A review of reported cases of HIV pre-exposure prophylaxis failure with resultant breakthrough HIV infections.

OBJECTIVES: Early randomized controlled trials (RCTs) have confirmed high efficacy of pre-exposure prophylaxis (PrEP) for preventing HIV infection in men who have sex with men (MSM) with high HIV exposure risk. Nevertheless, some PrEP failure cases have been reported despite adequate drug adherence. This review aims to summarize the common features of PrEP failure cases and discuss the implications of upscaling PrEP programmes. METHODS: A search based on articles and clinical trials was conducted through Medline and OVID, with keywords for accessing publications reporting 'true' PrEP failure in the presence of documented adherence to daily regimen of co-formulated tenofovir disoproxil fumarate/emtricitabone. RESULTS: Ten cases of 'true' PrEP failure were identified, all of which were preceded by continued practice of condomless anal sex, despite documented adherence. Dried blood spot and/or hair analyses provided supporting evidence of adherence in eight cases. There was strong association of PrEP failure with recurrent or multiple sexually transmitted diseases and infection with resistant HIV viruses. Seroconversion was usually atypical or delayed because of significantly suppressed viral load, making diagnosis a clinical challenge. DISCUSSION: Although it is uncommon, 'true' PrEP failure can occur in a real-world situation, contrary to the outcome of early RCTs. Failure to identify HIV infection while on PrEP can potentially lead to the emergence of drug-resistant virus. To achieve effective HIV prevention, PrEP programmes should emphasize safer sexual practice in addition to drug adherence. Early identification of PrEP failure is crucial, which requires the development of highly sensitive assays and their clinical application.

Increasing the coverage of influenza vaccination in healthcare workers: review of challenges and solutions.

Seasonal influenza vaccine uptake rate of healthcare workers (HCWs) varies widely from <5% to >90% worldwide. Perception of vaccine efficacy and side-effects are conventional factors affecting the uptake rates. These factors may operate on a personal and social level, impacting the attitudes and behaviours of HCWs. Vaccination rates were also under the influence of the occurrence of other non-seasonal influenza pandemics such as avian influenza. Different strategies have been implemented to improve vaccine uptake, with important ones including the enforcement of the local authority's recommendations, promulgation of practice guidelines, and mandatory vaccination polices. Practised in some regions in North America, mandatory policies have led to higher vaccination rate, but are not problem-free. The effects of conventional educational programmes and campaigns are in general of modest impact only. Availability of convenient vaccination facilities, such as mobile vaccination cart, and role models of senior HCWs receiving vaccination are among some strategies which have been observed to improve vaccination uptake rate. A multi-faceted approach is thus necessary to persuade HCWs to participate in a vaccination programme, especially in areas with low uptake rate.

Comparison of empirical continuous positive airway pressure (CPAP) treatment versus initial portable sleep monitoring followed by CPAP treatment for patients with suspected obstructive sleep apnoea.

BACKGROUND: Polysomnography is labour-intensive for diagnosing obstructive sleep apnoea (OSA). We compared two algorithms for initiating continuous positive airway pressure (CPAP) treatment for patients with suspected OSA. METHODS: Symptomatic OSA patients were randomised into either algorithm I or II. Algorithm I consisted of an empirical CPAP trial whereas algorithm II utilised an Apnea Risk Evaluation System, a wireless device applied on the forehead, for establishing a diagnosis before a CPAP trial for 3 weeks. Primary outcome was success of CPAP trial, defined as CPAP usage > 4 h/night and willingness to continue CPAP. Subjective usefulness of CPAP, accuracy of Apnea Risk Evaluation System versus polysomnography and CPAP adherence at 6 months were secondary end-points. RESULTS: Altogether 138 patients in algorithm I and 110 patients in algorithm II completed the CPAP trial. There were no significant differences between these algorithms with respect to the primary end-point. The sensitivity and specificity of algorithm I versus II as a diagnostic test for OSA were 0.3, 0.8 versus 0.31, 1.00 respectively. In predicting CPAP adherence at 6 months, the likelihood ratio positive for algorithms I and II was 2.7 and 5.27 respectively. The mean (SE) time taken from the first consultation to the end of CPAP trial in algorithm I and algorithm II was 60 (2) and 98 (5) days, respectively, P < 0.01. CONCLUSION: An ambulatory approach with portable sleep monitoring for diagnosing OSA before a CPAP trial can identify more patients who would adhere to CPAP at 6 months than empirical CPAP treatment alone.

Depressive symptoms among community-dwelling, post-stroke elders in Hong Kong.

BACKGROUND: Depressive symptoms adversely affect functional recovery among post-stroke elders. Such symptoms manifest when elders face difficulties in realistic daily living after being discharged. AIMS: The aim of this study was to examine (1) the prevalence of depressive symptoms among community-dwelling post-stroke elders, (2) the relationship between depressive symptoms and demographic and clinical characteristics among community-dwelling post-stroke elders, and (3) the demographic and clinical factors that differentiate post-stroke elders with and without depressive symptoms. METHODS: A descriptive cross-sectional survey was performed on 50 post-stroke elders from a geriatric day clinic. FINDINGS: Depressive symptoms were highly prevalent (68%) among the community-dwelling post-stroke elders. Depressive symptoms were negatively correlated with social support network, social support satisfaction and functional independence. Lastly, poor social support satisfaction and lower functional independence was found to differentiate those post-stroke elders with and without depressive symptoms. CONCLUSION: The inclusion of psychosocial assessment and delivery of appropriate psychosocial interventions to post-stroke elders are recommended.

Differential susceptibility of different cell lines to swine-origin influenza A H1N1, seasonal human influenza A H1N1, and avian influenza A H5N1 viruses.

BACKGROUND: The novel swine-origin influenza A H1N1 virus (S-OIV) causes the current pandemic. Its tissue tropism and replication in different cell lines are not well understood. OBJECTIVE: Compare the growth characteristics of cell lines infected by S-OIV, seasonal influenza A H1N1 (sH1N1) and avian influenza A H5N1 (H5N1) viruses and the effect of temperature on viral replication. STUDY DESIGN: Cytopathic effect (CPE), antigen expression by immunofluorescence (IF) and viral load profile by quantitative RT-PCR in 17 cell lines infected by S-OIV, sH1N1 and H5N1 were examined. Comparison of their replication efficiency in chick embryo was performed. The effect of temperature on viral replication in Madin-Darby canine kidney (MDCK) cells was determined by TCID(50) at 33 degrees C, 37 degrees C and 39 degrees C for 5 consecutive days. RESULTS: S-OIV replicated in cell lines derived from different tissues or organs and host species with comparable viral load to sH1N1. Among 13 human cell lines tested, Caco-2 has the highest viral load for S-OIV. S-OIV showed a low viral load with no CPE or antigen expression in pig kidney cell PK-15, H5N1 demonstrated the most diverse cell tropism by CPE and antigen expression, and the highest viral replication efficiency in both cell lines and allantoic fluid. All three viruses demonstrated best growth at 37 degrees C in MDCK cells. CONCLUSION: Cell line growth characteristics of S-OIV, sH1N1 and H5N1 appear to correlate clinically and pathologically with involved anatomical sites and severity. Low replication of S-OIV in PK-15 suggests that this virus is more adapted to human than swine.

Validation of a portable recording device (ApneaLink) for identifying patients with suspected obstructive sleep apnoea syndrome.

BACKGROUND: Polysomnography (PSG) is currently the standard diagnostic procedure for sleep apnoea. This study evaluates the diagnostic accuracy of a portable recording device, ApneaLink (AL; ResMed, Poway, CA, USA) for detection of sleep apnoea in comparisons against PSG. METHODS: The AL device is a three-channel screening tool that measures airflow through a nasal pressure transducer, oximetry and pulse, providing an apnoea-hypopnoea index (AHI) based on recording time. Nocturnal PSG (Alice 4; Healthdyne, Atlanta, GA, USA), with airflow measured by a nasal pressure transducer (ProTech PTAF2; ProTech, Woodinville, WA, USA) and AL recordings were carried out simultaneously in consecutive patients with suspected obstructive sleep apnoea syndrome (OSAS). The PSG recordings were analysed manually by a blinded investigator. The oxygen desaturation index of AL was also compared against the AHI based on PSG. RESULTS: Fifty consecutive subjects with symptoms of OSAS were recruited with mean age of 50 years and body mass index of 27.9 kg/m2. The AHI obtained by the AL device correlated closely to that obtained by PSG (Pearson correlation, r= 0.978, P < 0.001), whereas the correlation between PSG AHI and oxygen desaturation index by AL was also strong (r= 0.895, P < 0.001). Comparison of AHI based on the AL against the PSG demonstrated high sensitivity and specificity at AHI > or =10/h (sensitivity 0.977 and specificity 1.0) and at AHI > or =20/h (sensitivity 0.969 and specificity 1.0). CONCLUSION: The AL portable monitoring device is highly sensitive and specific in quantifying the apnoea-hypopnoea index when compared against hospital based polysomnography in patients with suspected OSAS. The simple device may be useful for screening and diagnostic purpose when access to PSG is limited.

Influenza-like illness in residential care homes: a study of the incidence, aetiological agents, natural history and health resource utilisation.

BACKGROUND: Influenza-like illness (ILI) among elderly people living in residential care homes (RCHEs) is a common cause for hospitalisation. A study was undertaken to examine the incidence, underlying aetiology, natural history and associated healthcare resource utilisation related to ILI in the RCHE population. METHODS: A prospective study of ILI in four RCHEs in Shatin, Hong Kong was conducted from April 2006 to March 2007. Each RCHE was monitored daily for the occurrence of ILI and followed up until resolution of illness or death. Clinical features were recorded and sputum, nasopharyngeal aspirate, blood and urine specimens were examined for underlying aetiology. RESULTS: 259 episodes of ILI occurred in 194 subjects, with mild peaks in winter and summer, over a sustained level throughout the year. The infectious agent was identified in 61.4% of all episodes, comprising bacterial infection in 53.3% and viral in 46.7%. Multiple infections occurred in 16.2% of subjects. The most frequent organism was Streptococcus pneumoniae, followed by respiratory syncytial virus, Pseudomonas aeruginosa, metapneumovirus and parainfluenza virus types 1 and 3. Clinical features did not vary according to the underlying aetiology, the common presenting features being a decrease in general condition, cognitive and functional deterioration, and withholding of food in addition to fever and respiratory symptoms. Overall, mortality at 1 month/discharge was 9.7%. Infection with methicillin-resistant Staphylococcus aureus, low body mass index and poor function predisposed to mortality. No association was observed between influenza vaccination status and underlying aetiology, clinical features or outcome. CONCLUSIONS: The clinical presentation of ILI is non-specific and is mainly due to bacterial and viral infections other than influenza in the RCHE population.

Nasal CPAP reduces systemic blood pressure in patients with obstructive sleep apnoea and mild sleepiness.

BACKGROUND: A randomised controlled study was undertaken to examine the effect of nasal continuous positive airway pressure (CPAP) on 24 hour systemic blood pressure (BP) in patients with obstructive sleep apnoea (OSA). METHODS: Patients were fitted with an ambulatory BP measuring device as outpatients during normal activities and recorded for 24 hours before starting therapeutic or subtherapeutic (4 cm H(2)O) CPAP treatment. BP monitoring was repeated before completion of 12 weeks of treatment. The primary end point was the change in 24 hour mean BP. RESULTS: Twenty three of 28 participants in each treatment arm completed the study. There was no significant difference between the two groups in age, body mass index, Epworth Sleepiness Score, apnoea-hypopnoea index, arousal index, and minimum Sao(2). Twenty four patients were hypertensive. The pressure in the therapeutic CPAP group was 10.7 (0.4) cm H(2)O. CPAP usage was 5.1 (0.4) and 2.6 (0.4) hours/night for the therapeutic and subtherapeutic CPAP groups, respectively (p<0.001). After 12 weeks of treatment there were significant differences between the two CPAP groups in mean (SE) changes in 24 hour diastolic BP (-2.4 (1.2) v 1.1 (1.0) mm Hg (95% CI -6.6 to -0.5), p = 0.025); 24 hour mean BP (-2.5 (1.3) v 1.3 (1.1) mm Hg (95% CI -7.2 to -0.2), p = 0.037); sleep time systolic BP (-4.1 (2.1) v 2.2 (1.8) mm Hg (95% CI -11.8 to -0.7), p = 0.028); and sleep time mean BP (-3.6 (1.7) v 1.3 (1.4) mm Hg (95% CI -9.2 to -0.4), p = 0.033). CONCLUSIONS: Compared with subtherapeutic CPAP, 12 weeks of treatment with therapeutic CPAP leads to reductions in 24 hour mean and diastolic BP by 3.8 mm Hg and 3.5 mm Hg, respectively, in mildly sleepy patients with OSA.

Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study.

BACKGROUND: Clarithromycin is frequently used to treat community-acquired pneumonia in elderly persons. Like erythromycin, it may interact with other drugs by interfering with metabolism by cytochrome P450 enzymes and with the P-glycoprotein transporter system. Colchicine, used for treatment of acute gout and for prophylaxis, may cause bone marrow toxicity. It is metabolized by CYP3A4 and is transported by P-glycoprotein. Initial case reports suggested potentially fatal interactions between clarithromycin and colchicine. METHODS: A retrospective study was conducted with 116 patients who were prescribed clarithromycin and colchicine during the same clinical admission. Case-control comparisons were made between patients who received concomitant therapy with the 2 drugs and patients who received sequential therapy. We assessed the clinical presentations and outcomes of the 2 patient groups and analyzed the risk factors associated with fatal outcomes. RESULTS: Nine (10.2%) of the 88 patients who received the 2 drugs concomitantly died. Only 1 (3.6%) of the 28 patients who received the drugs sequentially died. Multivariate analysis of the 88 patients who received concomitant therapy showed that longer overlapped therapy (relative risk [RR], 2.16; 95% confidence interval [CI], 1.41-3.31; P< or =.01), the presence of baseline renal impairment (RR, 9.1; 95% CI, 1.75-47.06; P<.001), and the development of pancytopenia (RR, 23.4; 95% CI, 4.48-122.7; P<.001) were independently associated with death. CONCLUSIONS: Clarithromycin increases the risk of fatal colchicine toxicity, especially for patients with renal insufficiency. Since there are other drugs for treatment of pneumonia and gout, these 2 drugs should not be coprescribed, because of the risk of fatality.

Alterations of RAS signalling in Chinese multiple myeloma patients: absent BRAF and rare RAS mutations, but frequent inactivation of RASSF1A by transcriptional silencing or expression of a non-functional variant transcript.

The methylation status, mutation and expression of RASSF1A, and mutations of RAS and BRAF were studied in 52 patients with multiple myeloma (MM), one plasma cell leukaemia (PCL) patient and four MM-derived cell lines. Aberrant methylation of RASSF1A was found in nine of 32 MM patients and in one of four MM cell lines (U266), where the associated loss of transcription was reversible by demethylation treatment. RASSF1A transcription was further investigated on anti-CD138-sorted plasma cell-enriched bone marrow samples from 10 MM, one PCL and three reactive plasmacytosis patients. While the wild-type RASSF1A transcript was detected in all three reactive plasmacytosis and the PCL samples, we found no detectable wild-type transcripts in six of 10 MM samples studied. In two MM samples, only the non-functional variant transcript was detected, whereas the other four showed loss of transcription. In great contrast to western data, RAS mutations were identified in only four of 31 (13%) MM patients. While no RASSF1A or BRAF mutation (V599E) was detected in any of the primary MM studied (n = 21), the latter was found in the U266 cell line. Taken together, these data indicate that alterations of RAS signalling are critical in MM pathogenesis. In our current studies of Chinese MM patients, these alterations involved frequent RASSF1A inactivation (60%) as a result of transcriptional silencing or expression of a non-functional variant transcript.

Frequent death-associated protein kinase promoter hypermethylation in multiple myeloma.

UNLABELLED: Death-associated protein (DAP) kinase is a novel gene regulating apoptosis induced by IFN-gamma. In B-cell malignancies, loss of DAP kinase expression is commonly associated with promoter hypermethylation. These characteristics of DAP kinase may be of particular relevance in multiple myeloma (MM), a B-lineage malignancy in which prolonged survival capacity of the malignant plasma cells may be critical in the induction and maintenance of tumor cells. PURPOSE: The involvement and potential role of DAP kinase in MM pathogenesis was examined. EXPERIMENTAL DESIGN: In this investigation, methylation-specific PCR was conducted on primary MM and MM cell lines. Methylation status findings were correlated with clinical parameters. RESULTS: We first demonstrated frequent DAP kinase hypermethylation in 24 of 36 primary MMs (20 of 26 at diagnosis and 4 of 10 with relapse/residual MM after treatment), 1 of 2 patients with monoclonal gammopathy of undetermined significance, and 1 of 3 MM cell lines studied. The high frequency of DAP kinase hypermethylation was similarly observed in MM of different stages, immunoglobulin isotypes, and histological grades, with or without plasmacytomas. Although not statistically significant, the overall survival of patients with DAP kinase methylation was notably shortened among 23 MM patients followed prospectively (P = 0.38 by Kaplan-Meier method and log-rank test). This preliminary finding suggests prognostic implications of DAP kinase in MM that may deserve further investigation. CONCLUSIONS: Our data suggest an important role for DAP kinase in MM tumorigenesis.

Comparison of the vascular relaxant effects of ATP-dependent K+ channel openers on aorta and pulmonary artery isolated from spontaneously hypertensive and Wistar-Kyoto rats.

The vasorelaxant actions of adenosine 5'-triphosphate (ATP)-dependent K+ channel openers and sodium nitroprusside in isolated thoracic aorta and pulmonary artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats (14-18 weeks old) were investigated. Cumulative addition of sodium nitroprusside and different ATP-dependent K+ channel openers (pinacidil, cromakalim, nicorandil, 2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro -2H-1-benzopyren (KR-30450) and aprikalim) to these preparations caused a concentration-dependent relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. The relative order of relaxation potency, estimated by comparing the IC50, was sodium nitroprusside > KR-30450 > aprikalim > or = cromakalim > pinacidil > nicorandil in pulmonary artery and aorta from both strains. At high concentrations (> or =1 microM), cromakalim, aprikalim and KR-30450 produced a greater percentage relaxation in SHR aorta than in WKY aorta. However, there was no apparent difference between SHR and WKY in the relaxation response to all drugs tested on the pulmonary artery. The effects of cromakalim, aprikalim, pinacidil and KR-30450 observed in aorta and pulmonary artery were significantly attenuated by 3 microM glibenclamide. 6-Anilino-5,8-quinolinequinone (LY 83583, 1 microM), a soluble guanylate cyclase inhibitor, abolished the vasorelaxant effects of nicorandil and sodium nitroprusside. In conclusion, sodium nitroprusside and ATP-dependent K+ channel openers cause relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. However, all the drugs tested failed to cause selective relaxation of the pulmonary artery relative to the thoracic aorta.

Relative efficacy of the argon green, argon blue-green, and krypton red lasers for 10-0 nylon subconjunctival laser suture lysis.

BACKGROUND AND OBJECTIVE: To determine the optimal wavelength for subconjunctival laser suture lysis. MATERIALS AND METHODS: 130 black monofilament 10-0 nylon sutures were sewn subconjunctivally into the bare sclera of enucleated rabbit globes. The lowest energy levels facilitating laser suture lysis were determined for the argon green (514.5 NM), argon blue-green (488.0 NM, 514.5 NM), and krypton red (647.1 NM) wavelengths. In addition, absorption spectroscopy was performed on the suture material and conjunctiva using the Perkin Elmer W/VIS Lambda 2 spectrometer. RESULTS: Krypton red produced the fewest buttonhole defects, and it was also the most efficient energy source for suture lysis (P = 0.0001) under nontenectomized conjunctiva. Absorbance spectra studies revealed peak absorbance at 628 NM for the 10-0 nylon suture material. CONCLUSIONS: Based on animal and absorption spectroscopy studies, krypton red may be a safer and more efficient wavelength for subconjunctival laser suture lysis.

Comparison of the effects of enucleation and orbital reconstruction using free-fat grafts, dermis grafts, and porous polyethylene implants in infant rabbits.

Twenty-nine infant rabbits from four litters were randomly assigned to three groups. No surgery was performed on left eyes. All right eyes were enucleated. Group 1, the control group, had no right-socket reconstruction. Group 2 had reconstruction using free-fat and dermis grafts. Group 3 had reconstruction using porous polyethylene implants. On attaining adult size, rabbits were killed, decapitated, and prepared for measurements. Orbital volume measurements were performed twice and orbital entrance areas were determined once. No significant differences were noted between first and second measurements of orbital volumes. Right orbital volumes were significantly smaller than left orbits in all groups except for the second measurement of the polyethylene implant group. Right orbital entrance areas were significantly smaller than left areas in the control and the free-fat and dermis graft groups. Right orbital entrance areas of the polyethylene group were not significantly smaller than the corresponding left orbital entrance areas. The use of free-fat and dermis grafts for orbital reconstruction in anophthalmic infant rabbits did not significantly stimulate orbital bone growth. In one trial, the polyethylene implant group displayed right orbital volumes and orbital entrance areas that were not significantly smaller than controls.

Histopathologic and immunohistochemical study of an autopsy eye with X-linked cone degeneration.

We performed a histopathologic and immunohistochemical study of eyes obtained at autopsy of an 84-year-old man from a family with X-linked cone degeneration in which affected members have a 6.5-kilobase deletion in the red cone pigment gene. At his most recent ocular examination, at age 71 years, this patient had had a visual acuity of 20/200 OU, fundus changes suggestive of macular degeneration, borderline-normal full-field rod electroretinograms, and profoundly reduced full-field cone electroretinograms. Histopathologic examination demonstrated marked loss of cone and rod photoreceptors and the retinal pigment epithelium in the central macula. The peripheral cone population was reduced, while the peripheral rod population was relatively preserved. Immunohistochemical examination with an antibody to both red and green cone opsin and an antibody to blue cone opsin disclosed a prominent loss of the red and green cone population and preservation of the blue cone population. These findings show that a defect in the red cone pigment gene can result in extensive degeneration of the red and green cone population across the retina.

Clinical and histopathologic findings in clumped pigmentary retinal degeneration.

OBJECTIVE: To describe the clinical and histopathologic features of clumped pigmentary retinal degeneration (CPRD). DESIGN: Retrospective case series. SETTING: Tertiary referral center. PATIENTS: Twenty-four patients, aged 7 to 83 years, were identified from the medical record filed of the Berman-Gund Laboratory, Boston, Mass, as having the clinical features of CPRD. The autopsy eye from a 56-year-old man with CPRD was studied with light and electron microscopy. MAIN OUTCOME MEASURES: Visual acuities, visual fields, dark-adaptation thresholds, and results of electroretinograms; histopathologic study of an autopsy eye. RESULTS: The functional deficit of patients with CPRD seems to be similar to that of patients with typical retinitis pigmentosa. Different degrees of severity were observed among patients of similar age. The histopathologic data showed that the clinically distinct areas of clumped pigment are due to excessive accumulation of melanin granules in retinal pigment epithelial cells. CONCLUSION: Based on the distinct clinical and histopathologic appearance, CPRD should be considered as a separate form of retinal degeneration.

Association and chance occurrence of aniridia and retinoblastoma.

PURPOSE/METHODS: A 9-month-old infant had inherited aniridia and unilateral retinoblastoma. Family history disclosed three generations of aniridia; yet there were no instances of retinoblastoma. The coincidental occurrence of retinoblastoma and aniridia is rare. RESULTS/CONCLUSIONS: With DNA probes from within the retinoblastoma gene, we were able to determine that a retinoblastoma-predisposing mutation was not inherited with aniridia in this family. The occurrence of these two diseases in the same individual therefore represents a chance event.