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Introduction Dosing recommendations for paliperidone long-acting injectable antipsychotic (LAIA) do not include oral antipsychotic (OAP) overlap; however, OAPs are often given concurrently despite limited evidence describing both the risks and benefits of this practice. Methods A retrospective chart review was conducted in patients initiated on paliperidone palmitate (PP) during a psychiatric hospitalization to compare patients who received OAP overlap versus those who did not. The primary outcome is the proportion of patients who receive prescription claims for benztropine, a medication commonly prescribed for extrapyramidal symptoms, at the time of LAIA discontinuation and 6 months postdischarge. Secondary outcomes include prescription claims for beta blockers and diphenhydramine, number of psychiatric emergency visits and hospitalizations, length of stay of the index hospitalization, frequency of LAIA discontinuation and the time to LAIA discontinuation. Results There is a significant difference in the proportion of benztropine prescription claims in the OAP overlap group versus the no-overlap group at the time of LAIA discontinuation (30% vs 0%, P = .046) but not at 6 months postdischarge. There are also significant differences in the number of psychiatric emergency visits (0.7 vs 0.1, P = .02) and psychiatric hospitalizations (0.6 vs 0.1, P = .029) at the time of LAIA discontinuation. No other differences are observed in defined secondary outcomes. Discussion Patients who receive OAP overlap while receiving PP receive more benztropine and have more psychiatric emergency visits and hospitalizations than those treated without OAP. Larger studies with better control for confounding variables are needed to confirm these results.

ObjectivesDolutegravir has replaced efavirenz as first-line treatment in universal HIV guidelines. We sought to ascertain the contributory effect of SNPs in four key genes linked to dolutegravir disposition (UGT1A1, ABCG2, CYP3A and NR1I2) on plasma dolutegravir pharmacokinetics.MethodsPaired pharmacogenetic/pharmacokinetic data from 93 subjects were analysed for association using multivariate linear regression.ResultsCo-occurring UGT1*28 and NR1I2 c.63396C>T homozygosity was associated with a 79% increase in AUC0–24 (P = 0.001; 27% if analysed individually), whilst combined ABCG2 c.421C>A and NR1I2 c.63396C>T variants were associated with a 43% increase in Cmax (P = 0.002) and a 39% increase in AUC0–24 (P = 0.002). When analysed individually, homozygosity for the NR1I2 c.63396C>T variant alleles was associated with a 28% increase in Cmax (P = 0.033) and homozygosity for the ABCG2 c.421C>A variant alleles was associated with a 28% increase in Cmax (P = 0.047). The UGT1A1*28 (rs8175347) poor metabolizer status (*28/*28; *28/*37; *37/*37) was individually associated with a 27% increase in AUC0–24 (P = 0.020). The combination of UGT1A1*28 poor metabolizer and UGT1A1*6 intermediate metabolizer statuses correlated with a 43% increase in AUC0–24 (P = 0.023).ConclusionsThis study showed a pharmacogenetic association between dolutegravir pharmacokinetics and variants in the ABCG2, UGT1A1 and NR1I2 genes, particularly when combined. Further research is warranted to confirm these associations in population-specific studies and to investigate their putative relationship with dolutegravir pharmacodynamics.

S-acylation, also known as palmitoylation, is the most widely prevalent form of protein lipidation, whereby long-chain fatty acids get attached to cysteine residues facing the cytosol. In humans, 23 members of the zDHHC family of integral membrane enzymes catalyze this modification. S-acylation is critical for the life cycle of many enveloped viruses. The Spike protein of SARS-CoV-2, the causative agent of COVID-19, has the most cysteine-rich cytoplasmic tail among known human pathogens in the closely related family of β-coronaviruses; however, it is unclear which of the cytoplasmic cysteines are S-acylated, and what the impact of this modification is on viral infectivity. Here we identify specific cysteine clusters in the Spike protein of SARS-CoV-2 that are targets of S-acylation. Interestingly, when we investigated the effect of the cysteine clusters using pseudotyped virus, mutation of the same three clusters of cysteines severely compromised viral infectivity. We developed a library of expression constructs of human zDHHC enzymes and used them to identify zDHHC enzymes that can S-acylate SARS-CoV-2 Spike protein. Finally, we reconstituted S-acylation of SARS-CoV-2 Spike protein in vitro using purified zDHHC enzymes. We observe a striking heterogeneity in the S-acylation status of the different cysteines in our in cellulo experiments, which, remarkably, was recapitulated by the in vitro assay. Altogether, these results bolster our understanding of a poorly understood posttranslational modification integral to the SARS-CoV-2 Spike protein. This study opens up avenues for further mechanistic dissection and lays the groundwork toward developing future strategies that could aid in the identification of targeted small-molecule modulators.

Background and objectives: Access to safe and reliable contraception in the context of ARVs is essential. This study aimed to investigate the steady-state pharmacokinetics (PK) of ethinylestradiol/levonorgestrel (EE/LNG) 30/150 μg (Microgynon®) and atazanavir/cobicistat (ATV/COBI) 300/150 mg (Evotaz®), co-administered in HIV negative female volunteers, and assess its safety and tolerability. Methods: This phase 1, open label, 57-day, cross over, PK study randomized participants to one of two groups: (i) group 1 received EE/LNG alone on days 1-21, EE/LNG (21 days) + ATV/COBI (14 days) in the co-administration phase (days 22-42) and ATV/COBI alone on days 43-56; (ii) group 2 followed the same sequence but started with ATV/COBI and concluding with EE/LNG. Each group underwent intensive PK sampling on days 14, 35, and 56. EE/LNG and ATV/COBI concentrations were measured using validated LC-MS/MS methods. Results: Of 14 healthy female volunteers screened, 11 attended baseline and six completed all PK phases (five withdrew secondary to side effects). Paired data were available for analysis in six subjects for EE/LNG and eight for ATV/COBI. Geometric mean ratios (GMR, with versus without ATV/COBI) and 90% confidence intervals (CI) for LNG Cmax, AUC0-24, C24 were 0.83 (0.68-1.02), 0.92 (0.71-1.18), 1.01 (0.73-1.38). GMR and 90% CI for EE Cmax, AUC0-24, C24 were 1.05 (0.92-1.19), 1.01 (0.83-1.22), 0.75 (0.60-0.93). No grade 3 or 4 adverse events or laboratory abnormalities were observed in the women who completed the study. Conclusions: Our findings showed no significant changes in LNG concentrations and a 25% decrease in EE C24 when EE/LNG was co-administered with ATV/COBI.

Neodymium-doped yttrium aluminum garnet (Nd:YAG) lasers are among the most commonly used lasers with a wide variety of applications from biomedicine to manufacturing. The ubiquity of these lasers increases the likelihood of accidental ocular injury resulting in permanent visual impairment. We performed dosimetry studies to determine retinal damage thresholds and hemorrhagic lesions in the porcine eye with Qswitched Nd:YAG lasers. The Yucatan miniature pig model exhibited similarities in ocular anatomy to human eyes. The Nd:YAG laser, tuned to 1064 nm with a pulse width of seven nanoseconds, delivered laser energy to the retina. Retinal imaging modalities including fundus photography, real-time video, confocal scanning laser ophthalmoscopy (cSLO), and spectral domain optical coherence tomography (SD-OCT) provided visualization of retinal morphology at multiple time points. Retinal damage thresholds were grouped into three categories: minimum visible lesion (MVL), contained hemorrhagic lesion (CHL), and vitreal hemorrhagic lesion (VHL). Probit analysis determined the effective dose for 50% probability of damage (ED50) for each lesion category. The threshold to produce a MVL was 0.193 mJ based on 24-hour assessments of the retina. The one-hour hemorrhagic lesion thresholds were 0.408 mJ and 1.52 mJ for CHL and VHL, respectively

Background We investigated the pharmacokinetics (PK) of atazanavir/cobicistat and darunavir/cobicistat once daily over 72 h following drug intake cessation in plasma, saliva and urine. Methods Healthy volunteers received a fixed-dose combination of 300/150 mg of atazanavir/cobicistat once daily for 10 days, followed by a 10 day washout period and then a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily for 10 days. Full PK profiles were assessed for each phase for 72 h following day 10 and parameters determined to the last measurable concentration in plasma, saliva and urine by non-compartmental methods. Results Sixteen subjects completed the study. Geometric mean (GM) terminal elimination half-life values to 72 h of atazanavir and darunavir were 6.77 and 6.35 h, respectively. All subjects had atazanavir concentrations above the suggested minimum effective concentration of 150 ng/mL 24 h post-dose and 14/16 subjects had concentrations higher than this target at 30 h post-dose (GM of 759 and 407 ng/mL, respectively). Thirteen out of 16 subjects had darunavir concentrations higher than the target of 550 ng/mL at 24 h post-dose and 5/16 subjects had concentrations higher than the target at 30 h post-dose (GM of 1033 and 382 ng/mL, respectively). Cobicistat half-life to 72 h was 4.21 h with atazanavir and 3.62 h with darunavir. GM values 24 h after the observed dose ( C 24 ) for atazanavir and darunavir were 141 and 43 ng/mL, respectively, in saliva and 24857 and 11878 ng/mL, respectively, in urine. Concentration decay in saliva/urine mirrored plasma concentrations for both drugs. Conclusions Different concentration decay patterns were seen for atazanavir and darunavir, which may be partially explained by cobicistat half-life (longer with atazanavir than darunavir). For the first time, we also measured drug PK forgiveness in saliva and urine, which represent easier markers of adherence.

Precontoured, low-profile plates with fixed dorsiflexion angles are becoming increasingly popular for first metatarsophalangeal joint fusion. We have concerns that the routine use of a precontoured plate can lead to excessive clinical dorsiflexion. The aim of our study was to investigate the relationship between the first metatarsophalangeal joint dorsiflexion intramedullary angle and the angle formed at the dorsal cortices where the plate is applied. We hypothesized that the dorsal cortical angle was significantly less dorsiflexed than the intramedullary angle. We measured both angles on lateral weightbearing radiographs of 40 consecutive individuals presenting with forefoot symptoms. The results demonstrated that the mean dorsal cortical angle was significantly smaller (mean 0.2° plantarflexion) compared with the intramedullary angle (mean 10.6° dorsiflexion; p

BackgroundDemographic data show an increasingly aging human immunodeficiency virus (HIV) population worldwide. Recent concerns over dolutegravir-related neuropsychiatric toxicity have emerged, particularly amongst older people living with HIV (PLWH). We describe the pharmacokinetics (PK) of dolutegravir (DTG) 50 mg once daily in PLWH aged 60 and older. Additionally, to address calls for prospective neuropsychiatric toxicodynamic data, we evaluated changes in sleep quality and cognitive functioning in this population after switching to abacavir (ABC)/lamivudine (3TC)/DTG over 6 months.MethodsPLWH ≥60 years with HIV-viral load ResultsIn total, 43 participants enrolled, and 40 completed the PK phase. Overall, 5 discontinued (2 due to sleep-related adverse events, 4.6%). DTG maximum concentration (Cmax) was significantly higher in patients ≥60 years old versus controls (geometric mean 4246 ng/mL versus 3402 ng/mL, P = .005). In those who completed day 180 (n = 38), sleep impairment (Pittsburgh Sleep Quality Index) was marginally higher at day 28 (P = .02), but not at days 90 or 180. Insomnia, daytime functioning, and fatigue test scores did not change statistically over time.ConclusionsDTG Cmax was significantly higher in older PLWH. Our data provides clinicians with key information on the safety of prescribing DTG in older PLWH.

Purpose of reviewThis review of recent published literature and data presented at scientific meetings on integrase stand transfer inhibitors (InSTIs) examines how these findings may impact on their future clinical use.Recent findingsElvitegravir (EVG), raltegravir (RAL) and dolutegravir (DTG) are InSTIs recommended as first-line options for treatment naive patients by the European AIDS Clinical Society, British HIV Association, International AIDS Society-USA and DHHS. InSTIs have gained a leading role in the management of HIV-1 because of increased viral suppression and maintaining undetectability with fewer side-effects.RAL 1200 mg once-daily (QD) has been shown to be noninferior to 400 mg BD, and the European Medicines Agency has approved QD RAL for review. RAL and DTG are not metabolized via cytochrome P450 (CYP) resulting in fewer drug interactions and less toxicity risk in patients receiving direct-acting antivirals and other coadministered medications.EVG is currently available as a single tablet regimen and requires cobisistat, a pharmacokinetic booster and CYP3A inhibitor to allow QD dosing. EVG will soon be available in combination with tenofovir alfenamide, which is as efficacious as tenofovir disoproxil fumarate, but offers better renal and bone outcomes.DTG has a high genetic barrier to resistance and has been the subject of a number of simplification and treatment failure trials and shown promise. There are some emerging reports of neuropsychiatric and gastrointestinal side-effects associated with DTG, which were not reported in clinical trials emphasizing the importance of real-life data.Carbotegravir, a long-acting InSTI, is currently in the pipeline of development.SummaryAll three InSTIs have impressive data on efficacy, tolerability and safety. The unique differences of each InSTI's pharmacokinetics and pharmacodynamics lend themselves to various clinical scenarios, enabling us as clinicians to provide better patient-centred care.

Personalized medicine remains an attractive concept in many areas of medicine, particularly where complex and potentially toxic therapies are prescribed over prolonged periods of time. The inter- and intraindividual variability observed in both therapeutic and toxic effects is governed by demographic, physiological, and genetic factors. The relative contribution of any of these factors to variability differs between populations and prescribed compounds. The completion of the Human Genome Project in 2001 heralded the beginning of great technological advancements in the era of personalized medicine. Over time, and particularly since 2000s, pharmacogenetic studies have utilized either a candidate gene approach or been genome-wide association studies and up to date findings in the fields of HIV, malaria and TB therapies are described in details here. Both these approaches have identified important associations but both also require rigorous clinical validation. This is central to minimizing spurious findings, which have historically led to confusion in the field and have therefore been a barrier to the uptake of pharmacogenetic testing. Spurious associations can also be avoided through thorough mechanistic evaluations to ensure biological plausibility. Understanding mechanisms will also increase the value of the data generated by helping to target future studies and by informing the drug development process. Despite an increase in the number and complexity of studies performed, the clinical utility of reported genotype–phenotype associations remains unclear in many studies. Therefore, there is a need for well-powered validation studies in ethnically diverse cohorts with well-characterized phenotypes.

Background:Dolutegravir combined with darunavir/cobicistat is a promising NRTI-sparing and/or salvage strategy for the treatment of HIV-1 infection. Methods:This Phase I, open-label, 57 day, crossover, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65 years, who were randomized to one of two groups. Group 1 received dolutegravir (50 mg) once daily for 14 days followed by a 7 day washout, then a 14 day dolutegravir/darunavir/cobicistat (DTG/DRV/COBI) once-daily co-administration period followed by a 7 day washout and finally a 14 day period of darunavir/cobicistat (800/150 mg) once daily. Group 2 followed the same sequence starting with darunavir/cobicistat and concluding with dolutegravir. Each group underwent intensive PK sampling over 24 h on day 14 of each drug period and DTG/DRV/COBI concentrations were measured using validated LC-MS/MS methods. Results:Twenty participants completed all PK phases. Thirteen were female and median age and BMI were 33.5 years and 27 kg/m2. Dolutegravir geometric mean ratios (GMR, DTG/DRV/COBI versus dolutegravir alone) and 90% CI for Cmax, AUC0-24 and C24 were 1.01 (0.92-1.11), 0.95 (0.87-1.04) and 0.9 (0.8-1.0), respectively. Darunavir GMR (DRV/COBI/DTG versus darunavir/cobicistat alone) and 90% CI for Cmax, AUC0-24 and C24 were 0.90 (0.83-0.98), 0.93 (0.86-1.00) and 0.93 (0.78-1.11), respectively. No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusions:Concentrations of dolutegravir and darunavir, when boosted with cobicistat, decreased by

Computed tomography (CT) imaging was applied to Mormon Mesa petrocalcic and related materials to observe the location, arrangement, and interconnectedness of void spaces and to visualize density differences that may define pedogenic mineral relationships. Density variations visualized by these scans reveal features that may result from long developed pedogenic processes within these unique soil materials. Voids are present as cracks (shown to interconnect three-dimensionally), elongated spaces filled with unconsolidated materials, and oblate-spheroidal shapes that appear to be associated with detrital carbonate clasts. Density variations viewed through CT imaging may show the products of mineral neoformation, mineral packing differences during crystal growth, and/or older, denser petrocalcic materials eroded and incorporated via subsequent recementation (pisoliths). Computed tomography scanning can be used to understand unique forms and processes that are vital to our understanding of dissolution/precipitation and other pedogenic processes at work in these mature petrocalcic soils. We encourage the application of CT imaging to similar soil materials.

Tibial diaphyseal stress fractures are rare in the general population, but are more frequently seen in the athletic and military communities. The diagnosis of this problem may be problematic and needs to be considered in all athletes and military recruits who present with shin or ankle pain. The female triad in athletes (low-energy availability/disordered eating, amenorrhea, and osteoporosis/osteopenia) should be considered in those women who sustain this injury. Management is usually conservative with a variety of rehabilitation programs suggested, but a pragmatic approach is to manage the patient symptomatically.

Ritonavir and cobicistat, used as pharmacokinetic enhancers in combination with some antiretrovirals (ARVs) for the treatment of HIV, are potent inhibitors of the CYP3A4 isoenzyme. Most glucocorticoids are metabolised via the CYP3A4 pathway and iatrogenic Cushing's syndrome (ICS), with possible secondary adrenal insufficiency (SAI), is a recognised complication following co-administration with ritonavir or cobicistat. A structured approach for identifying and managing potentially affected individuals has not been established.We systematically identified patients with ICS/SAI and found substantial heterogeneity in clinical practice across three large London HIV centres. While this significant drug interaction and its complications are now well-recognised, it is apparent that there is no standardised approach to management or guidance for the general physician. Here we describe the management of ICS/SAI in our current practice, review the available evidence and suggest practice recommendations.

Objectives To evaluate dolutegravir and elvitegravir/cobicistat pharmacokinetics in HIV-negative volunteers up to 10 days after drug cessation. Methods Healthy volunteers received 50 mg of dolutegravir once-daily for 10 days, then underwent a 9 day wash-out period, and then received elvitegravir/cobicistat as part of Stribild(®) (245 mg of tenofovir, 200 mg of emtricitabine, 150 mg of elvitegravir and 150 mg of cobicistat) for 10 days. Serial pharmacokinetic (PK) sampling occurred prior to the final dose of each course and at regular intervals for up to 216 h (10 days) after drug cessation. Concentrations were determined by LC-MS/MS, and PK parameters were illustrated as geometric mean and 90% CI. Results Seventeen volunteers completed the study. For dolutegravir, plasma terminal elimination t1/2 to the last measurable concentration (within 216 h) was longer than its t1/2 within the dosing interval (0-24 h): 14.3 h (12.9-15.7 h) versus 23.1 h (19.7-26.6 h); conversely, the terminal elimination t1/2 for elvitegravir was lower than its t1/2 within the dosing interval (0-24 h): 10.8 h (9.7-13.0 h) versus 5.2 h (4.7-6.1 h). Dolutegravir concentrations were above the protein-adjusted (PA) IC90 (64 ng/mL) in 100% of subjects after 36 and 48 h and in 94% after 60 and 72 h. All subjects had detectable dolutegravir concentrations at 96 h, a mean of 23.5% above the IC90. Elvitegravir concentrations were above the PA IC95 (45 ng/mL) in 100% of subjects at 24 h, 65% at 36 h but 0% after 48 h. Conclusions Our data show marked differences in the elimination rates of dolutegravir and elvitegravir following treatment interruption, which is likely to impact the extent to which drug doses can be delayed or missed. They suggest that clinical differences may emerge in patients who have suboptimal adherence.

Dolutegravir and Elvitegravir belongs to a class of integrase inhibitors which has recently been approved by the FDA for the treatment of HIV-infection. Elvitegravir and its co-administered booster drug, Cobicistat, has shown the potential to be a candidate for a one pill once a day regimen and is currently a component of many clinical trials. A sensitive LC-MS/MS method has been developed and validated for the simultaneous determination of these three drugs in human plasma. A liquid- liquid extraction was used as a sample preparation technique using 100μL of plasma. The method was validated from 10 to 4000ng/mL for Dolutegravir, Elvitegravir and Cobicistat. Chromatography was performed on XBridge C18 2.1mm×50mm column, using an 80:20 methanol/water mobile phase containing 0.1% formic acid on a gradient program. This method was successfully applied for ongoing clinical trials.

Older people form the largest group occupying acute hospital beds and many of them will have undiagnosed mental health problems. The creation of a Dementia Nurse Specialist role in a district general hospital provided the opportunity to assess the extent of the previously unmet need among patients, carers and nursing staff. Over 30 patients were seen each month, while around 6 to 12 were diagnosed as having dementia. Other activities undertaken as part of the role included providing information and support for carers, and advice on management of behaviours and support for ward staff. The role also involved policy writing, pathway and local strategy planning, care plan development, and formal and informal teaching on dementia. It is argued that this fixed-term post demonstrated that a Dementia Nurse Specialist could provide significant input in an acute hospital setting, by improving the experience of hospitalization for vulnerable older people and their carers.

Background: The standard treatment for a non-union of the hallux metatarsophalangeal joint fusion has been to revise the fusion. Revision fusion is technically more demanding, often involving bone grafting, more substantial fixation and prolonged period of immobilization postoperatively. We present data to suggest that removal of hardware and debridement alone is an alternative treatment option. Materials and Methods: A case note review identified patients with a symptomatic non-union after hallux metatarsophalangeal joint (MTPJ) fusion. It is our practice to offer these patients revision fusion or removal of hardware and debridement. For the seven patients that chose hardware removal and were left with a pseudarthrosis, a matched control group was selected from patients who had had successful fusions. Three outcome scores were used. Hallux valgus and dorsiflexion angles were recorded. Results: One hundred thirty-nine hallux MTPJ arthrodeses were carried out. Fourteen non-unions were identified. The rate of nonunion in males and following previous hallux MTPJ surgery was 19% and 24%, respectively. In females undergoing a primary MTPJ fusion, the rate was 2.4%. Twelve non-union patients were reviewed at 27 months (mean). Eleven patients had elected to undergo removal of hardware and debridement. Four patients with pseudarthrosis were unhappy with the results and proceeded to either revision fusion or MTPJ replacement. Seven non-union patients, who had removal of hardware alone, had outcome scores marginally worse compared to those with successful fusions. Conclusion: Removal of hardware alone is a reasonable option to offer as a relatively minor procedure following a failed arthrodesis of the first MTPJ. This must be accepted on the proviso that in this study four out of 11 (36%) patients proceeded to a revision first MTPJ fusion or first MTPJ replacement. We also found that the rate of non-union in primary first MTPJ fusion was significantly higher in males and those patients who had undergone previous surgery. Level of Evidence: III, Retrospective Comparative Series

Introduction: We investigated placental transfer and neurobehavioural effects in neonates exposed to citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline (SSRI's), or to venlafaxine (an SNRI). Methods: Women receiving antidepressants during pregnancy and their neonates were studied. Cord and maternal drug concentrations were measured at birth and in the neonates plasma on day 3. Neonates were also assessed using a range of neurobehavioral tests and compared to controls. Results: Median cord/maternal distribution ratio was 0.7-0.86 (range) for SSRIs, 0.72 for the SNRI venlafaxine and 1.08 for the O-desmethyl metabolite. Neonatal abstinence scores were significantly higher (p

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly upregulated in many neuronal tissues after nerve injury or disease. Over the last 10 years we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system. (Part of a Multi-author Review)

Background This prospective study investigates the use of intraoperative fluoroscopy in hallux valgus surgery. To our knowledge there have been no studies questioning the benefit and reliability of intraoperative fluoroscopy in hallux valgus surgery. Methods We performed a prospective investigation of 28 consecutive cases undergoing hallux valgus surgery. Fluoroscopic images were examined intraoperatively and any significant findings documented. A comparison was made between these images and weight bearing films 6 weeks postoperatively to examine their reliability. We excluded those patients that went on to have an Akin osteotomy. Results There were no unforseen intraoperative events that were revealed by the use of fluoroscopy and no surgical modifications were made as a result of the intraoperative images. The intraoperative films were found to be a reliable representation of the postoperative weight bearing films but a small increase in the hallux valgus angle was noted at 6 weeks and this is thought to be due to stretching of the medial soft tissue repair. Conclusions Intraoperative fluoroscopy is a reliable technique. This study was performed at a centre which performs approximately 100 hallux valgus operations per year and that should be taken into consideration when reviewing our findings. We conclude that there may be a role for fluoroscopy for surgeons in the early stages of the surgical learning curve and for those that infrequently perform hallux valgus surgery. We cannot, however, recommend that fluoroscopy be used routinely in hallux valgus surgery.

Objective: Examined the relation of alcohol abuse history to emo- tional adjustment and pressure sore occurrence during the 1st 3 years following Spinal Cord Injury (SCI). Study Design: Comparisons were made between varying levels of prior abuse and depression and disability acceptance. A model predicting pressure sore occurrence over 3 years was computed. Participants: One hundred seventy-five persons completed the self-report measures; 105 were available for pressure sore evaluations. Main Outcome Measures: The Inventory to Diagnose Depression, the Acceptance of Disability Scales, and pressure sore occurrence. Results: Alcohol abuse was not associated with depression or disability acceptance. Severe alcohol abuse history was associated with pressure sores over the 3 years. Conclusions: Persons with prior history of severe alcohol abuse may be at in- creased risk for pressure sore occurrence during the 1st years of SCI. Many persons who sustain severe physical disabilities have a significant history of alcohol and other substance abuse, and alcohol and substance abuse are often related to adjustment following disability (Bombardier, 2000). Alcohol abuse has been associated with impaired self-care activities up to 18 months following the onset of disability (Bombardier & Rimmele, 1998), and a predisability history of substance abuse has been associated with an increased rate of pressure sores 30 months after the onset of spinal cord injury (SCI; Hawkins & Heinemann, 1998). Persons with a significant preinjury alcohol abuse history may be susceptible to pressure sore development even if they abstain from alcohol following their return to the community (Heinemann & Hawkins, 1995). Alcohol abuse has also been associated with higher levels of depression and life stress and with ratings

The cytoplasmic tail of gp41 (gp41CT) remains the last HIV-1 domain with an unknown structure. It plays important roles in HIV-1 replication such as mediating envelope (Env) intracellular trafficking and incorporation into assembling virions, mechanisms of which are poorly understood. Herein, we present the solution structure of gp41CT in a micellar environment and characterize its interaction with the membrane. We show that the N-terminal 45 residues are unstructured and not associated with the membrane. However, the C-terminal 105 residues form three membrane-bound amphipathic a-helices with distinctive structural features such as variable degree of membrane penetration, hydrophobic and basic surfaces, clusters of aromatic residues, and a network of cation-p interactions. This work fills a major gap by providing the structure of the last segment of HIV-1 Env, which will provide insights into the mechanisms of Gag-mediated Env incorporation as well as the overall Env mobility and conformation on the virion surface.

A variety of sociodemographic, physical, and psychosocial variables are linked to depressive behaviour in family caregivers. This study was conducted to determine the best predictors of caregiver depression at onset of the caregiver role among persons providing care to a stroke survivor. The relative contributions of stroke survivor and caregiver sociodemographic characteristics, as well as caregiver general health, physical functioning, social support, life satisfaction, preparedness, and reaction in the prediction of depression status, were examined. A correlational study of 52 primary family caregivers of individuals who had a cerebrovascular accident was conducted. General health and physical functioning scales from the SF-36, and measures of caregiver social support, life satisfaction, preparedness, and reaction were used. Caregiver depression was best predicted by lower life satisfaction, lower physical functioning, and a lack of tangible social support.

Intractable pain out of proportion to the injury sustained is considered to be the earliest and most reliable indicator of a developing compartment syndrome. We report 4 cases where competent sensate patients developed compartment syndromes without any significant pain. The first patient developed a painless compartment syndrome in the well leg following surgery for femoral fracture on the other side. The second patient developed the silent compartment syndrome post-operatively following a tibial nailing for a tibial fracture. The third patient presented with the painless compartment syndrome following a tibial plateau fracture. Our prevailing culture of a high-index of clinical suspicion and surveillance prompted us to perform compartment pressure measurements. The surgical findings at immediate fasciotomy confirmed the diagnoses. Our experience indicates that pain is not a reliable clinical indicator for underlying compartment syndrome, so in a competent sensate patient the absence of pain does not exclude compartment syndrome. We believe that a high index of clinical suspicion must prevail in association with either continuous compartment pressure monitoring or frequent repeated documented clinical examination with a low threshold for pressure measurement.

We performed single-breath wash-in tests for He and SF6 in four subjects exposed to 14 days of microgravity (microG) during the Spacelab flight Spacelab Life Sciences-2. Subjects inspired a vital capacity breath of 5% He-1.25% SF6-balance O2 and then exhaled to residual volume at 0.5l/s. The tests were also performed with a 10-s breath hold at the end of inspiration. Measurements were also made with the subjects standing and supine in 1 G. Phase III slope was measured after the dead-space washout and before the onset of airway closure. In all subjects in 1 G, whether standing or supine, phase III slope for SF6 was significantly steeper than that for He. However, in microG, the slopes became the same. Furthermore, after breath holding in microG, the SF6 slopes were significantly flatter than those for He. On return to 1 G, the changes were reversed, and there was no difference between preflight and postflight values. Because most of the phase III slope reflects events occurring in the acinar regions of the lung, the results suggest that microG causes conformational changes in the acini or changes in cardiogenic mixing in the lung periphery, but in either case the mechanism is unclear.

The most commonly reported technique of reconstructive surgery for congenital pseudarthrosis of the clavicle involves resection of the pseudarthrosis, insertion of autologous iliac crest bone graft and internal fixation. In an attempt to avoid the potential complications of iliac crest bone graft harvest we used bovine cancellous xenograft (Tutobone). Two cases of pseudarthrosis of the clavicle treated with resection of the pseudarthrosis, Tutobone graft and internal fixation are presented. Both cases resulted in treatment failures, which were associated with significant osteolysis and failure of incorporation of the graft material. This required removal of the loose metal work and debridement of the failed graft material. We would caution surgeons against the use of Tutobone as a graft material in the surgical management of pseudarthrosis of the clavicle. The level of evidence was level IV case series.

Background: Bone mineral density (BMD) can predict fracture, however, the common use of historical risk factors to predict low BMD is unproven. Aims: To identify significant historical risk factors for osteopenia. To establish predicting equations for BMD and test their ability to identify those who should be referred for BMD scanning. Methods: Three hundred and twenty female and 131 male volunteers underwent questionnaire assessment of risk factors and BMD by dual photon absorptiometer at hip and spine. Significant risk factors (P < 0.05) were used to construct a linear regression model to predict BMD. This was cross validated on a second sample of 107 females and 131 males selected from the electoral roll analysing the ability to detect those subjects with BMD in the lower third of the age matched normal range. Results: In women lower BMD at the spine was associated with increased age, decreased weight, smoking, and delayed menarche. Lower femoral BMD was associated with increased age, decreased weight, family history, inactivity, and smoking. In men lower BMD at the lumbar spine was associated with lower weight, and inactivity. Lower BMD at the femur was associated with increased age, decreased weight, family history, and low calcium intake. When cross validated on the second sample, the models produced sensitivity of 86–89% and sensitivity of 25–46%. Referring those with these risk factors could save 10–23% on scanning. Measuring BMD at the site in question remains the only accurate way of assessing an individual's risk of osteopenia. (Aust NZ J Med 1993; 23: 458–462.)

Level of Evidence: V, Expert Opinion

The neuropeptide galanin is widely, but not ubiquitously, expressed in the adult nervous system. Its expression is markedly up-regulated in many neuronal tissues after nerve injury or disease. Over the last 10 years, we have demonstrated that the peptide plays a developmental survival role to subsets of neurons in the peripheral and central nervous systems with resulting phenotypic changes in neuropathic pain and cognition. Galanin also appears to play a trophic role to adult sensory neurons following injury, via activation of GalR2, by stimulating neurite outgrowth. Furthermore, galanin also plays a neuroprotective role to the hippocampus following excitotoxic injury, again mediated by activation of GalR2. Most recently, we have shown that galanin expression is markedly up-regulated in multiple sclerosis (MS) lesions and in the experimental autoimmune encephalomyelitis (EAE) model of MS. Over-expression of galanin in transgenic mice abolishes disease in the EAE model, whilst loss-of-function mutations in galanin or GalR2 increase disease severity. In summary, these studies demonstrate that a GalR2 agonist might have clinical utility in a variety of human diseases that affect the nervous system.

Spurious readings from a mass spectrometer have been reported following the administration of aerosol bronchodilators. We quantified the response of various respiratory gas analyzers to the aerosol propellant of albuterol inhalant (Proventil). The mass spectrometer systems tested, two Advantage systems, a SARA system, and a Model 6000 Ohmeda system, all displayed artifactual readings in response to the albuterol propellant. Each metered dose of the Proventil brand of albuterol contains 4 ml of Freon 11 (trichloromonofluoromethane) and 11 ml of Freon 12 (dichlorodifluoromethane). The concentration of propellant was expressed in doses/L, where each liter of gas contains 0.4 vol % of Freon 11 and 1.1 vol % of Freon 12 per dose. In proportion to the concentration of albuterol propellant, the two Advantage systems showed substantial readings of isoflurane (%) when no isoflurane was present (13% and 16% per dose/L) and reduced readings of enflurane (-8% and -10% per dose/L) and carbon dioxide (CO2) (-3 and +5 mm Hg per dose/L). The SARA system showed substantial CO2 readings when no CO2 was present (5 mm Hg per dose/L) and displayed small enflurane readings (0.1% per dose/L) when no enflurane was present. The Model 6000 unit showed CO2 readings when no CO2 was present (5 mm Hg per dose/L). Neither the Raman spectrometer, the infrared spectrometers, nor the piezoadsorptive analyzer we tested showed an artifactual effect of albuterol propellant on any of its readings. Simulation and clinical tests demonstrated that a single dose of albuterol propellant into a breathing circuit at the onset of inspiration resulted in concentrations of 0.8 and 0.3 dose/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

The testis has been shown to be a privileged site for transplantation of allogenic islets in rodents, and the testicular cell aggregates are thought to confer this immunologic privilege. Recently, a group in Mexico reported transplantation of cocultured neonatal porcine islets and Sertoli cells resulting in insulin independence in nonimmunosuppressed type 1 diabetes patients. We have transplanted similar islets alone (naked islets) or cocultured islets with Sertoli cells (islet/Sertoli cells) into an omental site and other locations of nonimmunosuppressed, streptozotocin-induced diabetic male Sprague Dawley (SD) rats. Histologic examination showed viable neonatal porcine islets survived in xenografted rodents for at least 2 days, and some glucagon and inhibin stained cells appear to have survived for 4 days posttransplantation. However, histological examination did not demonstrate any difference in xenograft survival in the islets/Sertoli cells mixture compared to naked islets when transplanted into these nonimmunosuppressed diabetic rats.

Digital X-ray radiogrammetry (DXR) is a technique to estimate bone mineral density (BMD) that can be available in any area able to take a standard radiograph of the hand. We aimed to establish the precision of this technique and compare this with that obtained by dual energy X-ray absorptiometry (DXA) at the hip and spine. We compared DXA and DXR in 28 women with osteoporosis defined by DXA at the femoral neck and in 28 women with normal BMD. We found that DXR has excellent precision of 0.004 g/cm 2 compared with 0.021 g/cm 2 and 0.015 g/cm 2 obtained by DXA at the hip and spine, respectively. We conclude that DXR measured by the automated Pronosco system has excellent precision.

Purpose The purpose of our study was to assess the diagnostic accuracy and reliability of contrast enhanced MR lung perfusion compared to perfusion scintigraphy in patients with CTEPH. Methods and Materials Retrospective analysis of patients investigated for CTEPH who had MR lung perfusion, perfusion scintigraphy and CTPA performed within a time interval of 5 days. The MR images were acquired using a time resolved 3D spoiled gradient echo sequence. The sequence parameters: TE 1.1 ms, TR 2.5 ms, flip angle of 30°, FOV=48 cm 2 , slice thickness of 5 mm, average of 32 slices and frame rate was 2 acquisitions per second. This was a breathhold sequence obtained after 0.05 ml/kg of Gadovist injection at 5 ml/s followed by a 20 ml saline flush. The subtraction images and positive enhancement dataset were analysed in the coronal plane. Four static views perfusion scintigraphy views were obtained. Final diagnosis of CTEPH or non-CTEPH was made at a multidisciplinary meeting following detailed multi-modality assessment. Results 27 patients had a diagnosis of CTEPH and 55 patients were diagnosed as non-CTEPH. In the CTEPH group, MRI lung perfusion diagnosed 26 patients as CTEPH and 1 patient with distal surgically inaccessible disease as non-CTEPH. In the non-CTEPH group, four patients were diagnosed as CTEPH and 48 patients were identified as non-CTEPH and three MRI were considered non-diagnostic. MR lung perfusion was not performed in 11 patients due to impaired renal function or patient unable to tolerate breathhold. None of the surgically accessible disease was missed with either modality. The MR lung perfusion had a sensitivity of 96%, specificity of 92%, PPV of 87%, NPV of 98% and accuracy of 94% for diagnosing CTEPH. Perfusion scintigraphy had a sensitivity of 93%, specificity of 90%, PPV of 83%, NPV of 96% and accuracy of 91%. Conclusion Our results show that MR lung perfusion compared to 4-view static perfusion scintigraphy has an overall higher accuracy compared to perfusion scintigraphy and has a role in assessment of patients with suspected CTEPH.

A Mexican group reported transplantation of cocultured neonatal porcine islets and Sertoli cells resulting in insulin independence in nonimmunosuppressed type 1 diabetes patients. We have transplanted similar islets alone (naked islets) or cocultured islets with sertoli cells (islet/sertoli cells) into an omental site and other locations of seven nondiabetic, nonimmunosuppressed, nonhuman primates. Porcine endogenous retrovirus was not detected in recipient blood 8 weeks after porcine islet grafts, and porcine C-peptide was detected at a very low level in all animals. Histology examination failed to demonstrate obviously recognizable islets, but in the animals transplanted with islet/Sertoli cells at the omentum site, there were some surviving glucagons, pan-cytokeratin, and inhibin stained cells at 8 weeks.