for lesions in transverse or distal descending colon and one had a staged procedure with colostomy formation. All had type III atresia. One patient had an early leak following primary colo-colic anastomosis for atresia extending from the hepatic flexure to the sigmoid colon. If it is desired to preserve the proximal colon in a right sided lesion with significant loss of colonic length then primary anastomosis may not be safe and we would advocate a staged procedure. Otherwise we would support current moves towards primary anastomosis in this condition. We also urge early investigation in all patients who exhibit intestinal dilatation on antenatal ultrasound.