Volumetric Analysis: Effect on Diagnosis and Management of Indeterminate Solid Pulmonary Nodules in Routine Clinical Practice.

OBJECTIVE: To evaluate the effect of volumetric analysis on the diagnosis and management of indeterminate solid pulmonary nodules in routine clinical practice. METHODS: This was a retrospective study with 107 computed tomography (CT) cases of solid pulmonary nodules (range, 6-15 mm), 57 pathology-proven malignancies (lung cancer, n = 34; metastasis, n = 23), and 50 benign nodules. Nodules were evaluated on a total of 309 CT scans (average number of CTs/nodule, 2.9 [range, 2-7]). CT scans were from multiple institutions with variable technique. Nine radiologists (attendings, n = 3; fellows, n = 3; residents, n = 3) were asked their level of suspicion for malignancy (low/moderate or high) and management recommendation (no follow-up, CT follow-up, or care escalation) for baseline and follow-up studies first without and then with volumetric analysis data. Effect of volumetry on diagnosis and management was assessed by generalized linear and logistic regression models. RESULTS: Volumetric analysis improved sensitivity (P = 0.009) and allowed earlier recognition (P < 0.05) of malignant nodules. Attending radiologists showed higher sensitivity in recognition of malignant nodules (P = 0.03) and recommendation of care escalation (P < 0.001) compared with trainees. Volumetric analysis altered management of high suspicion nodules only in the fellow group (P = 0.008). κ Statistics for suspicion for malignancy and recommended management were fair to substantial (0.38-0.66) and fair to moderate (0.33-0.50). Volumetric analysis improved interobserver variability for identification of nodule malignancy from 0.52 to 0.66 (P = 0.004) only on the second follow-up study. CONCLUSIONS: Volumetric analysis of indeterminate solid pulmonary nodules in routine clinical practice can result in improved sensitivity and earlier identification of malignant nodules. The effect of volumetric analysis on management recommendations is variable and influenced by reader experience.

The dynamic duo: A narrative review on the synergy between stereotactic body radiotherapy and immunotherapy in lung cancer treatment (Review).

Immunotherapy, particularly immune checkpoint inhibitors (ICIs), is undoubtedly one of the major breakthroughs in lung cancer research. Patient survival and prognosis have all been improved as a result, although numerous patients do not respond to immunotherapy due to various immune escape mechanisms of the tumor cells. Recent preclinical and clinical evidence has shown that stereotactic body radiotherapy (SBRT), also known as stereotactic ablative radiotherapy, has a prominent immune priming effect that could elicit antitumor immunity against specific tumor antigens and destroy distant tumor cells, thereby achieving the elusive abscopal effect, with the resulting immuno­active tumor environment also being more conducive to ICIs. Some landmark trials have already demonstrated the survival benefit of the dynamic duo of SBRT plus immunotherapy in metastatic non­small­cell lung cancer, while others such as PEMBRO­RT further suggest that the addition of SBRT to immunotherapy could expand the current indication to those who have historically responded poorly to ICIs. In the present review, the biological mechanisms that drive the synergistic effect of SBRT and immunotherapy were first briefly outlined; then, the current understanding from clinical trials was summarized and new insight into the evolving role of immunotherapy and SBRT synergy in lung cancer treatment was provided. Finally, novel avenues for discovery were highlighted. The innovation of the present review lies in the inclusion of non­ICI immunotherapy in the discussion, which provides a more comprehensive view on the current development and future trend of SBRT + immunotherapy synergy.

Orbital Vascular Malformations: Relationship Between Enophthalmos and Clinically Apparent Distensibility with Valsalva.

PURPOSE: Determining the hemodynamic characteristics of an orbital vascular malformation is a critical step in management. The purpose of this study is to assess the relationship between enophthalmos and clinically apparent distensibility of orbital vascular malformations, to optimize imaging and treatment. METHODS: In this cross-sectional cohort study consecutive patients at a single institution were screened for study entry. Data extracted included age, sex, Hertel measurements, presence or absence of distensibility during the Valsalva maneuver, whether lesions were primarily venous or lymphatic based on imaging, and location of the lesion relative to the globe. Enophthalmos was defined as ≥ 2 mm difference from the opposite side. Parametric and nonparametric statistics were used, and linear regression was performed to examine factors predictive of Hertel measurement. RESULTS: Twenty-nine patients met the inclusion criteria. Relative enophthalmos ≥2 mm was significantly associated with distensibility ( p = 0.03; odds ratio = 5.33). Distensibility and venous dominant morphology were the 2 most important factors associated with enophthalmos on regression analysis. The relative position of the lesion anterior or posterior to the globe did not have a significant bearing on baseline enophthalmos. CONCLUSIONS: The presence of enophthalmos increases the likelihood that an orbital vascular malformation is distensible. This group of patients was also more likely to be characterized by venous dominant malformations. Baseline clinical enophthalmos may serve as a useful surrogate marker for distensibility and venous dominance, which may be useful in guiding the selection of appropriate imaging.

Vision-dependent specification of cell types and function in the developing cortex.

The role of postnatal experience in sculpting cortical circuitry, while long appreciated, is poorly understood at the level of cell types. We explore this in the mouse primary visual cortex (V1) using single-nucleus RNA sequencing, visual deprivation, genetics, and functional imaging. We find that vision selectively drives the specification of glutamatergic cell types in upper layers (L) (L2/3/4), while deeper-layer glutamatergic, GABAergic, and non-neuronal cell types are established prior to eye opening. L2/3 cell types form an experience-dependent spatial continuum defined by the graded expression of ∼200 genes, including regulators of cell adhesion and synapse formation. One of these genes, Igsf9b, a vision-dependent gene encoding an inhibitory synaptic cell adhesion molecule, is required for the normal development of binocular responses in L2/3. In summary, vision preferentially regulates the development of upper-layer glutamatergic cell types through the regulation of cell-type-specific gene expression programs.

Case report and literature review: Conversion surgery for initially unresectable huge retroperitoneal liposarcoma after preoperative radiotherapy.

Background: Retroperitoneal liposarcoma (RPLS) is a rare malignancy that is notorious for recurrence. Surgical resection with clean margin is the current treatment of choice. However, owing to the large retroperitoneal space, RPLSs often grow to significant sizes before being diagnosed. Neoadjuvant and adjuvant therapies have potentials to improve long term treatment outcome. Case presentation: A 55-year-old Han Chinese male presented to the general surgery department with a one-year history of abdominal fullness and a one-week history of palpable right inguinal mass. At first, he was diagnosed with incarcerated inguinal hernia. However, abdominal computer tomography (CT) and biopsy confirmed his final diagnosis to be retroperitoneal well-differentiated liposarcoma, cT2bN0M0, stage IIb. The tumor, which measured 44.5cm in maximum diameter, was too large for primary surgical resection. Neoadjuvant radiotherapy with 70 Gy in 35 fractions was delivered to the tumor, which shrunk the target volume from 6300 cc to 4800 cc, as observed in the middle of the radiotherapy course. The right testicular mass also received 70Gy/35Fx. Conversion surgery was performed after radiotherapy. Unfortunately, due to residual tumor, adjuvant chemotherapy consisting of AIM (ifosfamide, Mesna, and doxorubicin) and MAID (Mesna, doxorubincin, ifosfamide, and dacarbazine) regimens were administered sequentially. Afterward, debulking surgery was conducted, plus another 18 cycles of ifosfamide monotherapy when residual tumor was still seen on CT. Since the completion of ifosfamide chemotherapy, the patient has been cancer free with no evidence of tumor recurrence for more than 26 months. Conclusion: Despite conflicting evidence in the literature, our case supports the use of high dose neoadjuvant radiotherapy and adjuvant chemotherapy in treating large, unresectable RPLSs. It also highlights the importance of using individualized, multidisciplinary approach in achieving cure for large, unresectable rare tumors.

Evaluating the optimization of the use of sedating antihistamines in a community pharmacy: a retrospective quality improvement study in Singapore.

OBJECTIVES: This study aimed to retrospectively assess whether community pharmacy customers accepted the pharmacist's recommendations for the selection of an antihistamine based on medicine optimization guidelines. METHODS: A retrospective study was conducted on the implementation of an antihistamine use optimization guide for patients who were seeking first-generation antihistamines between July and December 2019 across forty-five community pharmacies in Singapore. The primary outcome measure was the acceptance rate of ceasing or substituting first-generation antihistamine with a second-generation antihistamine. Secondary measures included the reduction in types of first-generation antihistamines used, adverse drug-related events reported, intended use of antihistamines and the types of recommendations. KEY FINDINGS: During the study period, 2328 patients fulfilled the inclusion criteria, out of which 523 patients agreed to optimize their use of sedating first-generation antihistamines. Chlorpheniramine (95.2%) was the most widely accepted first-generation antihistamine for optimization, with 59.6% of the users experiencing adverse events, the most common being drowsiness (53.2%). The main indication of use was allergic conditions (allergic rhinitis or atopic dermatitis) (70.3%). After implementation of the guide, most interventions were direct substitution (72.8%) with a less-sedating antihistamine, followed by gradual tapering (22.6%). Loratadine, a second-generation antihistamine, was most frequently (51.4%) used to substitute first-generation antihistamines. The optimization guide can potentially reduce adverse effects in 59.6% (297 patients) of chlorpheniramine users, which were mainly drowsiness (265 patients; 53.2%) and dry mouth (14 patients; 2.8%). CONCLUSIONS: This study highlighted the importance of assessing and reducing potentially inappropriate first-generation antihistamine self-use and that a guided approach and substitution with less-sedating antihistamines can be employed in the community pharmacy setting.

Using Online Survey Software to Enhance Radiology Learning.

RATIONALE AND OBJECTIVES: Online educational modules can augment radiology learning by creating opportunities to interact with images in more dynamic ways than with static presentation of images in lectures or journal articles. Building these modules on an online survey platform allows for quantitative assessment and learner feedback, without requiring programming knowledge or need for new website creation. MATERIALS AND METHODS: Interactive online tutorials were built on a web-based survey platform (Qualtrics, Provo, Utah) accessible by computer or mobile device to teach radiology imaging findings of selected high-morbidity diagnoses. Topics included congenital-type internal hernias (module 1), acute appendicitis in the pregnant patient (module 2), and unintentionally retained surgical instruments (RSI; module 3). Modules consisted of pretest, educational module, and post-test components. For modules 1 and 2, graphics interchange formats were utilized to show CT and MRI image stacks for the diagnosis of congenital-type internal hernias and acute appendicitis in pregnant patients, respectively. For module 3, the "Heat Map" format was chosen to showcase intraoperative radiograph cases, which allowed participants to click on the potential RSI in the image. Pre- and post-test scores were evaluated. To determine statistical significance, an alpha level of 0.05 was utilized. RESULTS: Module 1 (Internal Hernia): Twenty-one radiology trainees completed the module. The mean pretest score was 3.66 (±1.13) points out of a total 6 possible points (61%), compared to 4.52 (±1.03) points on the post-test (75%). This was a statistically significant increase on the post-test of 0.87 points (95% CI [confidence interval] 0.36, 1.38), t(20) = 3.53, p= 0.002. Module 2 (MR Appendicitis): Seventeen radiology trainees completed the module. The mean pretest score was 3.18 (±1.42) points out of a total 6 possible points (53%), compared to 5.12 (±0.86) points on the post-test (85%). This was a statistically significant increase on the post-test of 1.94 points (95% CI 1.12, 2.76), t(16) = 5.00, p< 0.001. Module 3 (RSI): One hundred seven participants completed the module. The mean pretest score was 3.60 (±1.53) points out of a total 6 possible points (60%), compared to 4.54 (±1.36) points on the post-test (76%). This was a statistically significant increase on the post-test of 0.94 points (95% CI 0.67, 1.21), t(106) = 6.84, p< 0.001. CONCLUSION: An online survey platform can be used to build interactive education modules. Post-test scores significantly improved from pretest scores with these educational modules.

Noninvasive detection of microaneurysms in diabetic retinopathy by swept-source optical coherence tomography.

BACKGROUND AND OBJECTIVES: A method of identifying retinal vascular microaneurysms (MAs) in nonproliferative diabetic retinopathy (NPDR) using swept-source optical coherence tomography (SS-OCT). PATIENTS AND METHODS: SS-OCT images were acquired in 17 eyes with NPDR using prototype SS-OCT device and fluorescein angiography (FA) images were obtained simultaneously. MAs identified on SS-OCT slabs were correlated to MAs identified on FA. RESULTS: MAs were identified in SS-OCT slabs in 15/17 eyes, resulting in NPDR diagnosis rate of 88%. Mean number of MAs identified on FA was 11.7±11.9 (total 199) and was 8.1±9.3 (total 137) on SS-OCT. Wilcoxon rank sum test showed no significant difference in MAs detected on SS-OCT and FA (P=0.2995) across eyes. Wilcoxon rank sum test showed SS-OCT detected slightly fewer MAs than FA per eye (3.65 less, P=0.0009). CONCLUSION: SS-OCT visualization of MAs could serve as a tool for diagnosing NPDR, and possibly applied as an imaging biomarker for population-based diabetic retinopathy screening.

Correlating the Sonographic Finding of Echogenic Debris in the Bladder Lumen With Urinalysis.

OBJECTIVES: The purpose of this study was to determine the significance of urinary bladder debris detected by sonography. METHODS: We conducted a retrospective analysis of urinalysis results in age-matched patients with and without bladder debris detected by transabdominal sonography. Patients were recruited from a radiology database search for bladder sonograms either with words suggesting echogenic debris or by a clinical history suggesting an infectious course. The sonograms were randomized and read by a single radiologist, who was blinded to case versus control. The urinalysis and sonographic results were analyzed by the Fisher exact test. RESULTS: There was no statistically significant correlation between the finding of debris on sonography and the frequency of abnormal urinalysis results, regardless of the quality of debris (layering versus floating). The only variable that was significantly associated with abnormal urinalysis results was a clinical history suggesting infection. CONCLUSIONS: A urinalysis should not be routinely recommended to work up the finding of urinary bladder debris on sonography.

Factors Associated With Poor Response to Aflibercept After Switching From Ranibizumab or Bevacizumab in Neovascular Age-related Macular Degeneration.

BACKGROUND AND OBJECTIVE: The purpose of this study was to analyze demographic and ocular features of patients with age-related macular degeneration who failed aflibercept (Eylea; Regeneron, Tarrytown, NY) treatment after switching from ranibizumab (Lucentis; Genentech, South San Francisco, CA) or bevacizumab (Avastin; Genentech, South San Francisco, CA). PATIENTS AND METHODS: Retrospective chart review of patients treated with aflibercept at the Byers Eye Institute from November 2011 to August 2014. Patient visual acuity was noted prior to aflibercept; after 1, 3, and 12 months; and on the most recent visit. Patients who improved vision after switching were compared to patients who lost vision. Demographic and imaging features were analyzed using univariate and multivariate statistics. RESULTS: Patients who lost vision had significantly higher BMI (P = .013, multivariate) and geographic atrophy (P = .0381, univariate; P = .1, multivariate) compared to patients who improved vision. CONCLUSION: BMI and geographic atrophy may be considered as potential indicators for poor response to aflibercept after switching from ranibizumab or bevacizumab. [Ophthalmic Surg Lasers Imaging Retina. 2016;47:458-465.].

The Action Research Program: Experiential Learning in Systems-Based Practice for First-Year Medical Students.

PROBLEM: Systems-based practice focuses on the organization, financing, and delivery of medical services. The American Association of Medical Colleges has recommended that systems-based practice be incorporated into medical schools' curricula. However, experiential learning in systems-based practice, including practical strategies to improve the quality and efficiency of clinical care, is often absent from or inconsistently included in medical education. INTERVENTION: A multidisciplinary clinician and nonclinician faculty team partnered with a cardiology outpatient clinic to design a 9-month clerkship for 1st-year medical students focused on systems-based practice, delivery of clinical care, and strategies to improve the quality and efficiency of clinical operations. The clerkship was called the Action Research Program. In 2013-2014, 8 trainees participated in educational seminars, research activities, and 9-week clinic rotations. A qualitative process and outcome evaluation drew on interviews with students, clinic staff, and supervising physicians, as well as students' detailed field notes. CONTEXT: The Action Research Program was developed and implemented at the University of California, San Francisco, an academic medical center in the United States. All educational activities took place at the university's medical school and at the medical center's cardiology outpatient clinic. OUTCOME: Students reported and demonstrated increased understanding of how care delivery systems work, improved clinical skills, growing confidence in interactions with patients, and appreciation for patients' experiences. Clinicians reported increased efficiency at the clinic level and improved performance and job satisfaction among medical assistants as a result of their unprecedented mentoring role with students. Some clinicians felt burdened when students shadowed them and asked questions during interactions with patients. Most student-led improvement projects were not fully implemented. LESSONS LEARNED: The Action Research Program is a small pilot project that demonstrates an innovative pairing of experiential and didactic training in systems-based practice. Lessons learned include the need for dedicated time and faculty support for students' improvement projects, which were the least successful aspect of the program. We recommend that future projects aiming to combine clinical training and quality improvement projects designate distinct blocks of time for trainees to pursue each of these activities independently. In 2014-2015, the University of California, San Francisco School of Medicine incorporated key features of the Action Research Program into the standard curriculum, with plans to build upon this foundation in future curricular innovations.

PROSPECTIVE TRIAL OF ENDOGENOUS FUNGAL ENDOPHTHALMITIS AND CHORIORETINITIS RATES, CLINICAL COURSE, AND OUTCOMES IN PATIENTS WITH FUNGEMIA.

PURPOSE: Former studies have found rates of endogenous endophthalmitis ranging from 0% to 37% in patients with fungemia. This study sought to prospectively determine the rate and risk factors for endogenous chorioretinitis and endophthalmitis in patients with fungemia. METHODS: A prospective cohort study was performed of consecutive adult inpatients at a single site from 2010 to 2013 of patients with positive blood cultures for fungus. One hundred and nineteen pieces of information were gathered for each patient. RESULTS: A total of 125 patients were enrolled in the study with 7 positive cases of chorioretinitis for a rate of 5.6%. Of these positive cases, 2 patients had endophthalmitis for a rate of 1.6%. Two patients who had a negative initial examination subsequently had a positive examination; 57% of the chorioretinitis patients who could report symptoms were asymptomatic, 57% of the chorioretinitis patients died, and 32% of negative cases died. Prolonged hospitalization, altered mental status, total parenteral nutrition, and gastrointestinal surgery were protective on univariate but not multivariate analysis. CONCLUSION: Despite modern antifungal therapy, fungal chorioretinitis and endophthalmitis continue to occur in patients with positive fungal cultures. Two dilated ophthalmic examinations should still be considered even in asymptomatic patients with fungemia.

Developmental Sculpting of Intracortical Circuits by MHC Class I H2-Db and H2-Kb.

Synapse pruning is an activity-regulated process needed for proper circuit sculpting in the developing brain. Major histocompatibility class I (MHCI) molecules are regulated by activity, but little is known about their role in the development of connectivity in cortex. Here we show that protein for 2 MHCI molecules H2-Kb and H2-Db is associated with synapses in the visual cortex. Pyramidal neurons in mice lacking H2-Kb and H2-Db (KbDb KO) have more extensive cortical connectivity than normal. Modified rabies virus tracing was used to monitor the extent of pyramidal cell connectivity: Horizontal connectivity is greater in the visual cortex of KbDb KO mice. Basal dendrites of L2/3 pyramids, where many horizontal connections terminate, are more highly branched and have elevated spine density in the KO. Furthermore, the density of axonal boutons is elevated within L2/3 of mutant mice. These increases are accompanied by elevated miniature excitatory postsynaptic current frequency, consistent with an increase in functional synapses. This functional and anatomical increase in intracortical connectivity is also associated with enhanced ocular dominance plasticity that persists into adulthood. Thus, these MHCI proteins regulate sculpting of local cortical circuits and in their absence, the excess connectivity can function as a substrate for cortical plasticity throughout life.

Electron cryotomography studies of maturing HIV-1 particles reveal the assembly pathway of the viral core.

UNLABELLED: To better characterize the assembly of the HIV-1 core, we have used electron cryotomography (ECT) to image infected cells and the viral particles cryopreserved next to them. We observed progressive stages of virus assembly and egress, including flower-like flat Gag lattice assemblies, hemispherical budding profiles, and virus buds linked to the plasma membrane via a thin membrane neck. The population of budded viral particles contains immature, maturation-intermediate, and mature core morphologies. Structural characteristics of the maturation intermediates suggest that the core assembly pathway involves the formation of a CA sheet that associates with the condensed ribonucleoprotein (RNP) complex. Our analysis also reveals a correlation between RNP localization within the viral particle and the formation of conical cores, suggesting that the RNP helps drive conical core assembly. Our findings support an assembly pathway for the HIV-1 core that begins with a small CA sheet that associates with the RNP to form the core base, followed by polymerization of the CA sheet along one side of the conical core toward the tip, and then closure around the body of the cone. IMPORTANCE: During HIV-1 assembly and release, the Gag polyprotein is organized into a signature hexagonal lattice, termed the immature lattice. To become infectious, the newly budded virus must disassemble the immature lattice by proteolyzing Gag and then reassemble the key proteolytic product, the structural protein p24 (CA), into a distinct, mature hexagonal lattice during a process termed maturation. The mature HIV-1 virus contains a conical capsid that encloses the condensed viral genome at its wide base. Mutations or small molecules that interfere with viral maturation also disrupt viral infectivity. Little is known about the assembly pathway that results in the conical core and genome encapsidation. Here, we have used electron cryotomography to structurally characterize HIV-1 particles that are actively maturing. Based on the morphologies of core assembly intermediates, we propose that CA forms a sheet-like structure that associates with the condensed viral genome to produce the mature infectious conical core.

Synapse elimination and learning rules co-regulated by MHC class I H2-Db.

The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons.

Structure and expression of propanediol utilization microcompartments in Acetonema longum.

Numerous bacteria assemble proteinaceous microcompartments to isolate certain biochemical reactions within the cytoplasm. The assembly, structure, contents, and functions of these microcompartments are active areas of research. Here we show that the Gram-negative sporulating bacterium Acetonema longum synthesizes propanediol utilization (PDU) microcompartments when starved or grown on 1,2-propanediol (1,2-PD) or rhamnose. Electron cryotomography of intact cells revealed that PDU microcompartments are highly irregular in shape and size, similar to purified PDU microcompartments from Salmonella enterica serovar Typhimurium LT2 that were imaged previously. Homology searches identified a 20-gene operon in A. longum that contains most of the structural, enzymatic, and regulatory genes thought to be involved in PDU microcompartment assembly and function. Transcriptional data on PduU and PduC, which are major structural and enzymatic proteins, respectively, as well as imaging, indicate that PDU microcompartment synthesis is induced within 24 h of growth on 1,2-PD and after 48 h of growth on rhamnose.

Relationship between retinal nerve fiber layer thickness and driving ability in patients with human immunodeficiency virus infection.

BACKGROUND: The aim of this work is to study the possible association between retinal nerve fiber layer (NFL) thickness and driving ability. METHODS: Thirty-eight drivers including 22 HIV-positive (HIV+) and 16 age-matched HIV-negative controls participants underwent a full ophthalmologic evaluation, including assessment of retinal NFL thickness. In the undilated state with standard optical correction and under standard illumination they also completed a computer-based, wide field-of-view driving simulation in which they were to obey traffic laws, engage in crash avoidance, and pass slower automobiles. Crashes, speeding and traffic light tickets, and off-road excursions contributed to a weighted score of driving errors. RESULTS: HIV-seropositive participants had a significantly higher weighted error score than control participants (18.4 [9.2] vs. 11.1 [4.5], p = 0.006). NFL thickness was significantly correlated with driving errors (r = -0.51, p = 0.025); there was a trend for participants with a CD4 nadir <100 to have more errors than those with a nadir >100 (29.7 [13.2] vs. 19.3 [8.4], p = 0.056). The highest number of driving errors occurred in individuals with both CD4 <100 and NFL thickness <80. CONCLUSIONS: Driving ability may be impacted by reductions in retinal nerve fiber layer thickness. Physicians should consider the potential impact that more complex ophthalmologic conditions in HIV-infected patients may have on driving performance.

Sequence motifs and antimotifs in beta-barrel membrane proteins from a genome-wide analysis: the Ala-Tyr dichotomy and chaperone binding motifs.

Beta-barrel membrane proteins are found in the outer membrane of gram-negative bacteria, mitochondria, and chloroplasts. Although sequence motifs have been studied in alpha-helical membrane proteins and have been shown to play important roles in their assembly, it is not clear whether over-represented motifs and under-represented anti-motifs exist in beta-barrel membrane proteins. We have developed probabilistic models to identify sequence motifs of residue pairs on the same strand separated by an arbitrary number of residues. A rigorous statistical model is essential for this study because of the difficulty associated with the short length of the strands and the small amount of structural data. By comparing to the null model of exhaustive permutation of residues within the same beta-strand, propensity values of sequence patterns of two residues and p-values measuring statistical significance are calculated exactly by several analytical formulae we have developed or by enumeration. We find that there are characteristic sequence motifs and antimotifs in transmembrane (TM) beta-strands. The amino acid Tyr plays an important role in several such motifs. We find a general dichotomy consisting of favorable Aliphatic-Tyr sequence motifs and unfavorable Tyr-Aliphatic antimotifs. Tyr is also part of a terminal motif, YxF, which is likely to be important for chaperone binding. Our results also suggest several experiments that can help to elucidate the mechanisms of in vitro and in vivo folding of beta-barrel membrane proteins.