Meta-analysis of prognostic factors for overall survival in patients with resected hilar cholangiocarcinoma.

BACKGROUND: Hilar cholangiocarcinoma is staged using the AJCC staging system. Numerous other prognostically important histopathological and demographic characteristics have been reported. The objective of this meta-analysis was to assess statistically the effect of postresectional tumour characteristics on overall survival of patients undergoing attempted radical curative resection for hilar cholangiocarcinoma. METHODS: Relevant studies were identified by searching the Ovid MEDLINE and PubMed databases. The search was limited to studies published between 2009 and 2017. Papers referring to intrahepatic or distal cholangiocarcinoma were excluded from review. Data extraction used standard Parmar modifications to determine pooled univariable hazard ratios (HRs). RESULTS: Twenty-four articles, containing 4599 patients, were assessed quantitatively. In pooled analyses, age (HR 1·16, 95 per cent c.i. 1·04 to 1·28), T category (HR 1·49, 1·30 to 1·70), lymph node involvement (HR 1·78, 1·65 to 1·93), microvascular invasion (HR 1·49, 1·34 to 1·68), perineural invasion (HR 1·54, 1·40 to 1·68) and tumour differentiation (HR 1·54, 1·38 to 1·72) were significant prognostic factors, with low heterogeneity. Portal vein resection (HR 1·54, 1·15 to 1·70) and resection margin status (HR 1·77, 1·57 to 1·99) had significant effects, but with high heterogeneity. Sex, tumour size and preoperative carbohydrate antigen 19-9 levels did not have a statistically significant effect on postoperative prognosis. CONCLUSION: Several tumour biological variables not included in the seventh edition of the AJCC classification affect overall survival. These require incorporation into prognostic models to ensure a personalized approach to prognostication and treatment.

Two-Photon Microscopy and Spectroscopy Studies to Determine the Mechanism of Copper Oxide Nanoparticle Uptake by Sweetpotato Roots during Postharvest Treatment.

The interaction of engineered nanoparticles with plant tissues is still not well understood. There is a lack of information about the effects of curing (postharvest treatment) and lignin content on copper uptake by sweetpotato roots exposed to copper-based nanopesticides. In this study, Beauregard-14 (lower lignin) and Covington (higher lignin) varieties were exposed to CuO nanoparticles (nCuO), bulk CuO (bCuO), and CuCl2 at 0, 25, 75, and 125 mg/L. Cured and uncured roots were submerged into copper suspensions/solutions for 30 min. Subsequently, root segments were sliced for imaging with a 2-photon microscope, while other root portions were severed into periderm, cortex, perimedulla, and medulla. They were individually digested and analyzed for Cu content by inductively coupled plasma-optical emission spectroscopy. Microscopy images showed higher fluorescence in periderm and cortex of roots exposed to nCuO, compared with bCuO. At 25 mg/L, only bCuO showed higher Cu concentration in the periderm and cortex of Beauregard-14 (2049 mg/kg and 76 mg/kg before curing; 6769 mg/kg and 354 mg/kg after curing, respectively) and in cortex of Covington (692 mg/kg before curing and 110 mg/kg after curing) compared with controls ( p ≤ 0.05). In medulla, the most internal tissue, only Beauregard-14 exposed to 125 mg bCuO/L showed significantly ( p ≤ 0.05) more Cu before curing (17 mg/kg) and after curing (28 mg/kg), compared with control. This research has shown that the 2-photon microscope can be used to determine CuO particles in nondyed plant tissues. The lack of Cu increase in perimedulla and medulla, even in roots exposed to high CuO concentrations (125 mg/L), suggests that nCuO may represent a good alternative to protect and increase the shelf life of sweetpotato roots, without exposing consumers to excess Cu.

Role of staging laparoscopy in the stratification of patients with perihilar cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is a rare cancer with a poor prognosis. Radical surgical resection is the only option for curative treatment. Optimal determination of resectability is required so that patients can be stratified into operative or chemotherapeutic treatment cohorts in an accurate and time-efficient manner. Staging laparoscopy is utilized to determine the presence of radiologically occult disease that would preclude further surgical treatment. The aim of this study was to analyse the utility of staging laparoscopy in a contemporary cohort of patients with perihilar cholangiocarcinoma. METHODS: Patients diagnosed with potentially resectable perihilar cholangiocarcinoma between January 2010 and April 2015 were analysed retrospectively from a prospective database linked to UK Hospital Episode Statistics data. Patients with distal cholangiocarcinoma and gallbladder cancer were excluded from analysis. RESULTS: A total of 431 patients with perihilar cholangiocarcinoma were referred for assessment of potential resection at a supraregional referral centre. Some 116 patients with potentially resectable disease subsequently underwent surgical assessment. The cohort demonstrated an all-cause yield of staging laparoscopy for unresectable disease of 27·2 per cent (31 of 114). The sensitivity for detection of peritoneal disease was 71 per cent (15 of 21; P < 0·001). The accuracy for all-cause non-resection for staging laparoscopy was 66 per cent (31 of 47) with a positive predictive value of progress to resection of 81 per cent (69 of 85). Neither the Bismuth-Corlette nor the Memorial Sloan Kettering Cancer Center preoperative scoring system was contingent with cause of unresectability at staging laparoscopy (P = 0·462 and P = 0·280 respectively). CONCLUSION: In the present cohort, staging laparoscopy proved useful in determining the presence of radiologically occult metastatic disease in perihilar cholangiocarcinoma.

Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy.

BACKGROUND: Human equilibrative nucleoside transporters (hENTs) are transmembranous proteins that facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, into the cell. The abundance of hENT1 transporters in resected pancreatic ductal adenocarcinoma (PDAC) might make hENT1 a potential biomarker of response to adjuvant chemotherapy. The aim of this study was to see whether hENT1 expression, as determined by immunohistochemistry, was a suitable predictive marker for subsequent treatment with gemcitabine-based adjuvant chemotherapy. METHODS: A systematic review was performed, searching databases from January 1997 to January 2016. Articles pertaining to hENT1 immunohistochemical analysis in resected PDAC specimens from patients who subsequently underwent adjuvant gemcitabine-based chemotherapy were identified. Eligible studies were required to contain survival data, reporting specifically overall survival (OS) and disease-free survival (DFS) with associated hazard ratios (HRs) stratified by hENT1 status. RESULTS: Of 42 articles reviewed, eight were suitable for review, with seven selected for quantitative meta-analysis. The total number of patients included in the meta-analysis was 770 (405 hENT1-negative, 365 hENT1-positive). Immunohistochemically detected hENT1 expression was significantly associated with both prolonged DFS (HR 0·58, 95 per cent c.i. 0·42 to 0·79) and OS (HR 0·52, 0·38 to 0·72) in patients receiving adjuvant gemcitabine but not those having fluoropyrimidine-based adjuvant therapy. CONCLUSION: Expression of hENT1 is a suitable prognostic biomarker in patients undergoing adjuvant gemcitabine-based chemotherapy.

Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99mTc-MDP bone scintigraphy, using an adaptive trial design.

BACKGROUND: The detection of occult bone metastases is a key factor in determining the management of patients with renal cell carcinoma (RCC), especially when curative surgery is considered. This prospective study assessed the sensitivity of (18)F-labelled sodium fluoride in conjunction with positron emission tomography/computed tomography ((18)F-NaF PET/CT) for detecting RCC bone metastases, compared with conventional imaging by bone scintigraphy or CT. PATIENTS AND METHODS: An adaptive two-stage trial design was utilized, which was stopped after the first stage due to statistical efficacy. Ten patients with stage IV RCC and bone metastases were imaged with (18)F-NaF PET/CT and (99m)Tc-labelled methylene diphosphonate ((99m)Tc-MDP) bone scintigraphy including pelvic single photon emission computed tomography (SPECT). Images were reported independently by experienced radiologists and nuclear medicine physicians using a 5-point scoring system. RESULTS: Seventy-seven lesions were diagnosed as malignant: 100% were identified by (18)F-NaF PET/CT, 46% by CT and 29% by bone scintigraphy/SPECT. Standard-of-care imaging with CT and bone scintigraphy identified 65% of the metastases reported by (18)F-NaF PET/CT. On an individual patient basis, (18)F-NaF PET/CT detected more RCC metastases than (99m)Tc-MDP bone scintigraphy/SPECT or CT alone (P = 0.007). The metabolic volumes, mean and maximum standardized uptake values (SUV mean and SUV max) of the malignant lesions were significantly greater than those of the benign lesions (P < 0.001). CONCLUSIONS: (18)F-NaF PET/CT is significantly more sensitive at detecting RCC skeletal metastases than conventional bone scintigraphy or CT. The detection of occult bone metastases could greatly alter patient management, particularly in the context when standard-of-care imaging is negative for skeletal metastases.

Mapping a Type 1 FHB resistance on chromosome 4AS of Triticum macha and deployment in combination with two Type 2 resistances.

Markers closely flanking a Type 1 FHB resistance have been produced and the potential of combining this with Type 2 resistances to improve control of FHB has been demonstrated. Two categories of resistance to Fusarium head blight (FHB) in wheat are generally recognised: resistance to initial infection (Type 1) and resistance to spread within the head (Type 2). While numerous sources of Type 2 resistance have been reported, relatively fewer Type 1 resistances have been characterised. Previous study identified a Type 1 FHB resistance (QFhs.jic-4AS) on chromosome 4A in Triticum macha. Little is known about the effect of combining Type 1 and Type 2 resistances on overall FHB symptoms or accumulation of the mycotoxin deoxynivalenol (DON). QFhs.jic-4AS was combined independently with two Type 2 FHB resistances (Fhb1 and one associated with the 1BL/1RS translocation). While combining Type 1 and Type 2 resistances generally reduced visual symptom development, the effect on DON accumulation was marginal. A lack of polymorphic markers and a limited number of recombinants had originally prevented accurate mapping of the QFhs.jic-4AS resistance. Using an array of recently produced markers in combination with new populations, the position of QFhs.jic-4AS has been determined to allow this resistance to be followed in breeding programmes.

A quasi-nonlinear analysis of the anisotropic behaviour of human gallbladder wall.

Estimation of biomechanical parameters of soft tissues from noninvasive measurements has clinical significance in patient-specific modeling and disease diagnosis. In this work, we present a quasi-nonlinear method that is used to estimate the elastic moduli of the human gallbladder wall. A forward approach based on a transversely isotropic membrane material model is used, and an inverse iteration is carried out to determine the elastic moduli in the circumferential and longitudinal directions between two successive ultrasound images of gallbladder. The results demonstrate that the human gallbladder behaves in an anisotropic manner, and constitutive models need to incorporate this. The estimated moduli are also nonlinear and patient dependent. Importantly, the peak stress predicted here differs from the earlier estimate from linear membrane theory. As the peak stress inside the gallbladder wall has been found to strongly correlate with acalculous gallbladder pain, reliable mechanical modeling for gallbladder tissue is crucial if this information is to be used in clinical diagnosis.

Recommendations for rescue of a submerged unresponsive compressed-gas diver.

The Diving Committee of the Undersea and Hyperbaric Medical Society has reviewed available evidence in relation to the medical aspects of rescuing a submerged unresponsive compressed-gas diver. The rescue process has been subdivided into three phases, and relevant questions have been addressed as follows. Phase 1, preparation for ascent: If the regulator is out of the mouth, should it be replaced? If the diver is in the tonic or clonic phase of a seizure, should the ascent be delayed until the clonic phase has subsided? Are there any special considerations for rescuing rebreather divers? Phase 2, retrieval to the surface: What is a "safe" ascent rate? If the rescuer has a decompression obligation, should they take the victim to the surface? If the regulator is in the mouth and the victim is breathing, does this change the ascent procedures? If the regulator is in the mouth, the victim is breathing, and the victim has a decompression obligation, does this change the ascent procedures? Is it necessary to hold the victim's head in a particular position? Is it necessary to press on the victim's chest to ensure exhalation? Are there any special considerations for rescuing rebreather divers? Phase 3, procedure at the surface: Is it possible to make an assessment of breathing in the water? Can effective rescue breaths be delivered in the water? What is the likelihood of persistent circulation after respiratory arrest? Does the recent advocacy for "compression-only resuscitation" suggest that rescue breaths should not be administered to a non-breathing diver? What rules should guide the relative priority of in-water rescue breaths over accessing surface support where definitive CPR can be started? A "best practice" decision tree for submerged diver rescue has been proposed.

Cross-bridge apparent rate constants of human gallbladder smooth muscle.

This paper studies human gallbladder (GB) smooth muscle contractions. A two-state cross-bridge model was used to estimate the apparent attachment and detachment rate constants, as well as increased Ca2+ concentration from the peak active stress during the isometric contraction. The active stress was computed from a mechanical model based entirely on non-invasive routine ultrasound scans. In the two-state cross-bridge model, the two apparent rate constants, representing the total attached/detached cross-bridges, respectively, were estimated using active stress prediction for 51 subjects undergoing cholecystokinin-provocation test, together with estimates from the four-state cross-bridge model for a swine carotid, bovine tracheal and guinea pig GB smooth muscles. The study suggests that the apparent rate constants should be patient-specific, i.e. patients with a lower stress level are characterized by smaller apparent rate constants. In other words, the diseased GB may need to develop fast cycling cross-bridges to compensate in the emptying process. This is a first step towards more quantitative and non-invasive measures of GB pain, and may provide useful insight in understanding GB motility and developing effective drug treatments.

Estimation of lean body mass in children.

BACKGROUND: In adults, dosages of some anaesthetic agents are based on lean body mass (LBM) rather than body weight. Our aim was to derive an equation for estimating LBM in children. METHODS: Patients comprised three groups: prospective kidney transplant donors from two separate centres (centres 1 and 3) and children referred to a further centre (centre 2) for the routine clinical measurement of glomerular filtration rate (GFR). GFR and extracellular fluid volume (ECV) were measured using Cr-51-EDTA. LBM was directly estimated (eLBM) in adults using an equation based on height and weight. ECV in children was estimated (eECV) from another equation based on height and weight, converted to eLBM using the relationship between eLBM and ECV determined in the adults from centre 1 and then compared with adult data from centre 3. RESULTS: In children, the ratio of eECV to ECV was 1.04 (SD 0.18). In centre 1, eLBM (kg) was 3.81 (SD 0.55) times greater than ECV (litres) in men (n=50) and 3.77 (0.77) times greater in women (n=51). eLBM in children was therefore derived by multiplying eECV by 3.8. In children, eLBM showed a close linear correlation with measured ECV (eLBM=3.50ECV+2.0; R(2)=0.857), similar to adults (eLBM=2.82ECV+14.5; R(2)=0.582). In all groups, eLBM/weight correlated inversely with weight. CONCLUSIONS: In terms of the relationships between eLBM, ECV, and weight, children are similar to adults. Therefore, drug dosage in children should also be based on eLBM rather than weight.

A proposal for the annotation of recurrent colorectal cancer: the 'Sheffield classification'.

AIM: Current classification systems of large bowel cancer only refer to metastatic disease as M0, M1 or Mx. Recurrent colorectal cancer primarily occurs in the liver, lungs, nodes or peritoneum. The management of each of these sites of recurrence has made significant advances and each is a subspecialty in its own right. The aim of this paper was to devise a classification system which accurately describes the site and extent of metastatic spread. METHOD: An amendment of the current system is proposed in which liver, lung and peritoneal metastases are annotated by 'Liv 0,1', 'Pul 0,1' and 'Per 0,1' in describing the primary presentation. These are then subclassified, taking into account the chronology, size, number and geographical distribution of metastatic disease or logoregional recurrence and its K-Ras status. CONCLUSION: This discussion document proposes a classification system which is logical and simple to use. We plan to validate it prospectively.

Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

BACKGROUND: Brain metastases from prostate cancer are rare and usually only occur in the context of widespread systemic disease. This is the first case report of a solitary brain oligometastasis, in a neurologically intact prostate cancer patient with no other systemic disease, detected using [68Ga]Ga-THP-PSMA PET/CT and only the second one using a PSMA-based radiopharmaceutical. CASE PRESENTATION: We report the case of a prostate cancer patient presenting 5 years after robot-assisted laparoscopic prostatectomy with biochemical recurrence, no neurological symptoms, and in the absence of metastatic lesions in the body on conventional imaging. A solitary cerebral metastasis was detected using [68Ga]Ga-THP-PSMA PET/CT, surgically resected, leading to a drop in serum PSA and a good recovery. CONCLUSION: In this case, [68Ga]Ga-THP-PSMA PET/CT resulted in a major change in clinical management and avoided additional morbidity associated with delayed diagnosis and treatment. This report demonstrates the importance of considering the presence of metastatic disease outside the conventional locations of prostate cancer spread, as well as the importance of ensuring comprehensive [68Ga]Ga-PSMA PET/CT coverage from vertex to upper thighs.

Correction to: Neurologically asymptomatic cerebral oligometastatic prostate carcinoma metastasis identified on [Ga]Ga-THP-PSMA PET/CT.

An amendment to this paper has been published and can be accessed via the original article.

Effect of copper oxide nanoparticles on two varieties of sweetpotato plants.

Little information is available on the interaction of CuO nanoparticles (nCuO) with tuberous roots. In this study, Beauregard-14 (B-14, low lignin) and Covington (COV, high lignin) sweetpotato varieties were cultivated until maturity in soil amended with nCuO, bulk copper oxide (bCuO) and CuCl2 at 25-125 mg/kg. The Cu treatments had no significant influence on chlorophyll content. Gas exchange parameters were not affected in B-14. In COV, however, at 125 mg/kg treatments, bCuO reduced the intercellular CO2 (11%), while CuCl2 increased it by 7%, compared with control (p ≤ 0.035). At 25 mg/kg nCuO increased the length of COV roots (20.7 ± 2.0 cm vs. 14.6 ± 0.8 cm, p ≤ 0.05). In periderm of B-14, nCuO, at 125 mg/kg, increased Mg by 232%, while the equivalent concentration of CuCl2 reduced P by 410%, compared with control (p ≤ 0.05). The data suggest the potential application of nCuO as nanofertilizer for sweetpotato storage root production.

Prospective assessment of patient directed outpatient communication from a patient and general practitioner perspective.

BACKGROUND: Following the NHS Cancer Plan of 2000, patients should automatically be offered copies of correspondence between NHS clinicians. All patients in this centre increasingly receive a copy of correspondence between the hospital clinicians and general practitioners (GPs). However, we challenged this further by providing patients with a letter written directly to them and sending a copy of this correspondence to the GP. METHODS: 125 patients were requested to complete a 22 item questionnaire to assess the satisfaction of the clinic letter and appointment between May and June 2007. We sent 234 GPs, who refer patients to the Royal Devon & Exeter Hospital, two samples of the new style clinic letters and a 9 item structured questionnaire to assess their satisfaction with these clinic letters. RESULTS: The study had a 90% response rate from patients and 61% from GPs, respectively. Patients felt the clinic letters accurately reflected their clinic appointment, with 94% of patients either satisfied or highly satisfied with the clinic letters. Overall 75% of patients preferred to receive patient directed letters to receiving a copy of the GP letter. However, only 79% of GPs felt patients should routinely receive a clinic letter. CONCLUSIONS: The majority of patients were satisfied with this new style of clinic letters and expect to receive them in the future. The high satisfaction rates could be attributed to the simple and clear language used in the letters. However, the views of patients have not been reflected by GPs, with 20% of GPs preferring to receive a personally directed letter.

Exploring the Effectiveness of an Integrated Mixed Martial Arts and Psychotherapy Intervention for Young Men's Mental Health.

This research sought to establish the impact of a 10-week program combining mixed martial arts (MMA) and one-to-one psychotherapy on young males' mental health and determine factors that predict help-seeking behavior in at-risk males. Preparticipation and post-participation interviews were employed as the method of data collection. Seven males (20-35 years; M = 24.57) completed preparticipation interviews and five completed follow-up interviews. Thematic analysis of preparticipation revealed that help-seeking behavior in at-risk males is impeded by the presence of male gender stereotypes, the absence of positive role models, as well as difficulty navigating challenging social landscapes. Post-participation interviews revealed that the sport provided structure and fitness for at-risk males, while the counseling was pivotal for personal growth. Improved relationships, work life, and self-esteem were also observed. The sporting element of the program helped to reduce stigma associated with engaging in psychotherapy, and positive male relationships were noted as particularly impactful. Findings support previous research indicating that combining sports and psychotherapy positively impacts young males' mental health. Sport provides an acceptable doorway to psychotherapy, providing space to explore personal issues.

Increased multimodality treatment options has improved survival for Hepatocellular carcinoma but poor survival for biliary tract cancers remains unchanged.

BACKGROUND: Primary hepatobiliary cancer incidence in the UK is rising and survival rates are low. Surgery is the main curative option for these cancers, but multimodality therapies are expanding. The aim of our original study was to determine trends in survival, over an 8-year period, of patients treated for primary hepatobiliary cancers at our tertiary referral Centre. METHOD: Patients treated for the most common types of primary hepatobiliary cancers, namely Hepatocellular carcinoma (HCC), Cholangiocarcinoma and Gallbladder cancer between January 2009 and December 2016 were retrospectively analysed from a prospective database linked to UK Hospital Episode Statistics data. RESULTS: A total of 1536 patients with primary hepatobiliary cancers were assessed and treatment plans formulated at our supra-regional specialist Hepatobiliary MDT. The primary hepatobiliary cancers treated were HCC (n = 836), Cholangiocarcinoma (n = 516), and Gallbladder cancer (n = 184). Survival for all the 3 cancers was significantly better with curative treatment. Overall median survival times were 350, 180, and 150 days respectively for HCC, Cholangiocarcinoma and Gallbladder cancer. Excluding best supportive care patients, the respective survival figures were 900, 600, and 400 days. Survival for HCC patients improved over time and was significantly increased in the final 3 years of the study (p ≤ 0.011 for all). Cholangiocarcinoma and Gallbladder cancer survivals were poor and did not change significantly over time. CONCLUSION: HCC outcome has improved in association with expanded multimodal therapies. Survivals for cholangiocarcinoma and gallbladder cancer remain poor in parallel with limited expansion of multimodal therapies highlighting an unmet therapeutic need for biliary tract cancers.

Reliability of the MDRD method for estimating glomerular filtration rate in relation to gender, body mass index and extracellular fluid volume.

BACKGROUND: The accuracy of estimating glomerular filtration rate from plasma creatinine (eGFR) has been questioned but it is unclear how much covert error in several reference methods that have been used has contributed to this perceived inaccuracy. The aim of the study was to evaluate eGFR in comparison with a second 'gold standard' to test the performance of the primary gold standard and to examine the influence of patient demographics (age, body mass index (BMI), extracellular fluid volume (ECV) and gender). DESIGN: Non-fasting multisample GFR and ECV were measured in 80 subjects simultaneously and independently with Cr-51-EDTA (GFR(EDTA)) and iohexol (GFR(iohexol)). Percentage bias and imprecision in the prediction of, and disagreement with, GFR(EDTA) were compared between eGFR and GFR(iohexol). Another simplified method for measuring GFR, the slope-only method ((SO)GFR), was also evaluated against multisample GFR (measured with the opposing indicator). Accuracies were assessed in all subjects and across age, BMI and ECV boundaries of 65 y, 29 kg m(-2) and 14 L. RESULTS: eGFR was less precise than GFR(iohexol) (imprecisions of 22.3% and 12.9%; P < 0.01). The precision of (SO)GFR was intermediate between eGFR and GFR(iohexol). Both GFR(iohexol) and eGFR were less precise in the elderly, the obese and men, but minimally influenced by ECV. (SO)GFR was minimally influenced by subject demographics. CONCLUSION: Although eGFR does not predict GFR (based on a primary gold standard) as accurately as a second gold standard, a significant component of its poor performance is the result of inaccuracy in the primary gold standard. (SO)GFR measured with Cr-51-EDTA is superior to eGFR.

CT finding of VGE in the portal veins and IVC in a diver with abdominal pain: a case report.

The finding of abdominal venous gas emboli (VGE) on computerized tomography (CT) is reported for the first time in a recreational diver. The patient presented 2-3 hours after surfacing from two deep air dives and subsequently complained of visual blurring and abdominal pain. Gas bubbles in the inferior vena cava (IVC) and portal veins were found incidentally by computerized tomography (CT) during his work-up for abdominal pain. The patient was treated for decompression sickness (DCS) with a US Navy Treatment Table 6 and achieved complete resolution of symptoms. The routine use of CT for venous bubble detection in symptomatic divers is not endorsed, but may provide objective evidence of VGE when DCS is in the differential diagnosis and corroborative evidence would alter management.

The clinical pharmacokinetics of a new pharmacokinetically enhanced formulation of amoxicillin/clavulanate.

BACKGROUND: A new oral pharmacokinetically enhanced formulation of the broad-spectrum antibiotic amoxicillin/clavulanate has been developed to provide more effective therapy against resistant pathogens than is provided by currently available formulations by maintaining therapeutically useful plasma amoxicillin concentrations for a longer period after dosing. OBJECTIVE: This study explored the pharmacokinetics of the new oral formulation of amoxicillin/clavulanate in healthy male and female subjects. METHODS: A single oral dose of pharmacokinetically enhanced amoxicillin/clavulanate (2000/125 mg; 16:1 ratio) was administered to subjects at the start of a meal. After dosing, blood samples were collected at frequent intervals up to 12 hours, and plasma was assayed for amoxicillin and clavulanate concentrations using validated procedures. The new formulation consisted of 1 layer of immediate-release amoxicillin and clavulanate and another of sustained-release amoxicillin in a proportion such that for an amoxicillin minimum inhibitory concentration (MIC) of 4 microg/mL, the time above the MIC (T >MIC) would be approximately > or = 40% over a 12-hour dosing interval. RESULTS: The study enrolled 24 and 31 healthy male and female subjects, respectively. Their mean age was 35 years (range, 18-58 years) and mean body weight was 69 kg (range, 51-86 kg). After the expected sharp peak in plasma amoxicillin concentration, there appeared to be a slower decline with the pharmacokinetically enhanced formulation than is usually seen with conventional formulations, and there was evidence of a second amoxicillin absorption phase. The mean T >MIC for an amoxicillin MIC of 4 microg/mL was 49.4% of a 12-hour dosing interval, a value that cannot be achieved with existing approved doses and formulations of amoxicillin/clavulanate. By 12 hours, plasma amoxicillin concentrations were very low (approximately 0.05 microg/mL), suggesting no expectation of notable dose-to-dose accumulation on repeat dosing with a BID regimen. The terminal half-lives of amoxicillin (1.27 hours) and clavulanate (1.03 hours) with the new formulation were similar to those of existing formulations of amoxicillin/clavulanate. No deaths or serious adverse events were reported. CONCLUSIONS: The enhanced pharmacokinetic profile of amoxicillin/clavulanate seen in this study suggests that this formulation is likely to be highly effective for the oral treatment of infections caused by bacteria--including beta-lactamase-producing organisms--and strains with amoxicillin MICs < or = 4 microg/mL.