The Relationship Between Canal Diameter and the Dorr Classification.

BACKGROUND: Particularly in broach-only uncemented total hip arthroplasty, a narrow femoral canal presents a technical challenge. Traditionally such femurs have been considered to be Dorr A. To our knowledge, however, no study has reported on the relationship between isthmus width and the Dorr classification. METHODS: We reviewed 500 high-quality, hard copy radiographs. Dorr classification and isthmus canal width were measured using an electronic caliper by 5 independent observers with intraobserver and interobserver error calculated. For this study, we defined a narrow canal as being ≤10 mm at its narrowest point (isthmus). RESULTS: Eight percent (40) were Dorr A, 85% (424) Dorr B, and 7% (36) Dorr C. With respect to isthmus width for Dorr A, 63% (25) were ≤10 mm compared to just 13% (55) of Dorr B. However, overall because there were more Dorr B femurs, 69% of those with an isthmus of ≤10 mm were Dorr B. CONCLUSION: In this population, almost 70% of patients with an isthmus ≤10 mm were Dorr B, with only 30% being Dorr A. When using a broach-only technique, isthmus width should be routinely measured on the preoperative anteroposterior radiographs so as to alert the surgeon to potential problems.

CT pulmonary angiography in lower limb arthroplasty: A retrospective review of 11 249 patients over 11 years.

Aims: The aims of this study were to determine the indications and frequency of ordering a CT pulmonary angiography (CTPA) following primary arthroplasty of the hip and knee, and to determine the number of positive scans in these patients, the location of emboli and the outcome for patients undergoing CTPA. Patients and Methods: We analyzed the use of CTPA, as an inpatient and up to 90 days as an outpatient, in a cohort of patients and reviewed the medical records and imaging for each patient undergoing CTPA. Results: Out of 11 249 patients, scans were requested in 229 (2.04%) and 86 (38%) were positive. No patient undergoing CTPA died within 90 days. The rate of mortality from pulmonary embolism (PE) overall was 0.08%. CTPA was performed twice as often following total knee arthroplasty (TKA) compared with total hip arthroplasty (THA), and when performed was twice as likely to be positive. Hypoxia was the main indication for a scan, being the indication in 149 scans (65%); and in 23% (11 of 47), the PE was peripheral and unilateral. Three patients suffered complications resulting from therapeutic anticoagulation for possible PE, two of whom had a negative CTPA. Conclusion: CTPA is more likely to be performed following TKA compared with THA. Hypoxia was the main presenting feature of PE. A quarter of PEs which were diagnosed were unilateral and peripheral. Further study may indicate which patients who have a PE after lower limb arthroplasty require treatment, and which can avoid the complications associated with anticoagulation. Cite this article: Bone Joint J 2018;100-B:938-44.

Hepatitis B virus: virology, molecular biology, life cycle and intrahepatic spread.

Hepatitis B virus is a member of the Hepadnaviridae family and responsible for causing acute and chronic hepatitis in humans. The current estimates of people chronically infected with the virus are put at 250 million worldwide. Immune-mediated liver damage in these individuals may lead to the development of cirrhosis and hepatocellular carcinoma later in life. This review deals with our current understanding of the virology, molecular biology, life cycle and cell-to-cell spread of this very important pathogen, all of which are considered essential for current and future approaches to antiviral treatment.

Falling age-related incidence of hip fractures in women, but not men, in Northern Ireland: 2001-2011.

Hip fractures place a large burden on healthcare and determining the variation in incidence is important to plan resources. We found, in Northern Ireland, that the age-related incidence for women is declining but the incidence for men and the total number of fractures remains static as the elderly population increases. INTRODUCTION: Hip fractures place a significant burden on healthcare systems throughout the world. Recent studies have shown that the incidence is starting to decline or plateau. We aimed to study the incidence of hip fractures in 2001 and 2011 within Northern Ireland and hope to guide further service provision. METHODS: The years 2001 and 2011 were selected as accurate census population data was available. The Hospital Inpatient System (HIS) database was used to collect the data and the search was carried out by a statistician using ICD codes S72.0 and S72.1. RESULTS: The total incidence of hip fractures in the population aged 50 and over fell from 358 per 100,000 to 274 per 100,000. In females, the incidence fell from 513 to 412 per 100,000. In males, the incidence increased from 172 to 178 per 100,000. The total number of hip fractures remained static (1737 in 2001 and 1739 in 2011) as a result of an increase in the elderly population. Incidence and total number of femoral neck fractures (S72.0) declined while the incidence and total number of pertrochanteric fractures (S72.1) increased. CONCLUSIONS: Our results are in keeping with the declining trend in hip fracture incidence in many Western countries, though we found that this is only true for women. The exact reasons for this remain unclear but are likely to be multifactorial. In the future, the number of fractures may increase further given the increasingly elderly population and further provision particularly for patients with pertrochanteric fractures will be required. Increased awareness, diagnosis and treatment of males with osteoporosis should be prioritised.

Treatment options beyond IFNα and NUCs for chronic HBV infection: expectations for tomorrow.

Chronic hepatitis B virus (HBV) infection may progress to cirrhosis, hepatocellular carcinoma (HCC) and end-stage liver failure with time. Interruption of this process can only be achieved through effective antiviral treatment. This approach has so far involved the use of immunomodulators such as pegylated interferon alpha (Peg-IFNα) for a finite period of up to a year and nucleos-(t)ide analogues (NUCs) for treatment over much longer periods of time. The latter act by suppressing HBV replication at the level of DNA synthesis by inhibiting the viral reverse transcriptase/DNA polymerase and causing premature termination of DNA synthesis. The ideal treatment end point is loss of HBsAg in both HBeAg+ve and HBeAg-ve patients following monotherapy. This, however, is only achievable in a minority of patients. Secondary outcomes are durable HBeAg loss and seroconversion to anti-HBe, which occur in about 18-30% of HBeAg+ve patients depending on the antiviral used, and sustained suppression of HBV-DNA accompanied by biochemical normalization and histological improvement in non-HBeAg+ve seroconverting and HBeAg-ve patients. There is therefore a need for additional direct-acting antivirals (DAAs) targeting different stages of the life cycle of the virus, as well as immunotherapeutic approaches. Such developments may pave the way for their use either alone or more likely in combination in the fight against chronic HBV infection. Such drugs or approaches, which are currently undergoing preclinical or clinical testing, are the subject of this review.

Effect of antiviral treatment on alfa-fetoprotein levels in HBV-related cirrhotic patients: early detection of hepatocellular carcinoma.

Alpha-fetoprotein (AFP) is a marker of the presence of hepatocellular carcinoma (HCC), but is also elevated in advanced chronic hepatitis B. The detection and usage of AFP tests need to be improved. A cohort of 101 patients with advanced chronic hepatitis B and elevated AFP values was treated with entecavir (ETV) or peginterferon-alpha2a. ETV was more effective in reducing AFP levels; mean time to AFP normalization was 11.9 weeks after ETV treatment initiation vs 22.3 weeks in peginterferon treated patients (P = 0.000). An additional cohort of 93 hepatitis B virus (HBV) cirrhotic patients with elevated AFP were treated with ETV prospectively and maintained under intensive surveillance. HCC developed in 16 (17.2%) patients in whom the strongest independent predictor was a continued AFP rise in spite of ongoing treatment. In this context, nodules of sizes 10-14 mm and 15-20 mm were detected in 40% of patients each. In conclusion, HBV cirrhotic patients with rising AFP levels were at very high risk of HCC development. Early detection of minute lesions may be possible by monitoring AFP levels, whilst patients are on treatment in conjunction with enhanced computed tomography examination.

Systematic review: hepatic fibrosis - regression with therapy.

BACKGROUND: Hepatic fibrosis occurs in response to chronic liver injury, regardless of the cause. An impressive amount of knowledge concerning the pathogenesis and treatment of liver fibrosis has emerged over the past few years. The hallmark of this event is the activation of the hepatic stellate cell. The latter event causes accumulation of extracellular matrix and formation of scar, leading to deterioration in hepatic function. AIM: To assess chronic liver injury, many invasive and non-invasive methods have been suggested. METHODS: Although transient elastography, image analysis of fractal geometry and fibrotest with actitest have been used in clinical practice, liver biopsy remains the recommended choice, especially when histological staging of fibrosis or response to treatment is needed. CONCLUSIONS: The recent advances in anti-viral therapy have resulted in many reports on fibrosis and even on cirrhosis regression, especially early and in young people. A number of new agents have been suggested for the treatment of fibrosis, with promising results in animals; however, their efficacy in humans remains to be elucidated. The investigation of heterogeneity and plasticity of hepatic stellate cells is a topic of scientific interest and may result in improvements in patient management.

Tailored regimen of interferon alpha for HBeAg-positive chronic hepatitis B: a prospective controlled study.

The response to interferon-alpha treatment of patients with chronic hepatitis B under the current protocol is not satisfactory. The aim of this study was to try an alternative approach to improve treatment outcome. Of 374 HBeAg-positive patients, 127 of them received 5 million units of interferon-alpha thrice weekly for 6 months and constituted the control group, while 247 in the study group received the same dosage but the duration of treatment was tailored. The study protocol provided for continuation of treatment if HBV DNA levels were continuously decreasing. The treatment ended when viral, antigenic and biochemical endpoints were reached or when HBV DNA levels were no longer decreasing. The median length of tailored treatment was 10 (range 6-24) months. The end-of-treatment response rates were 39.3% and 23.6% (P = 0.002), and after 12-month, follow-up, the sustained response rates were 40.5% and 28.3% (P = 0.013) in the study and control groups, respectively. Excluding the patients who dropped out, 228 and 115 completed a median of 40- and 44-month-long follow-up; the long-term response was thus 45.3% and 33.1% (P = 0.014) in the respective groups. Interferon-alpha treatment tailored in length demonstrated significantly increased efficacy in patients with chronic hepatitis B.

Hepatitis B virus reactivation in patients receiving chemotherapy for malignancies: role of precore stop-codon and basic core promoter mutations.

Hepatitis B virus (HBV) strains carrying the precore stop-codon mutation (A1896) have been considered among the predisposing factors for reactivation during chemotherapy for malignancies. The role of the T1762/A1764 basic core promoter (BCP) mutations has not been fully evaluated. We aimed to record any changes in HBV serological markers after reactivation, detect the presence of A1896 and BCP mutations and evaluate the type of cytotoxic drugs involved. We retrospectively screened eight patients presenting with HBV reactivation following chemotherapy for malignancies. The chemotherapy regimens used included corticosteroids (CSs), fludarabine and cyclophosphamide/adriamycine. The INNO-LiPA HBV PreCore kit was used for the detection of the A1896 and BCP mutations. Six patients who were hepatitis B surface antigen (HBsAg)-(+)/hepatitis B e antigen (HBeAg)-(-) before chemotherapy, had disease reactivation following a mean of four cycles of chemotherapy. Four survived and two died of hepatic failure. At the time of reactivation, all six patients carried the A1896 and five of them the BCP mutations. The remaining two patients were HBsAg-(-)/anti-HBs-(+)/anti-hepatitis B core (HBc)-(+)/HBeAg-(-) before chemotherapy. One of them reverted to HBeAg-(+) status but remained HBsAg-(-), while the other became HBsAg-(+)/HBeAg-(+), following three and eight cycles of fludarabine treatment, respectively. The former carried the A1896 and the latter the wild-type virus. Both died from causes associated with their haematological disease. All but one of our patients with HBV reactivation during chemotherapy carried the precore stop-codon and BCP mutations. Whether this occurs more frequently in such patients than those carrying the wild-type virus needs further investigation. Fludarabine should be added to the list of drugs inducing HBV reactivation. HBV reactivation following fludarabine treatment occurred in HBsAg-(-) patients who had been anti-HBs-(+).

Interferon-alpha therapy in HBeAg-negative chronic hepatitis B: a long-term prospective study from north-western Greece.

AIMS: To determine the long-term response to interferon-alpha therapy in patients with hepatitis B e antigen-negative chronic hepatitis B, and the factors independently associated with response and survival. METHODS: Sixty-three patients with documented hepatitis B e antigen-negative chronic hepatitis B treated with interferon-alpha for a year were followed-up for a period of 6 years. RESULTS: Sustained biochemical and virological response was seen in 34.91% and 33.33% of patients at 6 and 12 months of follow-up, respectively, and histological improvement in 54.5% of sustained responders compared with non-responders (7.1%, P = 0.004, chi-squared test), at 6 months of follow-up. Multivariate analysis showed that patients with hepatitis B virus-DNA levels at 6 months of treatment <10,000 copies/mL had a low probability of relapse, compared with those with levels >10 000 copies/mL (P = 0.032). Age (>65 years) and hepatitis B virus-DNA level at 6 months of treatment (>10,000 copies/mL) were the independent factors for disease progression and survival (P = 0.041 and P = 0.044 respectively). At 6 years, a sustained response was still present in 19.04% of patients and 4.8% of them had developed anti-HBs. CONCLUSION: Hepatitis B virus-DNA monitoring by quantitative polymerase chain reaction at 6 months of treatment may allow for early prediction of response to interferon-alpha, and may serve as an indicator of disease progression in the future.

Low HBeAg serum levels correlate with the presence of the double A1762T/G1764A core promoter mutation and a positive response to interferon in patients with chronic hepatitis B virus infection.

OBJECTIVE: To investigate the correlation of serum hepatitis B e antigen (HBeAg) levels with the presence of core promoter (CP) mutations, hepatitis B virus (HBV) viremia and the response to interferon (IFN) in patients with chronic hepatitis B. METHODS: Fourteen HBeAg-positive patients received alpha-2a IFN. Diluted serum samples of responders were tested for HBeAg positivity at dilutions of 1:40, 1:160 and 1:640 at the following time points: T0 (before starting IFN), T1 [at peak alanine aminotransferase (ALT) preceding HBeAg seroconversion], T2 (at ALT normalisation) and T3 (end of treatment). Nonresponder samples were similarly tested at times T0 and T3. The HBV CP and precore regions were sequenced at the same time points as for HBeAg testing. RESULTS: Six of 14 patients (43%) responded to IFN treatment and had lower HBeAg levels than nonresponders at T0 (p = 0.003). Five of 6 responders (83%) and none of the nonresponders had the A1762T/G1764A CP mutations (0/8, p < 0.003). At T0, HBeAg was negative at the 1:640 dilution in 5 of the 6 responders, who also had lower HBV DNA levels than nonresponders (p = 0.003). During IFN treatment, HBeAg levels decreased and HBV DNA became negative at T1 in responders. CONCLUSIONS: Low serum HBeAg and HBV DNA levels correlate with the presence of CP mutations and response to IFN treatment and can be considered as predictive markers of response to IFN.

Sequential analysis of hepatitis B virus core promoter and precore regions in cancer survivor patients with chronic hepatitis B before, during and after interferon treatment.

We analysed the hepatitis B virus (HBV) core-promoter (CP) and precore (PC) regions before, during and after interferon treatment in young Caucasian cancer survivors who had acquired HBV infection during chemotherapy for malignancies. Fourteen patients with chronic hepatitis B [hepatitis B e antigen (HBeAg) /HBV-DNA positive] received alpha-2a interferon (IFN), 5 MU/m2 t.i.w. for 12 months. HBV CP and PC region sequences were analysed following polymerase chain reaction (PCR) amplification. Sera from responders were studied at: T(0) (before starting IFN), T(1) [at alanine aminotransferase (ALT) peak preceding HBeAg seroconversion], T(2) (at ALT normalization), T(3) (at end of IFN) and T(4) (at one year after IFN) and in nonresponders at time points T(0), T(3) and T(4). Amplified HBV-DNA was cloned and sequenced automatically. Six of 14 patients (43%) responded to IFN treatment. Five of the six (83%) responders displayed the double CP mutation A1762T/G1764A always in association with a T1753C change. None of the nonresponders showed these mutations at any time point. The G1896A change creating the PC stop codon mutation was never detected in any of the patients. In our cancer survivors, IFN-induced HBeAg/anti-HBe seroconversion appeared to correlate with CP mutations and was not influenced by previous chemotherapy. These mutations in addition to low HBV DNA levels and elevated ALT can be considered favourable factors of response to IFN-induced anti-HBe seroconversion.

Hepatitis C virus phylogeny: a useful clinical tool.

In order to type 45 recent isolates of Hepatitis C virus (HCV) originating from four different geographic regions of the world, we performed phylogenetic analysis of a 192 nucleotides (nts) long sequence from the 5'non-coding region (5'-NCR) of the virus genome and compared them with 55 HCV isolates/strains of known type. The results of this study showed that phylogenetic studies can assign an HCV isolate to the correct type in 100% and to the correct subtype in 98%. A comparison ofthis method with other methods using commercial kits revealed that it is appropriate for clinical use and is cost effective.

Prevalence of HBV core promoter/precore/core mutations in Gambian chronic carriers.

One hundred forty-two precore/core sequences were obtained from Gambian chronic hepatitis B virus (HBV) carriers and the predominant variants defined. The two point mutations, from A to T and G to A at nt positions 1762 and 1764 in the basic core promoter region, were found in only 7/99 (7%) of the samples where this region was sequenced. These mutations were found in both HBeAg-positive and -negative patients. The precore stop-codon mutation at nt position 1896 was found in 14/51 (27%) of HBeAg-negative samples, which is a lower prevalence rate in comparison with other parts of the world with high carrier rates. In HBeAg-positive patients the core amino acid sequences were conserved, but after seroconversion to anti-HBe significantly more changes were apparent. Several of the amino acid substitutions found have been described previously been in wild-type viruses of other genotypes.

Reactivation of precore variant hepatitis B virus in a child with severe aplastic anaemia.

Reactivation of hepatitis B e antigen (HBeAg) negative chronic hepatitis B virus (HBV) infection due to selection of precore variant virus is an uncommon complication of previous hepatitis B infection, and virtually unrecognised in children and adolescents. A child who had received treatment with methylprednisolone and antilymphocyte globulin for severe aplastic anaemia developed high levels of detectable HBV DNA associated with hepatitis B e antibody (anti-HBe) positivity. HBV DNA was extracted, amplified and the core and precore regions sequenced from 2 samples. A mixture of wild-type and the precore variants A(1896) and A(1899) was detected in both samples, with the wild-type predominating in the second sample. Reinfection was excluded by phylogenetic analysis using Phylip and the neighbour-joining method. Precore variant Hepatitis B virus can be transmitted to children as a primary infection, and it is important that aggressive liver disease, particularly in the presence of the anti-HBe phenotype, be investigated. Further studies are needed to determine the frequency of these variants.

Prevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriers.

Previous studies have suggested that hepatitis B virus (HBV) variants may account for the presence of HBV DNA in hepatitis B surface antigen (HBsAg)-negative patients (occult HBV infection). However, it is not known how widespread these variants are and how they influence the course of liver disease. To determine the prevalence of variants within the major hydrophilic region (MHR) of HBsAg, we investigated 2,565 subjects, including subjects with chronic hepatitis, cryptogenic cirrhosis, hemodialysis patients, and blood donors. Fifty-one of them had occult HBV infection. The entire S gene from 46 of these patients was sequenced from amplified serum HBV DNA. Forty-three percent (20 of 46) had mutations in the MHR of HBsAg. Thirty-two amino acid substitutions between positions 100-160 of the MHR of HBsAg were detected in 18 patients, and these ranged from 1 to 4 per patient. These changes involved 11 positions inside and 5 outside of the historical first and second loops of the "a" determinant, and included the following: Q101K, T115A, K122N, T123A, T126N, Q129N, G130R, T131I, M133T, F134L, C138Y, K141E, P142S, G145R, N146S, and C147F/R. Combinations of mutations were detected in 9 patients, and 7 of these have not been described before. Two further patients had insertion mutations immediately before the "a" determinant. Monoclonal antibody binding tests with the Royal Free hepatitis B surface (RFHBs) panel of antibodies revealed decreased immunoreactivity in 6 novel variants of HBsAg. The existence of patients with occult HBV infection caused by HBsAg variants, therefore, has implications for their possible transmission through sexual contact and by blood transfusion.

Transmission of hepatitis B virus infection in Gambian families revealed by phylogenetic analysis.

BACKGROUND/AIMS: Transmission of hepatitis B virus (HBV) in Africa occurs horizontally, with most people becoming infected between the ages of 1 and 5 years. The index cases in such events have been assumed to come from within the family unit or from sources outside the immediate family, such as other families or inhabitants of the same compound or village. Here, we define these routes of transmission by phylogenetic tree analysis of sequences from the entire pre-core/core region of the virus, in Gambian chronic carriers. METHODS: Amplification by polymerase chain reaction of serum extracted HBV-DNA was followed by direct sequencing of the target region. Following editing and alignment of these sequences, phylogenetic tree analysis was performed using the neighbour-joining and maximum-likelihood methods. RESULTS: Despite the overall conserved nature of the sequences of the pre-core/core region from 142 chronic carriers, distinct clusters were easily defined at the family and village level, but not on a wider geographical separation. CONCLUSIONS: Phylogenetic tree analysis of sequences obtained from family members provided strong evidence of intrafamilial transmission of HBV in at least two-thirds of the families studied from Gambia.