Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid

Patients with primary biliary cirrhosis (PBC) may have additional features of autoimmune hepatitis (AIH). Corticosteroids usually contraindicated in PBC have been advocated for these patients. Patients with antimitochondrial antibody (AMA)-positive PBC from two previous randomized, controlled trials were assessed for features of AIH. Their biochemical, immunologic, and histologic responses to ursodeoxycholic acid (UDCA) versus placebo were compared with those without AIH features. The survival of patients testing positive or negative for antinuclear antibodies (ANA) was also examined. Features of AIH were defined by the presence of 2 or more of the following: 1) alanine transaminase (ALT) > 5 x the upper limit of normal (ULN); 2) immunoglobulin G (IgG) > 2 x ULN or positive anti-smooth muscle antibody (ASMA); and 3) moderate to severe lobular inflammation on pretreatment liver biopsy. Testing for AMA, ASMA, and ANA was done by immunofluorescence. The change in serum bilirubin, alkaline phosphatase (ALP), transaminases, IgM, and IgG from baseline to 2 years was compared. Of the 331 patients randomized, 16 (4.8%) had features of AIH (12 UDCA, 4 placebo). The median percent change in serum biochemistry and immunoglobulin values were similar in patients with PBC +/- features of AIH after 2 years of therapy with UDCA. Over 2 years, little change in histologic features of AIH was observed. Survival was similar for patients with PBC with and without ANA. In conclusion, features of AIH in PBC may be transient and response to UDCA therapy similar to patients with PBC without features of AIH.     

Hepatic Osteodystrophy in Primary Biliary Cirrhosis: Effects of Medical Treatment

Objectives : Osteoporosis is a frequent extrahepatic complication of primary biliary cirrhosis. Although histologically similar to the osteoporosis commonly seen in postmenopausal females, the pathogenesis and management of bone disease in patients with primary biliary cirrhosis is poorly understood. The experience with a subgroup of patients with primary biliary cirrhosis treated with vitamin D, calcium, and estrogen supplementation was reviewed to determine the effects of medical treatment on hepatic osteodystrophy. Methods : The records of 203 women with the diagnosis of primary biliary cirrhosis were reviewed retrospectively for lumbar spine bone mineral density, menopausal status, and supplementation with vitamin D, calcium, and estrogen. Results : The 16 postmenopausal patients treated with estrogen replacement had a statistically significant increase in the lumbar spine bone mineral density at 1 yr (+ 0.014 ± 0.049 vs. -0.03 ± 0.046 g/cm² p < 0.038), without a significant change in the serum bilirubin or alkaline phosphatase. In treated patients, vitamin D and calcium supplementation did not lead to significant improvement in lumbar spine bone mineral density. Conclusions : Calcium and vitamin D supplementation, even in the presence of vitamin D deficiency, do not improve lumbar spine bone mineral density in patients with primary biliary cirrhosis. Estrogen replacement in postmenopausal patients, however, does appear to improve lumbar spine bone mineral density without increasing clinical or biochemical cholestasis, a potential complication reported in animal studies. This study should serve as an impetus for a controlled trial of estrogen replacement in postmenopausal patients with primary biliary cirrhosis.     

Management of community-acquired pneumonia in the era of pneumococcal resistance: a report from the Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group

OBJECTIVE: To provide recommendations for the management of community-acquired pneumonia and the surveillance of drug-resistant Streptococcus pneumoniae (DRSP). METHODS: We addressed the following questions: (1) Should pneumococcal resistance to beta-lactam antimicrobial agents influence pneumonia treatment? (2) What are suitable empirical antimicrobial regimens for outpatient treatment of community-acquired pneumonia in the DRSP era? (3) What are suitable empirical antimicrobial regimens for treatment of hospitalized patients with community-acquired pneumonia in the DRSP era? and (4) How should clinical laboratories report antibiotic susceptibility patterns for S pneumoniae, and what drugs should be included in surveillance if community-acquired pneumonia is the syndrome of interest? Experts in the management of pneumonia and the DRSP Therapeutic Working Group, which includes clinicians, academicians, and public health practitioners, met at the Centers for Disease Control and Prevention in March 1998 to discuss the management of pneumonia in the era of DRSP. Published and unpublished data were summarized from the scientific literature and experience of participants. After group presentations and review of background materials, subgroup chairs prepared draft responses, which were discussed as a group. CONCLUSIONS: When implicated in cases of pneumonia, S pneumoniae should be considered susceptible if penicillin minimum inhibitory concentration (MIC) is no greater than 1 microg/mL, of intermediate susceptibility if MIC is 2 microg/ mL, and resistant if MIC is no less than 4 microg/mL. For outpatient treatment of community-acquired pneumonia, suitable empirical oral antimicrobial agents include a macrolide (eg, erythromycin, clarithromycin, azithromycin), doxycycline (or tetracycline) for children aged 8 years or older, or an oral beta-lactam with good activity against pneumococci (eg, cefuroxime axetil, amoxicillin, or a combination of amoxicillin and clavulanate potassium). Suitable empirical antimicrobial regimens for inpatient pneumonia include an intravenous beta-lactam, such as cefuroxime, ceftriaxone sodium, cefotaxime sodium, or a combination of ampicillin sodium and sulbactam sodium plus a macrolide. New fluoroquinolones with improved activity against S pneumoniae can also be used to treat adults with community-acquired pneumonia. To limit the emergence of fluoroquinolone-resistant strains, the new fluoroquinolones should be limited to adults (1) for whom one of the above regimens has already failed, (2) who are allergic to alternative agents, or (3) who have a documented infection with highly drug-resistant pneumococci (eg, penicillin MIC > or =4 microg/mL). Vancomycin hydrochloride is not routinely indicated for the treatment of community-acquired pneumonia or pneumonia caused by DRSP.     

Lowering LDL cholesterol in adults: a prospective, community-based practice initiative

Purpose

The purpose of our study was to see if a clinic-wide initiative, with low-density lipoprotein cholesterol (LDL)-lowering interventions, could be an effective health maintenance strategy to decrease LDL levels to <100 mg/dL in a community-based, internal medicine outpatient setting.

Methods

There were 1375 patients screened with an initial/baseline LDL (LDL₁) measurement. Patients whose LDL₁ levels were >100 mg/dL were put on a lipid-lowering action plan and re-evaluated with a follow-up LDL (LDL₂) in 3-4 months. An additional action plan was given to patients whose LDL₂ values were still too high, and their values retested in 3-4 months for a third LDL (LDL₃). LDL₁ levels versus postintervention LDL measurement (LDL₂ or LDL₃) levels were the primary endpoints, with secondary endpoints of total cholesterol, total triglyceride, and high-density lipoprotein cholesterol (HDL) levels over the 3 measurement periods.

Results

Of 514 patients who were given action plans, 443 returned for their follow-up lipid assessment. LDL levels in this group fell from 140.7 ± 29.2 (mean ± 1 SD) mg/dL (LDL₁) to 110.9 (29.6) mg/dL (LDL₂) (P <.05). Of these 443 patients, 167 individuals had LDL₂ levels that now met National Cholesterol Education Program/Third Adult Treatment Panel III guidelines (<100 mg/dL) and 87 were now considered by their primary care provider as controlled (LDL 100-130 mg/dL). However, 158 individuals had LDL₂ levels that were either not controlled or not meeting National Cholesterol Education Program/Third Adult Treatment Panel guidelines. These 158 patients were provided with a second action plan, and of these, 50 (32%) returned to the clinic for a third lipid panel. Their LDLs, as a group, subsequently fell from an LDL₂ of 139.9 (24.4) mg/dL to 112.5 (28.2) mg/dL (LDL₃) (P <.05). Sixteen of 50 now had LDLs <100 mg/dL, and 26 of 50 were considered controlled. Initial HDL (HDL₁) levels rose from 55.4 (17.2) mg/dL to 57.3 (14.6) mg/dL (HDL₂) (n = 443). Blood levels of triglycerides and cholesterol also decreased in our returning patients over this time period (P <.05).

Conclusions

Community-based physicians can help their patients realize significant reductions in low-density lipoprotein cholesterol levels by implementing and closely monitoring lipid-lowering initiatives for their patients, resulting in potentially large positive impacts on the long-term health and well-being of their patients.     

I Just Want My Research Credit: Frequency of Suboptimal Effort in a Non-Clinical Healthy Undergraduate Sample

Although performance validity testing is becoming fairly routine in clinical settings, research protocols involving neuropsychological tests infrequently include assessments of performance validity. The current study utilized an embedded measure of effort over two administrations of CNS Vital Signs to determine the frequency of poor effort in non-clinical healthy undergraduate students participating in a research study for course credit. Results indicate that more than 1 in 10 college students participating in a cognitive test battery for research showed test scores consistent with inadequate effort, which was associated with poor performance on testing across many domains. This conclusion was supported by poor performance on many other subtests. Healthy college students with suboptimal effort (n = 11) had an overall score in the 15th percentile on average compared to the 48th percentile in the rest of the students (n = 66). Those who failed validity indicators on the baseline administration were more likely to fail validity indicators on the repeat administration. Those who were tested in the morning were also more likely to fail validity indicators. The current study provides evidence for the potential limitations of conducting research using neuropsychological tests with healthy college student volunteers in the absence of performance validity testing. Revised college-level cutoffs are proposed.     

Sexually dimorphic facial features vary according to level of autistic-like traits in the general population

Background

In a recent study, Bejerot et al. observed that several physical features (including faces) of individuals with an autism spectrum disorder (ASD) were more androgynous than those of their typically developed counterparts, suggesting that ASD may be understood as a ‘gender defiant’ disorder. These findings are difficult to reconcile with the hypermasculinisation account, which proposes that ASD may be an exaggerated form of cognitive and biological masculinity. The current study extended these data by first identifying six facial features that best distinguished males and females from the general population and then examining these features in typically developing groups selected for high and low levels of autistic-like traits.

Methods

In study 1, three-dimensional (3D) facial images were collected from 208 young adult males and females recruited from the general population. Twenty-three facial distances were measured from these images and a gender classification and scoring algorithm was employed to identify a set of six facial features that most effectively distinguished male from female faces. In study 2, measurements of these six features were compared for groups of young adults selected for high (n = 46) or low (n = 66) levels of autistic-like traits.

Results

For each sex, four of the six sexually dimorphic facial distances significantly differentiated participants with high levels of autistic-like traits from those with low trait levels. All four features were less masculinised for high-trait males compared to low-trait males. Three of four features were less feminised for high-trait females compared to low-trait females. One feature was, however, not consistent with the general pattern of findings and was more feminised among females who reported more autistic-like traits. Based on the four significantly different facial distances for each sex, discriminant function analysis correctly classified 89.7% of the males and 88.9% of the females into their respective high- and low-trait groups.

Conclusions

The current data provide support for Bejerot et al.’s androgyny account since males and females with high levels of autistic-like traits generally showed less sex-typical facial features than individuals with low levels of autistic-like traits.     

Translation and validation of the Danish Foot Function Index (FFI‐DK)

The objective of this study was to translate the Foot Function Index (FFI) for use in Danish‐speaking patients with foot complaints. The FFI consists of 23 items scored on a numeric rating scale from 0 to 10. The 23 items are grouped into three subscales: pain (nine items), activity limitation (five items), and disability (nine items). The Danish FFI was developed according to the recommended forward/backward translation protocol. The data analysis included reliability [intraclass correlation coefficient (ICC) 2.1] and internal consistency (Cronbach's alpha). Excellent internal consistency was shown for the three subscales: pain (0.99), disability (0.98), and activity limitation (0.98), as for the total score (0.97). The test‐retest reliability was excellent: pain subscale: ICC 0.98 [95% confidence interval (CI): 0.97–0.99]; activity limitation subscale: ICC: 0.95 (95% CI: 0.91–0.98); disability subscale: ICC 0.97 (95% CI: 0.95–0.98); total score: ICC: 0.95 (95% CI: 0.91 to 0.98). The mean difference between test and retest was below 1 point and P > 0.08. Bland–Altman plots showed no significant or clinically relevant differences from test to retest in any of the subscales or in the total score. The Danish version of the FFI was found to be valid and reliable and therefore acceptable for use in the Danish population.     

A randomised controlled trial of bilateral dual transversus abdominis plane blockade for laparoscopic appendicectomy

We investigated the effects of pre‐operative ultrasound‐guided bilateral dual transversus abdominis plane blocks on pain when sitting up and pain at rest after laparoscopic appendicectomy. We allocated 28 participants to injection with 60 ml ropivacaine 0.375% and 28 participants to 60 ml isotonic saline. The median (IQR [range]) cumulative pain scores during the first 12 postoperative hours were less after ropivacaine than saline (maximum 120): on sitting, 34 (19‐46 [0‐59]) vs 50 (30‐59 [0‐97]), respectively, p = 0.009; and at rest, 25 (10‐33 [0‐49]) vs 31 (24‐43 [0‐72]), respectively, p = 0.035. There were no differences in morphine consumption, nausea, vomiting, time in recovery or time to walk.     

Remdesivir: Review of Pharmacology,Pre-clinical Data,and Emerging Clinical Experience for COVID-19

The global pandemic of novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an urgent need for effective antivirals. Remdesivir (formerly GS-5734) is a nucleoside analogue pro-drug currently being evaluated in COVID-19 clinical trials. Its unique structural features allow high concentrations of the active triphosphate metabolite to be delivered intracellularly and it evades proofreading to successfully inhibit viral RNA synthesis. In pre-clinical models, remdesivir has demonstrated potent antiviral activity against diverse human and zoonotic β-coronaviruses, including SARS-CoV-2. In this article, we critically review available data on remdesivir with an emphasis on biochemistry, pharmacology, pharmacokinetics, and in vitro activity against coronaviruses as well as clinical experience and current progress in COVID-19 clinical trials.     

Baricitinib: A Review of Pharmacology,Safety, and Emerging Clinical Experience in COVID-19

A hyperinflammatory response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, reminiscent of cytokine release syndrome, has been implicated in the pathophysiology of acute respiratory distress syndrome and organ damage in patients with coronavirus disease 2019 (COVID-19). Agents that inhibit components of the pro-inflammatory cascade have garnered interest as potential treatment options with hopes that dampening the proinflammatory process may improve clinical outcomes. Baricitinib is a reversible Janus-associated kinase (JAK)-inhibitor that interrupts the signaling of multiple cytokines implicated in COVID-19 immunopathology. It may also have antiviral effects by targeting host factors that viruses rely for cell entry and by suppressing type I interferon driven angiotensin-converting-enzyme-2 upregulation. However, baricitinib’s immunosuppressive effects may be detrimental during acute viral infections by delaying viral clearance and increasing vulnerability to secondary opportunistic infections. The lack of reliable biomarkers to monitor patients’ immune status as illness evolves complicates deployment of immunosuppressive drugs like baricitinib. Furthermore, baricitinib carries the risk of increased thromboembolic events, which is concerning given the proclivity towards a hypercoagulable state in patients with COVID-19. In this article, we review available data on baricitinib with an emphasis on immunosuppressive and antiviral pharmacology, pharmacokinetics, safety, and current progress in COVID-19 clinical trials.