Combinatorial assembly and design of enzymes.

The design of structurally diverse enzymes is constrained by long-range interactions that are necessary for accurate folding. We introduce an atomistic and machine learning strategy for the combinatorial assembly and design of enzymes (CADENZ) to design fragments that combine with one another to generate diverse, low-energy structures with stable catalytic constellations. We applied CADENZ to endoxylanases and used activity-based protein profiling to recover thousands of structurally diverse enzymes. Functional designs exhibit high active-site preorganization and more stable and compact packing outside the active site. Implementing these lessons into CADENZ led to a 10-fold improved hit rate and more than 10,000 recovered enzymes. This design-test-learn loop can be applied, in principle, to any modular protein family, yielding huge diversity and general lessons on protein design principles.

Addressing high cervical cancer rates in the Rio Grande Valley along the Texas-Mexico border: a community-based initiative focused on education, patient navigation, and medical provider training/telementoring.

AIMS: Cervical cancer incidence and mortality rates are approximately 55% higher in the Rio Grande Valley (RGV) along the Texas-Mexico border compared with the average rates in the US. Our aim was to improve cervical cancer prevention efforts in the RGV through a comprehensive multilevel intervention initiative focused on community education, patient navigation, and training of local providers. METHODS: We initiated a program in the RGV which consisted of (1) community education, (2) patient navigation, and (3) a training/mentoring program for local medical providers including hands-on training courses coupled with telementoring using Project ECHO® (Extension for Community Health Outcomes). We assessed the number of women undergoing cervical cancer screening, diagnosis, and treatment at three participating clinics caring for underserved women in the region. RESULTS: From November 2014 to October 2018, 14,846 women underwent cervical cancer screening. A total of 2030 (13.7%) women underwent colposcopy for abnormal results (179% increase over baseline) and 453 women underwent loop electrosurgical excision procedures (LEEPs) for treatment of cervical dysplasia. Invasive cancer was diagnosed in 39 women who were navigated to a gynecologic oncologist for treatment. Seven local medical providers were trained to perform colposcopy and/or LEEP. Project ECHO telementoring videoconferences were held every 2 weeks for a total 101 sessions with an average of 22 participants per session and a total of 180 patient cases presented and discussed. CONCLUSIONS: Our program led to a large number of women undergoing diagnosis and treatment of cervical dysplasia in the RGV. If sustained, we anticipate these efforts will decrease cervical cancer rates in the region. The program is currently being expanded to additional underserved areas of Texas and globally to low- and middle-income countries.

[Continuous intraoperative neuromonitoring (cIONM) in head and neck surgery-a review. German version]. / Kontinuierliches intraoperatives Neuromonitoring (cIONM) in der Kopf-Hals-Chirurgie ­ eine Übersicht.

Although the history of intraoperative neuromonitoring (IONM) dates back to the 19th century, the method did not evolve further than the mere differentiation of nerves until recently. Only the development of continuous IONM (cIONM) has allowed for non-stop analysis of excitation amplitude and latency during surgical procedures, which is nowadays integrated into the software of almost all commercially available neuromonitoring devices. The objective of cIONM is real-time monitoring of nerve status in order to recognize and prevent impending nerve injury and predict postoperative nerve function. Despite some drawbacks such as false-positive/negative alarms, technical artefacts, and rare adverse effects, cIONM remains a good instrument which is still under development. Active (acIONM) and passive (pcIONM) methods of cIONM are described in literature. The main fields of cIONM implementation are currently thyroid surgery (in which the vagal nerve is continuously stimulated) and surgery to the cerebellopontine angle (in which the facial nerve is either continuously stimulated or the discharge signal of the nerve is analyzed via pcIONM). In the latter surgery, continuous monitoring of the cochlear nerve is also established.

Continuous intraoperative neuromonitoring (cIONM) in head and neck surgery-a review.

Although the history of intraoperative neuromonitoring (IONM) dates back to the 19th century, the method did not evolve further than the mere differentiation of nerves until recently. Only the development of continuous IONM (cIONM) has allowed for non-stop analysis of excitation amplitude and latency during surgical procedures, which is nowadays integrated into the software of almost all commercially available neuromonitoring devices. The objective of cIONM is real-time monitoring of nerve status in order to recognize and prevent impending nerve injury and predict postoperative nerve function. Despite some drawbacks such as false-positive/negative alarms, technical artefacts, and rare adverse effects, cIONM remains a good instrument which is still under development. Active (acIONM) and passive (pcIONM) methods of cIONM are described in literature. The main fields of cIONM implementation are currently thyroid surgery (in which the vagal nerve is continuously stimulated) and surgery to the cerebellopontine angle (in which the facial nerve is either continuously stimulated or the discharge signal of the nerve is analyzed via pcIONM). In the latter surgery, continuous monitoring of the cochlear nerve is also established.

Perspectives on cervical cancer screening and prevention: challenges faced by providers and patients along the Texas-Mexico border.

BACKGROUND: The Rio Grande Valley (RGV) and Laredo regions located along the Texas-Mexico border consist of seven counties with a population of approximately 1.5 million people and a high uninsured rate (33.5%). Cervical cancer mortality in these border counties is approximately 30% higher than the rest of Texas. The RGV and Laredo areas were studied to better understand the state of access to cervical cancer prevention services along the Texas-Mexico border. METHODS: Data on the population served and the services provided were analyzed to determine the gap between cervical cancer screenings recommended versus those received. Through interviews, we gathered the perspectives of 16 local stakeholders regarding cervical cancer screening for underserved individuals in the region. FINDINGS: It is estimated that 69,139 uninsured women aged 21-64 years in the RGV/Laredo per year are recommended to undergo cervical cancer screening with Papanicolaou (Pap) and/or human papillomavirus (HPV) testing, but only 8941 (12.9%) Pap tests are being performed by the Federally Qualified Health Center (FQHC) serving uninsured women in these regions. Systemic barriers identified include insufficient provider clinical capacity, the high cost of healthcare, and uncertainty about government funding sources. Patient barriers identified include inadequate knowledge on navigating the local healthcare system, low health literacy, lack of money and childcare, an inability to miss work, limited transportation, and fear of deportation. CONCLUSION: Decreasing the disparity between cervical cancer screening services provided and those recommended requires addressing the barriers, identified by local experts, which prevent uninsured women from accessing care. These challenges are being addressed through ongoing programs and collaborations.

Clinical impact of radiographic carotid artery involvement in neck metastases from head and neck cancer.

The treatment of lymph node metastases involving the carotid artery is controversial. The aim of the present study was to determine the outcomes of head and neck cancer patients with radiographic carotid artery involvement in neck metastases. A total of 27 patients with head and neck cancer and radiologically diagnosed advanced metastases involving the common carotid artery or internal carotid artery were enrolled. All patients underwent a primary or salvage neck dissection and surgical carotid peeling. The oncological outcome and survival of all patients were analyzed. Loco-regional control was observed in 13 of the 27 patients (48.1%). During follow-up, five patients (18.5%) developed second primaries and 11 (40.7%) developed distant metastases. The survival time was poor independent of regional control. The median overall survival was 1.55 years and disease-free survival was 0.71 year. Radiographic carotid artery involvement in neck metastases in head and neck cancer appears to correlate with a poor long-term prognosis, with a high rate of distant metastases despite loco-regional control.

Hepatitis C virus in Mexican Americans: a population-based study reveals relatively high prevalence and negative association with diabetes.

This study aimed to estimate the prevalence and risk factors for hepatitis C virus (HCV) infection in Mexican Americans living in South Texas. We tested plasma for the presence of HCV antibody from the Cameron County Hispanic Cohort (CCHC), a randomized, population-based cohort in an economically disadvantaged Mexican American community on the United States/Mexico border with high rates of chronic disease. A weighted prevalence of HCV antibody of 2·3% [n = 1131, 95% confidence interval (CI) 1·2-3·4] was found. Participants with diabetes had low rates of HCV antibody (0·4%, 95% CI 0·0-0·9) and logistic regression revealed a statistically significant negative association between HCV and diabetes (OR 0·20, 95% CI 0·05-0·77) after adjusting for sociodemographic and clinical factors. This conflicts with reported positive associations of diabetes and HCV infection. No classic risk factors were identified, but important differences between genders emerged in analysis. This population-based study of HCV in Mexican Americans suggests that national studies do not adequately describe the epidemiology of HCV in this border community and that unique risk factors may be involved.

Depression in Mexican Americans with diagnosed and undiagnosed diabetes.

BACKGROUND: Depression and diabetes commonly co-occur; however, the strength of the physiological effects of diabetes as mediating factors towards depression is uncertain. METHOD: We analyzed extensive clinical, epidemiological and laboratory data from n = 2081 Mexican Americans aged 35-64 years, recruited from the community as part of the Cameron County Hispanic Cohort (CCHC) divided into three groups: Diagnosed (self-reported) diabetes (DD, n = 335), Undiagnosed diabetes (UD, n = 227) and No diabetes (ND, n = 1519). UD participants denied being diagnosed with diabetes, but on testing met the 2010 American Diabetes Association and World Health Organization definitions of diabetes. Depression was measured using the Center for Epidemiological Studies - Depression (CES-D) scale. Weighted data were analyzed using dimensional and categorical outcomes using univariate and multivariate models. RESULTS: The DD group had significantly higher CES-D scores than both the ND and UD (p ⩽ 0.001) groups, whereas the ND and UD groups did not significantly differ from each other. The DD subjects were more likely to meet the CES-D cut-off score for depression compared to both the ND and UD groups (p = 0.001), respectively. The UD group was also less likely to meet the cut-off score for depression than the ND group (p = 0.003). Our main findings remained significant in models that controlled for socio-demographic and clinical confounders. CONCLUSIONS: Meeting clinical criteria for diabetes was not sufficient for increased depressive symptoms. Our findings suggest that the 'knowing that one is ill' is associated with depressive symptoms in diabetic subjects.

Multimode optomechanical dynamics in a cavity with avoided crossings.

Cavity optomechanics offers powerful methods for controlling optical fields and mechanical motion. A number of proposals have predicted that this control can be extended considerably in devices where multiple cavity modes couple to each other via the motion of a single mechanical oscillator. Here we study the dynamic properties of such a multimode optomechanical device, in which the coupling between cavity modes results from mechanically induced avoided crossings in the cavity's spectrum. Near the avoided crossings we find that the optical spring shows distinct features that arise from the interaction between cavity modes. Precisely at an avoided crossing, we show that the particular form of the optical spring provides a classical analogue of a quantum non-demolition measurement of the intracavity photon number. The mechanical oscillator's Brownian motion, an important source of noise in these measurements, is minimized by operating the device at cryogenic temperature (500 mK).

Indications for reconstruction of mucosal defects in oropharyngeal cancer using a supraclavicular island flap.

The use of the supraclavicular island flap (SCIF) for the reconstruction of facial and neck skin defects is increasing. The value of this fasciocutaneous flap as a reconstructive modality for oropharyngeal defects in cancer patients is unclear. In the present study, a SCIF was used for reconstruction of mucosal defects following resection of the tumour in a group of four patients with T2 squamous cell carcinoma of the oropharynx and a clinical N0 neck. Reconstruction was performed following transoral tumour resection and selective neck dissection at levels I-III in the same session. Intraoperative and postoperative complications were analyzed, and functional and aesthetic results for the neck and shoulder region were evaluated in follow-up examinations. In addition, sensation to the flap was evaluated. No flap failures were observed. Only minor surgical complications were evident, which did not cause any relevant functional or aesthetic impairments. Sensation to the flap was observed in all cases. The SCIF appears to be a good and time-saving alternative to free flaps for oropharyngeal reconstruction following oncological resection in selected patients.

Silicon based tandem cells: novel photocathodes for hydrogen production.

A photovoltaic tandem cell made of amorphous silicon (a-Si) and microcrystalline silicon (µc-Si) was investigated as a photocathode for hydrogen evolution in a photoelectrochemical device. The electronic and electrochemical properties of the samples were characterized using X-ray photoemission spectroscopy (XPS) and cyclic voltammetry (CV), whereas the morphology of the surface in contact with the electrolyte was investigated by scanning electron microscopy (SEM). The electric efficiency of the tandem cell was determined to be 5.2% in a photoelectrochemical (PEC) setup in acidic solution which is only about half of the photovoltaic efficiency of the tandem cell. A significant improvement in efficiency was achieved with platinum as a catalyst which was deposited by physical vapour deposition (PVD) under ultra-high vacuum (UHV) conditions.

[Clinical aspects of transoral laser surgery and neck dissection for oro- and hypopharyngeal cancer in elderly patients]. / Klinische Aspekte der transoralen Laserchirurgie und Neck-Dissection bei Oro- und Hypopharynxkarzinomen im fortgeschrittenen Lebensalter.

BACKGROUND: The number of elderly patients with head and neck cancer is increasing. However, there are few valid data on postoperative course after head and neck cancer surgery in elderly patients. The aim of this study was to evaluate the oncological outcome of elderly patients after surgical treatment for oro- and hypopharyngeal cancer. MATERIAL AND METHODS: The clinical data of 81 patients, separated into two age groups (62 < 65 years vs. 19 ≥ 65 years), were retrospectively analysed. The cohort comprised T1 and T2 oro- and hypopharyngeal cancer patients, who had undergone primary treatment with transoral laser surgery and neck dissection. Overall and disease-free survival times of the patients were analysed. Additionally, comorbidities and perioperative complications were compared between the two age groups. Median follow-up time was 5.9 years. RESULTS: Comparison of different clinical and histopathological data revealed no significant differences between the age groups. The Kaplan-Meier method revealed no significant difference in disease-free survival between the age groups (p = 0.52). Age had no effect on disease-free survival in uni- or multivariate analysis (p = 0.53 vs. 0.94). Surgery-related complications were observed in 13 patients (16 %), 11 cases of which concerned the younger group of patients. CONCLUSION: Transoral laser surgery and neck dissection can lead to satisfactory oncological and surgical outcomes in elderly patients with oro- and hypopharyngeal cancer.

Thermostatted micro-reactor NMR probe head for monitoring fast reactions.

A novel nuclear magnetic resonance (NMR) probe head for monitoring fast chemical reactions is described. It combines micro-reaction technology with capillary flow NMR spectroscopy. Two reactants are fed separately into the probe head where they are effectively mixed in a micro-mixer. The mixed reactants then pass through a capillary NMR flow cell that is equipped with a solenoidal radiofrequency coil where the NMR signal is acquired. The whole flow path of the reactants is thermostatted using the liquid FC-43 (perfluorotributylamine) so that exothermic and endothermic reactions can be studied under almost isothermal conditions. The set-up enables kinetic investigation of reactions with time constants of only a few seconds. Non-reactive mixing experiments carried out with the new probe head demonstrate that it facilitates the acquisition of constant highly resolved NMR signals suitable for quantification of different species in technical mixtures. Reaction kinetic measurements on a test system are presented that prove the applicability of the novel NMR probe head for monitoring fast reactions.

Optically mediated hybridization between two mechanical modes.

In this Letter we study a system consisting of two nearly degenerate mechanical modes that couple to a single mode of an optical cavity. We show that this coupling leads to nearly complete (99.5%) hybridization of the two mechanical modes into a bright mode that experiences strong optomechanical interactions and a dark mode that experiences almost no optomechanical interactions. We use this hybridization to transfer energy between the mechanical modes with 40% efficiency.

Persisting role of healthcare settings in hepatitis C transmission in Pakistan: cause for concern.

Transmission of hepatitis C (HCV) in Pakistan is a continuing public health problem; 15 years ago it was linked to the practice of reusing therapeutic instruments in healthcare settings. We sought to examine current risk factors for HCV transmission in a hospital population in Karachi, Pakistan. We enrolled 300 laboratory-confirmed HCV-positive participants and 300 laboratory confirmed HCV-negative participants from clinics at Indus Hospital. Independent and significant risk factors for both men and women were: receiving o12 injections in the past year, blood transfusions, having had dental work performed, and delivery in hospital or transfusion for women. Interestingly, being of Mohajir origin or born in Sindh province were protective.Encouragingly, a strong protective effect was observed for those that reported bringing their own needle for injections (59%). The widespread reuse of therapeutic needles in healthcare settings in Karachi remains a major driver of the HCV epidemic.

Host susceptibility to tuberculosis: insights from a longitudinal study of gene expression in diabetes.

Tuberculosis (TB) remains a major global disease, and diabetes, which is documented to increase susceptibility to TB threefold, is also becoming pandemic. This susceptibility has been attracting extensive research interest. The increased risk of TB in diabetes may serve as a unique model to understand host susceptibility to specific pathogens in humans. To examine this rationale, we investigated the expression of reported TB candidate genes in a longitudinal diabetes study. Two genes, HK2 and CD28, emerged as potential culprits in diabetes-increased TB susceptibility.

The sensitivity of interferon-gamma release assays is not compromised in tuberculosis patients with diabetes.

SETTING AND OBJECTIVES: the sensitivity of the interferon-gamma release assays (IGRAs) in the detection of Mycobacterium tuberculosis infection or disease may be affected by immune dysregulation in diabetes. As millions of type 2 diabetes patients are at risk for tuberculosis (TB) worldwide, it is important to determine if the sensitivity of IGRAs is compromised in this vulnerable population. DESIGN: the sensitivity of the IGRAs QuantiFERON®-TB Gold (QFT-G) and T-SPOT®.TB was evaluated among specimens from newly diagnosed adults with microbiologically confirmed TB with and without diabetes. We also evaluated the association between QFT-G results and diabetes-associated conditions (dyslipidemia, obesity). RESULTS: QFT-G sensitivity was 70% among TB patients. Patients with diabetes, chronic hyperglycemia or overweight/obesity were more than twice as likely to have positive test results in multivariate models (P < 0.05). Low high-density lipoprotein cholesterol or high triglycerides were not associated with assay results. In a separate group of TB patients (n = 43), T-SPOT.TB was 93% sensitive, with similar performance in patients with and without diabetes. CONCLUSION: IGRA sensitivity is not compromised by diabetes in TB patients. Accordingly, IGRAs may also be suitable for diagnosing TB infection in diabetes patients, which is required to assess TB risk.

Type 2 diabetes and tuberculosis in a dynamic bi-national border population.

The epidemic of type 2 diabetes in the United States prompted us to explore the association between diabetes and tuberculosis (TB) on the South Texas-Mexico border, in a large population of mostly non-hospitalized TB patients. We examined 6 years of retrospective data from all TB patients (n=5049) in South Texas and northeastern Mexico and found diabetes self-reported by 27.8% of Texan and 17.8% of Mexican TB patients, significantly exceeding national self-reported diabetes rates for both countries. Diabetes comorbidity substantially exceeded that of HIV/AIDS. Patients with TB and diabetes were older, more likely to have haemoptysis, pulmonary cavitations, be smear positive at diagnosis, and remain positive at the end of the first (Texas) or second (Mexico) month of treatment. The impact of type 2 diabetes on TB is underappreciated, and in the light of its epidemic status in many countries, it should be actively considered by TB control programmes, particularly in older patients.

Background demographics and risk behaviors of injecting drug users in Karachi, Pakistan.

OBJECTIVE: To find the prevalence of HIV infection and risk behaviors among injecting drug users (IDUs) in Karachi, Pakistan. DESIGN: A cross-sectional study of IDUs conducted in Karachi, Pakistan from February through June 1996. RESULTS: Of the 242 IDUs, 11 (4%) refused HIV testing. One (0.4%; 95% confidence interval (CI) = 0.37-0.48%) was HIV positive. All subjects were male. Over the past 6 months 47% had engaged in receptive needle sharing, 38% had perceived a change in their social network, 22% had had sexual intercourse, of whom only 7% always used condoms, and none had washed their needles with bleach. Younger age (28 vs. 31 years; p = 0.01), younger age at first injection (25 vs. 28 years; p = 0.001), fewer years of schooling (3 vs. 5 years; p = 0.001), lower monthly income (70 dollars vs. 80 dollars; p = 0.03), inhaling fumes of heroin from a foil in the year before injecting (OR = 4.8; CI = 2.2-10.3), injecting first time with heroin (OR = 3.6; CI = 1.2-12.6), having a temporary job (OR = 2.5; CI = 1.2-5.2), and a perceived change in one's social network (OR = 4.4; CI = 2.4-7.9) were all associated with receptive needle sharing. IDUs who knew about HIV spread through contaminated needles were less likely to share (OR = 0.4; CI 0.2-0.8). In the final logistic regression model receptive needle sharing was associated with inhaling of fumes of heroin on a foil in the year prior to injecting (adjusted OR = 5.6; CI = 2.6-12.0), a perceived change in one's social network (adjusted OR = 4.0; CI = 2.2-7.4), and inversely associated with age at first time of injection (beta = -0.07; p = 0.002). CONCLUSION: Background HIV prevalence was low among IDUs in Karachi despite high-risk behavior in 1996. In order to control HIV transmission among IDUs in Pakistan, continual HIV surveillance with well-coordinated and effective HIV risk reduction, and drug demand reduction programs need to be implemented among drug users.