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This research examined the perspective of the Huntington’s disease (HD) community regarding the use of predictive biomarkers as endpoints for regulatory approval of therapeutics to prevent or delay the onset of clinical HD in asymptomatic mutation carriers.
An online, choice-based conjoint survey was shared with HD community members including untested at-risk individuals, presymptomatic mutation carriers, and symptomatic individuals. Across 15 scenarios, participants chose among two proposed therapies with differing degrees of biomarker improvement and side effects or a third option of no treatment.
Two hundred and thirty-eight responses were received. Attributes reflecting biomarker efficacy (e.g., prevention of brain atrophy on magnetic resonance imaging, reduced mutant huntingtin, or reduced inflammation biomarkers) had 3- to 7-fold greater importance than attributes representing side effects (e.g., increased risk of heart disease, cancer, and stroke over 20 years) and were more influential in directing choice of treatments. Reduction in mutant huntingtin protein was the most valued attribute overall. Multinomial logit model simulations based on survey responses demonstrated high interest among respondents (87–99% of the population) for drugs that might prevent or delay HD solely based upon biomarker evidence, even at the risk of serious side effects.
These results indicate a strong desire among members of the HD community for preventive therapeutics and a willingness to accept significant side effects, even before the drug has been shown to definitively delay disease onset if the drug improves biomarker evidence of HD progression. Preferences of the HD community should inform regulatory policies for approving preventive therapies.
This report is on the synthesis by electrospinning of multiferroic core-shell nanofibers of strontium hexaferrite and lead zirconate titanate or barium titanate and studies on magneto-electric (ME) coupling. Fibers with well-defined core–shell structures showed the order parameters in agreement with values for nanostructures. The strength of ME coupling measured by the magnetic field-induced polarization showed the fractional change in the remnant polarization as high as 21%. The ME voltage coefficient in H-assembled films showed the strong ME response for the zero magnetic bias field. Follow-up studies and potential avenues for enhancing the strength of ME coupling in the core–shell nanofibers are discussed.
A novel pure-vision egomotion estimation algorithm is presented, with extensions to Unmanned Aerial Systems (UAS) navigation through visual odometry. Our proposed method computes egomotion in two stages using panoramic images segmented into sky and ground regions. Rotations (in 3DOF) are estimated by using a customised algorithm to measure the motion of the sky image, which is affected only by the rotation of the aircraft, and not by its translation. The rotation estimate is then used to derotate the optic flow field generated by the ground, from which the translation of the aircraft (in 3DOF) is estimated by another customised, iterative algorithm. Segmentation of the rotation and translation estimations allows for a partial relaxation of the planar ground assumption, inherently increasing the robustness of the approach. The translation vectors are scaled using stereo-based height to compute the current UAS position through path integration for closed-loop navigation. Outdoor field tests of our approach in a small quadrotor UAS suggest that the technique is comparable to the performance of existing state-of-the-art vision-based navigation algorithms, whilst also removing all dependence on additional sensors, such as an IMU or global positioning system (GPS).
High frequency of low birth weight (LBW) is observed in rural compared with urban Indian women. Since maternal BMI is known to be associated with pregnancy outcomes, the present study aimed to investigate factors associated with BMI in early pregnancy of urban and rural South Indian women.
Prospective observational cohort.
A hospital-based study conducted at an urban and a rural health centre in Karnataka State.
Pregnant women (n 843) aged 18–40 years recruited in early pregnancy from whom detailed sociodemographic, environmental, anthropometric and dietary intake information was collected.
A high proportion of low BMI (32 v. 26 %, P<0·000) and anaemia (48 v. 23 %, P<0·000) was observed in the rural v. the urban cohort. Rural women were younger, had lower body weight, tended to be shorter and less educated. They lived in poor housing conditions, had less access to piped water and good sanitation, used unrefined fuel for cooking and had lower standard of living score. The age (β=0·21, 95 % CI 0·14, 0·29), education level of their spouse (β=1·36, 95 % CI 0·71, 2·71) and fat intake (β=1·24, 95 % CI 0·20, 2·28) were positively associated with BMI in urban women.
Our findings indicate that risk factors associated with BMI in early pregnancy are different in rural and urban settings. It is important to study population-specific risk factors in relation to perinatal health.
Recently developed direct-acting antiviral (DAA) treatments for hepatitis C virus (HCV) are groundbreaking in their high efficacy across disease genotypes and lack of severe side effects. This study used a cost-of-illness (COI) approach to estimate the net value conferred by one of these novel drug combinations, sofosbuvir and velpatasir (SOF/VEL), recently licensed for generic manufacture in India.
This study considered COI from lifetime earnings lost due to disability and premature death from HCV infection. Risk of death and disability in future years was calculated using a Markov state-transition model with parameters determined from the literature. The future earnings of sampled patients were predicted using an empirical earnings model, with coefficients determined from India Human Development Survey data. Costs to both the patient and secondarily infected individuals were considered.
Preliminary results suggested that curing individuals diagnosed with chronic HCV in India would preserve INR 3.7 million (USD 55,750) in earnings per person. For non-cirrhotic (NC) and compensated cirrhotic (CC) individuals, the expected benefits associated with preventing secondary infections were worth between one and forty-one percent of the value of benefits conferred to the diagnosed individuals (depending on sex and extent of liver damage). Treating decompensated cirrhotic (DC) individuals with DAAs alone offered minimal earnings benefits because these individuals will likely remain disabled and unable to work without a liver transplant. Expected net benefits of treatment were substantial for NC and CC patients, ranging from INR 640,349 (USD 9,531) for NC women to INR 10.7 million (USD 158,968) for CC men. The cost of treatment for DC individuals exceeded the expected earnings benefits.
For average NC and CC individuals, the cost of treatment with SOF/VEL is offset by the benefits of increased future productivity. Increased earnings are not sufficient to offset the cost of treatment for DC individuals, but treatment may still be justified on the basis of the intrinsic value of health improvements and other treatment benefits.
The history of glacier length fluctuations serves as a reliable indicator of the past climate. In this paper, a numerical flowline model has been used to study the relationship between length variations of Chhota Shigri glacier and local climate since 1876. The simulated front positions of Chhota Shigri glacier are in agreement with those observed. After a successful simulation of the past retreat, the model was also used to predict future evolution of the glacier for the next 100 years under different climatic scenarios. These simulations indicate that the Chhota Shigri glacier may lose ~90% of its present volume by 2100 if the local temperature increases by 2.4 K, and for a temperature rise of 5.5 K, the glacier loses almost all its volume.
Prior studies on design ideation have demonstrated the efficacy of using patents as stimuli for concept generation. However, the following questions remain: (a) From which part of the large patent database can designers identify stimuli? (b) What are their implications on ideation outcomes? This research aims to answer these questions through a design experiment of searching and identifying patent stimuli to generate new concepts of spherical rolling robots. We position the identified patent stimuli in the home, near and far fields defined in the network of patent technology classes, according to the network’s community structure and the knowledge proximity of the stimuli to the spherical rolling robot design. Significant findings are: designers are most likely to find patent stimuli in the home field, whereas most patent stimuli are identified in the near field; near-field patents stimulate the most concepts, which exhibit a higher average novelty; combined home- and far-field stimuli are most beneficial for high concept quality. These findings offer insights on designers’ preferences in search for patent stimuli and the influence of stimulation distance on ideation outcomes. The findings will also help guide the development of a computational tool for the search of patents for design inspiration.
Pneumonia due to either Streptococcus pneumoniae (Sp) or Staphylococcus aureus (Sa) accounts for most mortality after influenza and acute respiratory illness (ARI). Because carriage precedes infection, we estimated Sp and Sa carriage to examine the co-colonization dynamics between Sp, Sa and respiratory viruses in the presence of ARI in the oropharynx. We tested oropharyngeal specimens of community subjects (aged ⩾2 years) with ARI for the presence of influenza A and B, 11 other common respiratory viruses, Sp and Sa, using real-time PCR. A total of 338 participants reported 519 ARI episodes of which 119 (35%) carried Sp, 52 (13%) carried Sa and 25 (7%) carried both. Thirty-five subjects tested positive for influenza, of which 14 (40%) carried Sp and six (17%) carried Sa, significantly more than in the influenza-negative group (P = 0·03 and P = 0·04, respectively). In subjects infected by any virus compared to those with no virus, Sp carriage (39·2% vs. 27·9%, P = 0·03) but not Sa carriage (11·6% vs. 14%, P = 0·6) was more frequent. For children, when Sa was present, Sp carriage tended to be less frequent than expected given the presence of viral infection, but not significantly [observed relative risk 1·14, 95% confidence interval (CI) 0·4–3·1; with a relative excess risk due to interaction of –0·11]. Independent of age, Sp carriers were more likely to return that season with subsequent ARI (odds ratio 2·14, 95% CI 1·1–4·3, P = 0·03). Both Sp and Sa carriage rates in the oropharynx increase during influenza infection in children. However, no negative interaction between Sp and Sa was observed. Sp carriers are more likely to suffer subsequent ARI episodes than non-carriers.
Internal analogies are created if the knowledge of source domain is obtained only from the cognition of designers. In this paper, an understanding of the use of internal analogies in conceptual design is developed by studying: the types of internal analogies; the roles of internal analogies; the influence of design problems on the creation of internal analogies; the role of experience of designers on the use of internal analogies; the levels of abstraction at which internal analogies are searched in target domain, identified in source domain, and realized in the target domain; and the effect of internal analogies from the natural and artificial domains on the solution space created using these analogies. To facilitate this understanding, empirical studies of design sessions from earlier research, each involving a designer solving a design problem by identifying requirements and developing conceptual solutions, without using any support, are used. The following are the important findings: designers use analogies from the natural and artificial domains; analogies are used for generating requirements and solutions; the nature of the design problem influences the use of analogies; the role of experience of designers on the use of analogies is not clearly ascertained; analogical transfer is observed only at few levels of abstraction while many levels remain unexplored; and analogies from the natural domain seem to have more positive influence than the artificial domain on the number of ideas and variety of idea space.
The aim of this study was to identify and develop entomopathogenic fungi as biopesticides for management of Maruca vitrata (Fabricius). Fourteen isolates of Metarhizium anisopliae (Metchnikoff) Sorokin and six of Beauveria bassiana (Bals.-Criv.) Vuill. were screened against first instar larvae of M. vitrata. The two most virulent isolates were selected and further tested for production in four liquid media. Different formulations of one isolate were evaluated against different developmental stages. Metarhizium anisopliae ICIPE 18 and ICIPE 69 caused highest larval mortality of 91 and 81%, with lethal time to 50% mortality (LT50) values of 1.8 and 1.7 days and LC50 of 1.07 × 107 and 3.01 × 106conidia/ml, respectively. ICIPE 69 yielded more biomass and propagules in two liquid media than ICIPE 18. All developmental stages and adult moths were susceptible to fungal infection and horizontal transmission caused a significant reduction in fecundity. Isolate ICIPE 69 was identified as the most potent isolate for managing M. vitrata based on demonstrated efficacy against different developmental stages and amenability to production in liquid media and could be utilized as an alternative to pesticides in cowpea IPM.
ZrO2/Ge is potential high-k dielectric candidate to replace silicon based devices. Controlling stress in zirconia film and stabilizing high dielectric constant phase is crucial for high-k application. A precise control of stress and phase selectivity in high-k thin films is demonstrated. Thin films of ZrO2 were grown by reactive sputter deposition. Wide range of growth stress in thin films from -0.3 to -2.8 GPa can be tuned by growth rate control. Adatom incorporation into grain boundary was the dominant source of observed stress. Phase selectivity in zirconia was achieved by tuning growth parameters.
To analyse trends in two-week rule referrals for head and neck cancer over 10 years.
Data from two-week referrals received by the Wirral University Hospital NHS Trust between 1 January and 30 June 2012 were compared with similar data from 2002.
A total of 357 referrals were received during the 6-month audit period, compared with 149 during the whole of 2002. Cancer pick-up rates were 9 per cent and 5 per cent in the first and second cycles, respectively.
The annual number of two-week referrals made to our department increased by over 450 per cent in 10 years, but the resulting cancer pick-up rate fell by nearly 50 per cent. Whilst cancer patients need to be seen quickly, the current system is inefficient in parts. Modifications to the treatment pathway should be considered to improve patient care quality and reduce pressure on ENT departments.
We estimate the distribution of ice thickness for a Himalayan glacier using surface velocities, slope and the ice flow law. Surface velocities over Gangotri Glacier were estimated using sub-pixel correlation of Landsat TM and ETM+ imagery. Velocities range from ˜14–85 m a–1 in the accumulation region to ˜20–30 m a–1 near the snout. Depth profiles were calculated using the equation of laminar flow. Thickness varies from ˜540 m in the upper reaches to ˜50–60 m near the snout. The volume of the glacier is estimated to be 23.2 ± 4.2 km3.
In patients with blunt abdominal trauma, emergent or urgent laparotomy is performed for hypotension and abdominal hemorrhage (frequently confirmed by diagnostic peritoneal lavage or surgeon-performed ultrasound), overt peritonitis, or obvious signs of abdominal visceral injury without the need for further advanced diagnostic studies. Included are patients with significant blood per rectum after pelvic fracture, evidence of air in the peritoneal cavity or retroperitoneum, intraperitoneal bladder rupture, or renal artery/kidney injury on contrast-enhanced radiographs. All other stable patients whose abdominal examinations are compromised by an abnormal sensorium (related to alcohol, drugs, brain injury), abnormal sensation (due to spinal cord injury), or adjacent injuries are best evaluated by contrasted abdominal helical computed tomography. The use of surgeon-performed ultrasound known as FAST (focused assessment for the sonographic evaluation of the trauma patient) is now routinely performed in all high-volume trauma centers as an adjunct to the secondary survey. The FAST exam has contributed substantially to streamlined algorithms for care of patients assessed after multi-system trauma.
In patients with stab wounds to the abdomen, emergent or urgent laparotomy is performed for abdominal distension and hypotension, overt peritonitis, significant evisceration, or obvious signs of abdominal visceral injury without the need for further advanced diagnostic studies. The last group of patients includes individuals with hematemesis, blood per rectum, or hematuria, patients with a palpable diaphragmatic defect prior to chest tube insertion, and patients with genitourinary injuries detected on contrast-enhanced studies. All other stable and reasonably cooperative patients undergo local exploration of the stab wound to verify peritoneal penetration. Asymptomatic patients with peritoneal penetration can either be watched for 24 hours, undergo a diagnostic peritoneal lavage, or undergo diagnostic laparoscopy to make certain that there is no underlying visceral injury. The diagnosis of intra-abdominal injury is rarely delayed more than 10–12 hours in patients with false-negative results on initial physical examination. Patients who undergo wound exploration that confirms absence of peritoneal penetration can be discharged from the emergency room.
Open or laparoscopic colon resection is performed for a variety of conditions, the most common of which are benign or malignant neoplasms (tubular or villoglandular adenoma, adenocarcinoma, carcinoid, lymphoma); complications of diverticular disease (perforation with peritonitis or abscess, stricture, bleeding); extensive traumatic perforations; angiodysplasia or arteriovenous malformation with lower gastrointestinal bleeding; and inflammatory bowel disease (ulcerative colitis, segmental colonic Crohn's disease, toxic megacolon). Less common indications for resection include volvulus of the sigmoid colon or cecum; thrombotic, embolic, or low-flow infarction; and premalignant conditions (familial polyposis, Gardner's syndrome).
Hemicolectomy for malignant neoplasms involves excision of the area of the tumor, at least 10 cm of normal proximal colon or small bowel, and 5 cm of normal distal colon as well as excision of the regional lymphatics that accompany the major vessels in the mesentery. In contrast, segmental resection for complications of diverticular disease, Crohn's disease, colonic volvulus, or infarction involves only grossly diseased bowel without excision of the regional lymphatics. Subtotal abdominal colectomy with ileorectostomy is performed for patients with non-familial synchronous scattered benign or malignant neoplasms. It is also used in some patients with megacolon secondary to obstructing neoplasms of the sigmoid or rectosigmoid colon or of the upper rectum, and for patients with non-localized diverticular bleeding. For patients with severe medically refractory ulcerative colitis, familial polyposis, or Gardner's syndrome, a near-total abdominal colectomy is preferred. This involves preservation of a seromuscular short rectal cuff and the sphincter muscles to preserve anal continence and the creation of an ileal pouch–anal anastomosis.
Appendectomy is performed for acute appendicitis (simple, suppurative, gangrenous, gangrenous with perforation); chronic or recurrent appendicitis; as an interval procedure after recovery from an appendiceal abscess; for small (< 2 cm) carcinoid tumors or benign mucoceles not involving the appendiceal orifice; and prophylactically during laparotomy for other conditions. The accuracy of diagnosis in acute appendicitis has increased to over 90% in several series using diagnostic adjuncts such as graded-compression ultrasound and special CT protocols. With graded compression ultrasound, a uniform pressure is applied to the right lower quadrant of the abdomen by a hand-held transducer. Normal loops of intestine are either displaced or compressed between the anterior and posterior abdominal walls. An inflamed appendix, however, is aperistaltic and non-compressible. In addition, percutaneous drainage of periappendiceal abscesses may allow for a subsequent single laparoscopic operation to remove the remnant of the perforated appendix (interval appendectomy). Interval appendectomy is generally performed 6–8 weeks after the initial abscess drainage.
With the patient under general anesthesia, appendectomy may be performed through a right lower quadrant muscle-splitting incision or by a laparoscopic approach using three ports. The laparoscopic operation affords an operative advantage in morbidly obese patients and patients with a retrocecal appendix, allowing for anatomy to be more easily visualized by virtue of the laparoscope. With simple, suppurative, or gangrenous appendicitis, the stress of operation is minimal. For patients with perforated gangrenous appendicitis and diffuse peritonitis or with a large intra-abdominal abscess, stress can be moderate or major. The duration of a simple appendectomy is 45 minutes, but this increases to 60 to 75 minutes in obese patients with retrocecal appendicitis and rupture. In some of these patients, the usual 6- to 7-cm incision must be extended to gain exposure of the posterior cecum and ascending colon. Blood transfusion is generally not required.
Abdominoperineal resection (APR, Miles' operation), with excision of the rectum, anus, and sphincter muscles and the creation of a permanent end colostomy, is performed to remove malignant neoplasms of the distal one-third of the rectum or the anus. The most common indication for resection is adenocarcinoma of the rectum or anus that cannot be removed with adequate margins at the time of primary resection, or recurrent disease. Less common indications for APR include residual squamous cell carcinoma of the anus after chemo-radiation treatment, carcinoid, cloacogenic carcinoma, basal cell carcinoma, and malignant melanoma. Abdominoperineal resection is most commonly performed for non-malignant disease in the setting of medically refractory Crohn's disease with severe perianal fistulae.
The operation is conducted with a transabdominal laparoscopic approach or through a low midline laparotomy incision and a circumferential perianal incision. Included in the excision are the rectosigmoid colon, the rectum, the pelvic mesocolon, the lymph nodes associated with the three sets of hemorrhoidal vessels, the levator muscles out to the ischial tuberosities, the anus, and the perianal skin. The resection of the levator and anal complex necessitates an end-descending colostomy. In instances when the surgeon is able to excise a 2 cm margin of normal bowel beyond the rectal tumor, a Miles' procedure with a permanent colostomy can be avoided by performing a low hand-sewn or stapled coloanal anastomosis accompanied by a temporary diverting ostomy while the anastomosis heals.