Development and internal validation of clinical prediction models for outcomes of complicated intra-abdominal infection.

BACKGROUND: Complicated intra-abdominal infections (cIAIs) are associated with significant morbidity and mortality. The aim of this study was to describe the clinical characteristics of patients with cIAI in a multicentre study and to develop clinical prediction models (CPMs) to help identify patients at risk of mortality or relapse. METHODS: A multicentre observational study was conducted from August 2016 to February 2017 in the UK. Adult patients diagnosed with cIAI were included. Multivariable logistic regression was performed to develop CPMs for mortality and cIAI relapse. The c-statistic was used to test model discrimination. Model calibration was tested using calibration slopes and calibration in the large (CITL). The CPMs were then presented as point scoring systems and validated further. RESULTS: Overall, 417 patients from 31 surgical centres were included in the analysis. At 90 days after diagnosis, 17.3 per cent had a cIAI relapse and the mortality rate was 11.3 per cent. Predictors in the mortality model were age, cIAI aetiology, presence of a perforated viscus and source control procedure. Predictors of cIAI relapse included the presence of collections, outcome of initial management, and duration of antibiotic treatment. The c-statistic adjusted for model optimism was 0.79 (95 per cent c.i. 0.75 to 0.87) and 0.74 (0.73 to 0.85) for mortality and cIAI relapse CPMs. Adjusted calibration slopes were 0.88 (95 per cent c.i. 0.76 to 0.90) for the mortality model and 0.91 (0.88 to 0.94) for the relapse model; CITL was -0.19 (95 per cent c.i. -0.39 to -0.12) and - 0.01 (- 0.17 to -0.03) respectively. CONCLUSION: Relapse of infection and death after complicated intra-abdominal infections are common. Clinical prediction models were developed to identify patients at increased risk of relapse or death after treatment, these now require external validation.

Implementation of early management of iron deficiency in pregnancy during the SARS-CoV-2 pandemic.

Iron deficiency is the commonest cause for anaemia worldwide making it a formidable issue particularly during pregnancy because of increased iron demands. This study looked at establishing a lower limit of normal for haemoglobin concentration (Hb) in our population and to proactively address potentially symptomatic iron deficiency during the current SARS-CoV-2 pandemic. The lower limit of normal for Hb in our 1715 first trimester pregnancy cohort was 116 g/L. This is in contrast with guidance suggesting Hb levels down to 110 g/L are normal. In addition there was evidence of limited testing performed to look for iron deficiency with only 18 % having a serum ferritin checked. Most anaemia was normocytic suggesting that microcytosis is only a late marker of iron deficiency lacking sensitivity. A strategy to avoid hospital contact during the COVID-19 pandemic is proposed.

Methicillin-Resistant Staphylococcus aureus Harboring mecC Still Eludes Us in East London, United Kingdom.

Reports of methicillin-resistant Staphylococcus aureus (MRSA) harboring the mecC gene have increased in the UK since first being described. To our diagnostic S. aureus multiplex PCR, a mecC primer set was designed and implemented, and then the prevalence in our patient population was investigated. Fewer than 1% of the clinical isolates possessed the mecC gene, confirming that mecA remains the dominant genetic determinant of MRSA in East London.

The selective outpatient treatment of adults with imported falciparum malaria: a prospective cohort study.

BACKGROUND: Current UK malaria treatment guidelines recommend admission for all patients diagnosed with falciparum malaria. However, evidence suggests that certain patients are at lower risk of severe malaria and death and may be managed as outpatients. AIM: To prospectively assess the risk of post-treatment severe falciparum malaria in selected cases managed as outpatients. The readmission rate and treatment tolerability were assessed as secondary outcomes. DESIGN: Prospective cohort study. METHODS: Adults (>15 years old) diagnosed with falciparum malaria between May 2008 and July 2012 were selected for outpatient treatment using locally defined clinical and laboratory indicators based on known risk factors for severity and death. Treatment outcomes were assessed in clinic or by telephone 4-6 weeks after treatment. RESULTS: 269 adults were diagnosed with falciparum malaria on blood film between May 2008 and July 2012. Of 255 eligible participants, 106 patients were offered ambulatory treatment, of which 95 completed the study. The severe malaria rate was 0% (95% confidence interval (CI) 0-3.8%) and the readmission rate was 5.3% (95% CI 1.7-11.9) in the outpatient group. In addition, 10.6% (95% CI 5.2-18.7%) of outpatients reported drug-related side effects. CONCLUSIONS: The outpatient treatment of selected cases of falciparum malaria is effective in our high volume UK setting. We recommend adopting a similar approach to managing this infection in other non-endemic settings where immediate access to specialist advice is available.

Role of individualization of hepatitis C virus (HCV) therapy duration in HIV/HCV-coinfected individuals.

OBJECTIVE: The aim of this study was to assess the efficacy, safety and tolerability of pegylated interferon and ribavirin in HIV/hepatitis C virus (HCV)-coinfected patients, prescribed for the same duration and at the same dosage as that used in HCV monoinfection studies. DESIGN: It was an open-label, single-centre, prospective study. METHODS: Forty-five patients coinfected with HIV and HCV with CD4 counts >200 cells/microL were treated with pegylated interferon-alpha2b 1.5 microg/kg/week and ribavirin 1000-1200 mg/day for 24-48 weeks depending on HCV genotype. Safety and tolerability were assessed weekly for the first month and monthly thereafter. Virological response was assessed at weeks 4, 12 and 24 and at the end of treatment and 12 and 24 weeks post completion of treatment. The primary endpoint was defined as undetectable HCV RNA at 24 weeks post completion of treatment [sustained virological response (SVR)]. RESULTS: The majority of patients were male and had been injecting drug users. Sixty per cent were on antiretroviral therapy. In an intention-to-treat analysis, 53% had an SVR (genotype 1, 19% and genotype 2/3, 75%). All patients who had undetectable HCV RNA at week 4 of HCV treatment [very early virological response (VEVR)] had a SVR. On multivariate analysis only HCV genotype predicted SVR. Adverse events occurred frequently. CONCLUSIONS: These results indicate that 24 weeks of HCV treatment may be adequate for HIV-infected individuals coinfected with HCV genotype 2 or 3. VEVR can predict SVR in this group and may be used to guide the subgroup of genotype 2/3 individuals who will respond to 24 weeks of treatment.

Experimental determination of the lifetime for the 2p3d(1P0) helium doubly excited state.

Two recent theoretical studies [C. Liu, Phys. Rev. A 64, 010501 (2001)]; M. Zitnik, ibid. 65, 032520 (2002)]] predict that the fluorescence lifetimes of helium doubly excited states converging to He+ N=2 should be longer than that of the He+ 2p ion state. This effect is caused by the electric field of the outer electron which, through Stark mixing, gives the inner fluorescing electron some series specific, stabilizing 2s character. We have obtained the first experimental evidence that confirms this effect by measuring the lifetime of the 2p3d(1P0) doubly excited state. This was determined to be 190+/-30 ps compared to 100 ps for the He+ 2p ion state. The measurements were performed using short pulses of synchrotron radiation to form doubly excited states and recording the arrival time of photons from fluorescence.

Observation of triplet doubly excited states in single photon excitation from ground state helium.

We have observed, for the first time, LS-forbidden triplet doubly excited states, in single photon excitation of ground state helium, below the second ionization threshold. These states are identified as (3)D(o) and (3)P(o) and their excitation is due to spin-orbit interaction that mixes them with the optically allowed (1)P(o) states. This observation is possible due to the very high efficiency in detecting metastable atoms created after the fluorescence decay of the doubly excited states, and the new capabilities of third generation synchrotron vacuum ultraviolet sources with high resolution beam lines.

Stimulatory effect of insulin on creatine accumulation in human skeletal muscle.

This study investigated the effect of insulin on plasma and muscle creatine accumulation and limb blood flow in humans after creatine administration. Seven men underwent a 300-min euglycemic insulin clamp combined with creatine administration on four separate occasions. Insulin was infused at rates of 5, 30, 55, or 105 mU. m-2. min-1, and on each occasion 12.4 g creatine was administered. During infusion of insulin at rates of 55 and 105 mU. m-2. min-1, muscle total creatine concentration increased by 4.5 +/- 1.4 (P < 0. 05) and 8.3 +/- 1.0 mmol/kg dry mass (P < 0.05), and plasma creatine concentrations were lower at specific time points compared with the 5 mU. m-2. min-1 infusion rate. The magnitude of increase in calf blood flow (plethysmography) was the same irrespective of the rate of insulin infusion, and forearm blood flow increased to the same extent as the three highest infusion rates. These findings demonstrate that insulin can enhance muscle creatine accumulation in humans but only when present at physiologically high or supraphysiological concentrations. This response is likely to be the result of an insulin-mediated increase in muscle creatine transport rather than creatine delivery.

The effect of single doses of pramlintide on gastric emptying of two meals in men with IDDM.

In a previous study we have shown that an intravenous infusion of pramlintide (an analogue of human amylin) delayed gastric emptying, but the dose of pramlintide was supraphysiological in relation to the amylin response to food in non-diabetic subjects. The purpose of this study was to examine the dose response relationship of subcutaneous injections of pramlintide on gastric emptying and to determine whether administration of the drug before one meal has an impact on the subsequent meal. Eleven men with insulin-dependent diabetes mellitus were studied in a double-blind, randomised, four-way crossover design. None had autonomic neuropathy. Euglycaemia was maintained overnight before the study day. At -30 min the patients self-injected their usual morning insulin and at -15 min they injected the study drug (either placebo or 30, 60 or 90 microg pramlintide) subcutaneously. At 0 min they ate a standard meal consisting of a pancake, labelled with 99mTc, and a milkshake containing 3-ortho-methylglucose (3-OMG). Gastric emptying images were obtained for the next 8 h. At 240 min the subjects ate a similar meal, but on this occasion the pancake was labelled with (111)In. All three doses of pramlintide delayed emptying of the solid component of the first meal (p < 0.004) with no significant difference between the drug doses. There were no differences between placebo and pramlintide after the second meal. All three doses of pramlintide resulted in a prolongation in the time to peak plasma 3-OMG level (p < 0.0001) after the first meal but there was no difference after the second meal.

Long-term follow-up of patients with hyperprolactinaemia.

AIM: To determine the frequency with which hyperprolactinaemic illness tends to resolve with time. STUDY DESIGN: A retrospective case-notes review from a specialist endocrine unit in a provincial teaching hospital and tertiary referral centre. PATIENTS: Seventy women with hyperprolactinaemia referred to the unit in the 15 year period between May 1979 and May 1994. All those with a non-pituitary cause or with macroadenoma had been excluded, as were those who did not have high-resolution imaging, or who were on treatment at the time of referral. INTERVENTION: Intermittent course of treatment with dopamine receptor agonists according to individual need. ENDPOINTS: Latest serum PRL concentration in those who had discontinued treatment, and whether serum PRL tended to be lower in any particular group. RESULTS: There was a significant fall in median PRL concentration from 2000 (714-8000) to 1000 mU/l (220-5600) in the 31 women who had discontinued therapy (P < 0.0005), and serum PRL was normal (< 700 mU/l) in 11 of them. Serum PRL also fell to normal in three of ten women who had no treatment at all. Final PRL concentration was normal in 35% of women who had had at least one pregnancy during the period of follow-up compared to 14% who had not (P < 0.05). CONCLUSIONS: These data confirm the findings of others that hyperprolactinaemia will prove self-limiting in up to one-third of women, and that pregnancy may be one factor which triggers a return to normal function.

Adenosine triphosphatase in nerves and ganglia of rats with streptozotocin-induced diabetes or galactosaemia; effects of aldose reductase inhibition.

This study measured the ouabain-sensitive and ouabain-resistant adenosine triphosphatase activity in homogenates of the sciatic nerves and of pooled fourth and fifth lumbar dorsal root ganglia from rats fed 20% galactose or made diabetic with streptozotocin for either 4 or 8 weeks. Diabetes caused reductions in both fractions of sciatic nerve adenosine triphosphatase activity. After 8 weeks the ouabain-sensitive fraction was 54% of control (p less than 0.05) and the ouabain-resistant fraction was 57% of control (p less than 0.05). Galactose feeding more than doubled the ouabain-sensitive adenosine triphosphatase activity in the sciatic nerve (225% of control after 4 weeks, 215% of control after 8 weeks of galactose feeding, both p less than 0.01) and produced a progressive increase in the ouabain-resistant fraction (119% of control at 4 weeks (p less than 0.05) and 176% of control at 8 weeks (p less than 0.01)). In a group of rats fed galactose for 5 days, sciatic nerve ouabain-sensitive adenosine triphosphatase activity was 165% of control. Treatment with the aldose-reductase inhibitors tolrestat, ponalrestat or sorbinil prevented accumulation of polyol and depletion of myo-inositol in the sciatic nerves, indicating effective inhibition of aldose reductase. These drugs prevented completely the effect of galactose on the sciatic nerve adenosine triphosphatase activity, but had no significant effect on the reduction in adenosine triphosphatase activity in the sciatic nerves of diabetic rats. In the dorsal root ganglia galactose feeding had no measurable effect on the adenosine triphosphatase activity. Diabetes caused a modest numerical reduction in the ouabain-sensitive activity only.(ABSTRACT TRUNCATED AT 250 WORDS)

Does galactose feeding provide a valid model of consequences of exaggerated polyol-pathway flux in peripheral nerve in experimental diabetes?

This study was designed to examine the effect of exaggerated polyol-pathway flux on sciatic nerve content of polyols, myo-inositol, and water. Rats with streptozocin-induced diabetes of 3- and 12-wk duration and nondiabetic rats fed for 5 days on a diet containing 20% galactose were employed initially. All three conditions showed marked elevation of nerve polyol content, combined with fructose accumulation in the diabetic rats. Galactose-fed rats showed a significant (P less than .01) increase in nerve water content of approximately 30% (when expressed as water/unit dry wt tissue). Diabetic rats showed no change in nerve water. Both diabetic and galactose-fed rats showed a depletion of nerve free myo-inositol, although the extent of depletion was greater in the latter. All these changes were prevented or attenuated by the aldose reductase inhibitor Statil (ICI 128436). When diabetic rats were fed a 20% galactose diet for 5 days, nerves of 3- but not 12-wk diabetic rats showed marked increases in water content. A more mild degree of galactosemia, induced by 5 or 21 days of feeding a diet containing 10% galactose to nondiabetic rats, provoked an increase in nerve water content associated with polyol levels of a similar order to those seen in diabetes. We do not know why polyol-pathway metabolites cause nerve hyperhydration in galactosemia but not in streptozocin-induced diabetes. Such differences urge caution in the use of galactose feeding to model the consequences of exaggerated polyol-pathway flux in nerve to face questions related to neuronal dysfunction in diabetes.

Opposite effects of diabetes and galactosaemia on adenosine triphosphatase activity in rat nervous tissue.

This study measured the ouabain-sensitive adenosine triphosphatase activity in sciatic nerve, lumbar dorsal root ganglia and superior cervical ganglia from control rats, rats with 8 weeks streptozotocin-induced diabetes and rats fed a diet containing 20% galactose for 8 weeks. Whilst the sciatic nerves of the diabetic rats showed a 42% reduction in ouabain-sensitive adenosine triphosphatase activity, the galactose-fed rats showed an increase of 124% (p less than 0.01 and p less than 0.005, respectively, compared to controls). There was also a reduction (by 30% compared to controls; p less than 0.05) in the ouabain-sensitive adenosine triphosphatase activity of the dorsal root ganglia from the diabetic rats, but their superior cervical ganglia did not show a significant fall. The ganglia of the galactosaemic rats showed no change in ouabain-sensitive adenosine triphosphatase activity compared to controls. These changes coexisted with increases in appropriate polyol pathway metabolites in all tissues of both diabetic and galactosaemic rats. There were also depletions of myo-inositol in the sciatic nerves and dorsal root ganglia of diabetic and galactosaemic rats, but their superior cervical ganglia contained levels of myo-inositol which were similar to those of controls. The nerves of the galactosaemic rats showed increased water content; the nerves of the diabetic rats did not. The data argue against a simple relationship between myo-inositol depletion and impaired Na/K adenosine triphosphatase activity in association with exaggerated polyol pathway flux in peripheral nervous tissue.