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Summary Background The Gambia introduced seven-valent pneumococcal conjugate vaccine (PCV7) in August 2009, followed by PCV13 in May, 2011, using a schedule of three primary doses without a booster dose or catch-up immunisation. We aimed to assess the long-term impact of PCV on disease incidence. Methods We did 10 years of population-based surveillance for invasive pneumococcal disease (IPD) and WHO defined radiological pneumonia with consolidation in rural Gambia. The surveillance population included all Basse Health and Demographic Surveillance System residents aged 2 months or older. Nurses screened all outpatients and inpatients at all health facilities using standardised criteria for referral. Clinicians then applied criteria for patient investigation. We defined IPD as a compatible illness with isolation of Streptococcus pneumoniae from a normally sterile site (cerebrospinal fluid, blood, or pleural fluid). We compared disease incidence between baseline (May 12, 2008–May 11, 2010) and post-vaccine years (2016–2017), in children aged 2 months to 14 years, adjusting for changes in case ascertainment over time. Findings We identified 22 728 patients for investigation and detected 342 cases of IPD and 2623 cases of radiological pneumonia. Among children aged 2–59 months, IPD incidence declined from 184 cases per 100 000 person-years to 38 cases per 100 000 person-years, an 80% reduction (95% CI 69–87). Non-pneumococcal bacteraemia incidence did not change significantly over time (incidence rate ratio 0·88; 95% CI, 0·64–1·21). We detected zero cases of vaccine-type IPD in the 2–11 month age group in 2016–17. Incidence of radiological pneumonia decreased by 33% (95% CI 24–40), from 10·5 to 7·0 per 1000 person-years in the 2–59 month age group, while pneumonia hospitalisations declined by 27% (95% CI 22–31). In the 5–14 year age group, IPD incidence declined by 69% (95% CI −28 to 91) and radiological pneumonia by 27% (95% CI −5 to 49). Interpretation Routine introduction of PCV13 substantially reduced the incidence of childhood IPD and pneumonia in rural Gambia, including elimination of vaccine-type IPD in infants. Other low-income countries can expect substantial impact from the introduction of PCV13 using a schedule of three primary doses. Funding Gavi, The Vaccine Alliance; Bill & Melinda Gates Foundation; UK Medical Research Council; Pfizer Ltd.

Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab’s clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P

BackgroundAs concerns about the prevalence of infections that are resistant to available antibiotics increase, attention has turned toward the use of these medicines both within and outside of formal healthcare settings. Much of what is known about use beyond formal settings is informed by survey-based research. Few studies to date have used comparative, mixed-methods approaches to render visible patterns of use within and between settings as well as wider points of context shaping these patterns.DesignThis article analyses findings from mixed-methods anthropological studies of antibiotic use in a range of rural and urban settings in Zimbabwe, Malawi and Uganda between 2018 and 2020. All used a ‘drug bag’ survey tool to capture the frequency and types of antibiotics used among 1811 households. We then undertook observations and interviews in residential settings, with health providers and key stakeholders to better understand the stories behind the most-used antibiotics.ResultsThe most self-reported ‘frequently used’ antibiotics across settings were amoxicillin, cotrimoxazole and metronidazole. The stories behind their use varied between settings, reflecting differences in the configuration of health systems and antibiotic supplies. At the same time, these stories reveal cross-cutting features and omissions of contemporary global health programming that shape the contours of antibiotic (over)use at national and local levels.ConclusionsOur findings challenge the predominant focus of stewardship frameworks on the practices of antibiotic end users. We suggest future interventions could consider systems—rather than individuals—as stewards of antibiotics, reducing the need to rely on these medicines to fix other issues of inequity, productivity and security.

Summary Background Little information is available about the effect of pneumococcal conjugate vaccines (PCVs) in low-income countries. We measured the effect of these vaccines on invasive pneumococcal disease in The Gambia where the 7-valent vaccine (PCV7) was introduced in August, 2009, followed by the 13-valent vaccine (PCV13) in May, 2011. Methods We conducted population-based surveillance for invasive pneumococcal disease in individuals aged 2 months and older who were residents of the Basse Health and Demographic Surveillance System (BHDSS) in the Upper River Region, The Gambia, using standardised criteria to identify and investigate patients. Surveillance was done between May, 2008, and December, 2014. We compared the incidence of invasive pneumococcal disease between baseline (May 12, 2008–May 11, 2010) and after the introduction of PCV13 (Jan 1, 2013–Dec 31, 2014), adjusting for changes in case ascertainment over time. Findings We investigated 14 650 patients, in whom we identified 320 cases of invasive pneumococcal disease. Compared with baseline, after the introduction of the PCV programme, the incidence of invasive pneumococcal disease decreased by 55% (95% CI 30–71) in the 2–23 months age group, from 253 to 113 per 100 000 population. This decrease was due to an 82% (95% CI 64–91) reduction in serotypes covered by the PCV13 vaccine. In the 2–4 years age group, the incidence of invasive pneumococcal disease decreased by 56% (95% CI 25–75), from 113 to 49 cases per 100 000, with a 68% (95% CI 39–83) reduction in PCV13 serotypes. The incidence of non-PCV13 serotypes in children aged 2–59 months increased by 47% (−21 to 275) from 28 to 41 per 100 000, with a broad range of serotypes. The incidence of non-pneumococcal bacteraemia varied little over time. Interpretation The Gambian PCV programme reduced the incidence of invasive pneumococcal disease in children aged 2–59 months by around 55%. Further surveillance is needed to ascertain the maximum effect of the vaccine in the 2–4 years and older age groups, and to monitor serotype replacement. Low-income and middle-income countries that introduce PCV13 can expect substantial reductions in invasive pneumococcal disease. Funding GAVI's Pneumococcal vaccines Accelerated Development and Introduction Plan (PneumoADIP), Bill & Melinda Gates Foundation, and the UK Medical Research Council.

A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.

We report herein a dual-purpose role for polyacidic domains in an aqueous-phase polymer amphiphile assembly. In addition to their typical role as ionized water-solubilizing and self-repulsive motifs, we find that polycarboxylic acid domains uniquely enable high levels of hydrophobic drug encapsulation. By attenuated total reflectance infrared spectroscopy, we find significant differences in the carbonyl stretching region of the nanoparticles formed by polyacidic amphiphiles relative to those in soluble, single-domain poly(acrylic acid), suggesting that stabilization may be derived from limited ionization of the carboxylate groups upon assembly. Acidic-hydrophobic diblock polyacrylates were prepared and coassembled with up to 60 wt % camptothecin (CPT) into nanoparticles, the highest loading reported to date. Controlled release of bioactive CPT from polymer nanoparticles is observed, as well as protection from human serum albumin-induced hydrolysis. Surface protection with PEG limits uptake of the CPT-loaded nanoparticles by MCF-7 breast cancer cells, as expected. Acidic-hydrophobic polymer amphiphiles thus have the hallmarks of a useful and general drug delivery platform and are readily accessible from living radical polymerization of cheap, commercially available monomers. We highlight here the potential utility of this common polymer design in high-capacity, controlled-release polymer nanoparticle systems.

Summary Background In survivors of Ebola virus disease, clinical sequelae including uveitis, arthralgia, and fatigue are common and necessitate systematic follow-up. However, the infection risk to health-care providers is poorly defined. Here we report Ebola virus RT-PCR data for body site and fluid samples from a large cohort of Ebola virus survivors at clinic follow-up. Methods In this cross-sectional cohort study, consecutive survivors of Ebola virus disease attending Kerry Town survivor clinic (Freetown, Sierra Leone), who had been discharged from the Kerry Town Ebola treatment unit, were invited to participate. We collected and tested axillary, blood, conjunctival, forehead, mouth, rectal, semen, urine, and vaginal specimens for presence of Ebola virus using RT-PCR. We regarded samples to be positive for Ebola virus disease if the cycle threshold was 40 or lower. We collected demographic data from survivors of their age, sex, time since discharge from the treatment unit, and length of acute admission in the Ebola treatment unit using anonymised standard forms. Findings Between April 2, and June 16, 2015, of 151 survivors of Ebola virus disease invited to participate, 112 (74%) provided consent. The median age of participants was 21·5 years (IQR 14–31·5) with 34 (30%) participants younger than 16 years. 50 (45%) of 112 participants were male. We tested a total of 555 specimens: 103 from the axilla, 93 from blood, 92 from conjunctiva, 54 from forehead, 105 from mouth, 17 from the rectum, one from semen, 69 from urine, and 21 from the vagina. The median time from Ebola treatment unit discharge to specimen collection was 142 days (IQR 127–159). 15 participants had a total of 74 swabs taken less than 100 days from discharge. The semen sample from one participant tested positive for Ebola virus at 114 days after discharge from the treatment unit; specimens taken from the axilla, blood, conjunctiva, forehead, mouth, rectum, and urine of the same participant tested negative. All specimens from the other 111 participants tested negative. Interpretation Patients recovering from Ebola virus disease who do not meet the case definition for acute disease pose a low infection risk to health-care providers 6 weeks after clearance of viraemia. Personal protective equipment after this time might be limited to standard barrier precautions, unless contact with fluids from sanctuary sites is envisaged. Funding Save the Children International, Public Health England.

Summary Background Over the past 20 years, there has been a steady growth in the number of reported cases of malaria in the UK. With increasing Internet flight sales over recent years, online travel operator websites may be the only place many travellers could conceivably receive pre-travel malaria prevention advice. Methods 29 Travel operator websites which allow for online flight purchases to malarious areas from the UK, identified using a Google ® web search and the website of the International Air Transport Association, were assessed for the existence, accuracy and accessibility of malaria prevention advice available through internal and external website links. Results Eight (28%) websites provided malaria prevention information on their own pages. Five (17%) websites contained country specific malaria information relevant to the requested destination, including variation of malaria risk within that country and accurate destination specific chemoprophylaxis advice. No malaria information was available, either on internal or external links, on 8 (28%) websites. On average, it took 2.4 additional mouse clicks to access malaria information during the online flight booking process. Six of the 29 websites (21%) allowed for access to information with only 1 click. Conclusions Malaria prevention information on online travel operator websites is most often absent or inadequate. Even on websites where such information is of good quality, it can be difficult to access. The travel industry should introduce and enforce guidelines for the malaria information provided by online travel operators.

The clinical utility of indirect computed tomography venography (CTV) of the legs, performed after computed tomography pulmonary angiography (CTPA), to evaluate for deep venous thrombosis (DVT) remains a subject of ongoing debate. Visualization of DVT on CTV requires adequate opacification of venous blood. The objective of this study is to measure the Hounsfield unit (HU) clot-to-blood gradient on CTV and CTPA. Secondary analysis of computed tomography images from a prospective clinical trial was performed. All images were interpreted independently by a radiologist. Using the "region of interest" tool feature of the picture archiving and communication system, observers measured the HU of blood and thrombus on CTPA and CTV, using a structured anatomic approach. Interobserver coefficient of variability (CV%) was examined in all disease-positive cases and in a random sample of 25 disease-negative cases. One hundred seventy-nine patients were enrolled; and 23 had pulmonary embolus (PE) without DVT (13%), one had DVT without PE (0.6%), and 18 had both (10%), leaving 137 (77%) who had no venous thromboembolism (VTE). For the 137 patients with no VTE, the mean (+/-standard deviation) HU values measured for contrast-containing blood with no thrombus were as follows: left and right main pulmonary arteries (MPA), 291+/-73 and 291+/-76; left and right common femoral vein (CFV), 92+/-17 and 88+/-19; and left and right popliteal vein (PV), 87+/-20 and 84+/-20. On CTPA, the HU measured from the filling defects interpreted as acute PE was 5+/-20, suggesting a between-group HU gradient of 250 or 471% for MPA (PE-to-blood). On CTV, the HU for DVT was 63, suggesting a gradient of 27 HU or 43% for CFV (DVT-to-blood) and 23 HU or 37% for PV (DVT-to-blood). Interobserver CV% were: left and right MPA, 5+/-4.0% and 7+/-5.4%; left and right CFV, 7+/-6.8% and 7+/-7.3%; left and right PV, 7+/-8.4%, 6+/-8.2%, and 32+/-27.1% for PE thrombus, and 20+/-30.5% for DVT thrombus. CTV imaging produces a very small HU gradient between clot and blood in leg veins. These findings highlight the importance of ancillary radiological findings in assessing presence of DVT on CTV.

The safety and efficacy of periodontal disease treatment by intrapocket placement of tetracycline (TC) fibers was investigated in a 60-day multicenter study conducted by selecting 4 sites in each subject with 6-10 mm pockets that bled on probing. Sites were randomly assigned to 1 of 4 test groups: TC fiber therapy, scaling, control fiber (fibers without drug), or untreated. TC fibers and control fibers were placed to fill the pocket and were maintained with a cyanoacrylate adhesive for 10(+/- 2) d. Scaling was performed for a minimum of 5 min under local anesthesia. Following initial tooth cleaning procedures, pocket depth, attachment level and bleeding on controlled-force probing were measured at baseline and at 30 d, and 60 d following therapy. Analysis of data from 107 subjects who had complete clinical data sets indicated that TC fiber therapy significantly decreased pocket depth, increased attachment level, and decreased bleeding on controlled-force probing to a greater extent than observed in all other test groups including scaling. These effects were greater than, and in addition to, effects that occurred due to prophylaxis and improved home care. No serious adverse side-effects attributed to TC fiber therapy were observed. No TC fiber-treated sites abscessed and superinfection was not noted. A transient redness at fiber removal was seen at 21% of the sites. Although fibers were placed without anesthesia, mild pain on initial placement was infrequent (19%) and abated rapidly. The results indicate that TC fiber placement provides a safe and effective means for treatment of periodontal infections.

Charts of 28 patients with a diagnosis of delayed union or nonunion were reviewed. There were four delayed unions and 25 nonunions. Comorbidities, risk factors, treatments, and outcomes were evaluated. Comorbidities were common and included cardiovascular, pulmonary, and renal compromise, as well as endocrinopathies and rheumatologic disease. Consensus risk factors included: unstable fractures (comminuted or short oblique, 83% (24/29); advanced age, 57% (16/28); obesity, 35% (9/28); daily tobacco use, 38% (10/28); and multiple long bone fractures, 21% (6/29). Sixty-nine percent (20/29) of the fractures united; 21% (6/29) failed to heal. Healing outcome for 11% (3/29) could not be determined because of death or loss to follow-up. Patients presenting for primary treatment with any of the aforementioned risk factors should be cautioned regarding possible nonunion.

The study design and baseline characteristics of a multicenter trial to test the effectiveness and safety of locally delivered tetracycline for treatment of adult periodontitis are described. Local delivery was provided by 0.5 mm diameter ethylene vinyl acetate copolymer fibers loaded 25% with tetracycline hydrochloride which were placed into periodontal pockets and maintained by an adhesive for 10 (±2) days. A total of 113 subjects (56 male and 57 female; mean age 49.3 yr) at five centers participated in the study. Subjects were selected who had 4 nonadjacent teeth with 6–10 mm pockets that bled on probing. The selected sites in each subject were randomly assigned to 4 test groups: tetracycline fiber, control fiber, scaling with root planing, or untreated. A balanced experimental design was thereby established in which each subject contributed equally by providing 4 clinically comparable sites for evaluation. To provide a more specific model for testing periodontitis therapy, gingivitis was treated prior to the initiation of the study by prophylaxis with supragingival calculus removal and home care instruction. Clinical response variables measured were pocket depth reduction, attachment level gain and bleeding on controlled-force probing measured at baseline, 30 d, and 60 d. Levels of 6 bacterial species selected as probable periodontal pathogens were measured by DNA probe analysis of plaque samples. The design of this study provided several unique analytical opportunities. Controls included a comparison with conventional treatment, analysis of vehicle effects, and effects at untreated sites. Comparison of the test group with controls permitted evaluation of the principal variables that could effect interpretation of results. The balanced design created by equal representation of each subject in each test provided means to compensate for individual differences between subjects. The combination of these factors resulted in an experimental design which addresses many of the concerns that have been expressed relating to the conduct of clinical trials of periodontal treatments.

Root planing depends on quality instrument cutting edges. The sharpness and wear of stainless steel (SS) and high carbon steel (HCS) dental curettes were compared before and after standardized root planing procedures. Forty working edges of dental curettes, 20 of each alloy, were examined by scanning electron microscope (SEM) prior to any root planing (control), after 15 strokes, and after 45 strokes. Root planing was carried out on freshly extracted, single-rooted teeth, mounted in natural positions in mannikin jaws. Working areas measuring 3 x 5 mm were marked on root surfaces previously exposed by periodontitis. Each working edge was examined at points 1 mm and 2 mm from the tip under the same magnification (x 240). Microscopic observations showed that edge deformation increased from the control (factory sharpened) group, to the "15 stroke" group, and from the "15" to the "45 stroke" group, in both SS and HCS curettes. SS curettes, however, demonstrated significantly more wear than HCS curettes. After 45 strokes, only 5% of the SS curettes were sharp, compared to 20% of the HCS curettes. While 65% of the SS curettes showed severe edge deformation by the end of the study, only 20% of the HCS curettes were severely deformed (P less than 0.01). The results indicate that HCS curettes are more resistant to wear than SS curettes. Further study is indicated to evaluate the relationship between actual bevel dimensions and root planing effectiveness.

The Chardack-Greatbatch implantable pacemaker has proved a worthwhile device for the management of both congenital and acquired heart block. The procedure used for implantation in 38 patients is described. The most frequent indication for use of the pacemaker is syncope due to heart block. Progressive cardiac enlargement was also an indication for pacemaker implantation in two of four children with congenital heart block. The pacemaker has also been useful in the management of surgically induced heart block and coexisting heart block that accompanies intracardiac lesions, such as aortic stenosis, which require open-heart surgery. Pacemaker failure due to electrode breakage occurred in two patients. In both instances, a replacement unit was successfully used. Three of the 38 patients have subsequently died from causes unrelated to pacemaking while one death resulted from pacemaker failure 12 months after implantation. The remaining 34 patients have remained free from cardiac symptoms during observation periods of 2 to 24 months.

Dental plaque was collected, dried, and weighed on a gold insert that fit into the buccal aspect of a posterior crown. The plaque weight was determined by calculating the difference between the postcollection insert weight and the precollection insert weight. This system for measurement of the dry weight of in vivo accumulated dental plaque was found to be a practical means of plaque quantification.

Root planing instrumentation was accomplished on extracted teeth using the hand curette, the Cavitron Ultrasonic, and the Alpha-Sonic instruments. Histologic methods were used to determine the composition of the surfaces following instrumentation. The surface roughness after instrumentation was evaluated with a profilometer and a scanning electron microscope. Hand curettes produced the surfaces with the lowest roughness values and the least apparent irregularities in the SEM photographs. In this study none of the instrumentation methods consistently removed all of the cementum.

The Negro-white arrest rate differential for selected years between 1942 and 1965 in a northern industrial community is analyzed with respect to age, sex, and the socioeconomic variables of employment status, occupation, and migration. Although the incidence of recorded Negro crime has greatly increased since 1942 owing to the increase in the Negro population, the rate of Negro crime has decreased. The magnitude of the excess of the Negro over the white arrest rate reflects the wider distribution among Negroes of the lower social class characteristics of unemployment, employment in unskilled and semiskilled occupations, and migration from the rural South. The findings do not support color-caste theories which interpret Negro criminal behavior as a response to racial proscriptions or which construe Negro criminality as a function of racially suppressive law enforcement tactics. (Abstract Adapted from Source: American Sociological Review, 1970. Copyright © 1970 by the American Sociological Association) Racial Differences Racial Factors 1940s 1950s 1960s Black-White Comparison Offender Arrest Adult Arrest Adult Crime Adult Offender African American Adult African American Crime African American Offender Caucasian Adult Caucasian Crime Caucasian Offender Social Class Class Factors Sociocultural Factors Socioeconomic Factors Employment Factors Unemployment Factors 07-02

The sentences imposed in consecutive criminal cases are analyzed in terms of psychophysical theory. The findings reveal that the severity of the individual sentence relative to the sentences imposed in legally equivalent cases tends to shift significantly toward the relative severity of the sentence in the preceding case; the greater the similitude in substantive legal makeup between the two cases, the more pronounced is the shift. The displacements in judgment result from changes in the affective rather than the cognitive component of judicial attitudes and suggest an operational model of the juridical concept of "judicial temperament." The direction of the shift toward rather than away from the judgment in the preceding case and the powerful effect of the recency of the prior stimulation illustrate the socio-psychological foundation of the legal principle of stare decisis. This is a report of an inquiry into the effect of stimulus arrangements upon normative judgment in a natural social setting. The medium of investigation consists of sentences meted out by criminal court judges to convicted offenders. The study deals in particular with the effect of the individual judge's assessment of the gravity of preceding cases upon variance in the gravity of the sentences imposed in succeeding cases. Whereas the lore of the legal profession attributes the disparity in sentences for cases of equivalent legal makeup to the vagaries of judicial temperament, this study proposes that deviation from self-consistency derives substantially from a continuous shifting in the individual judge's standard of judgment produced by the variation in seriousness between consecutive cases disposed of in the daily docket of the court. The theoretical framework of this study rests upon a foundation of experimentation which reveals the systematic operation of general processes underlying variability in judgment, whether in the physical, esthetic, or ethical modalities of experience (Sherif, and Hovland et al., 1961 provide a concise synthesis of the literature concerning the psychodynamics of judgment). The results of that research show that scales of judgment develop out of the repeated experiencing of stimuli of a particular type within a given range of

The control of plaque formation on tooth surfaces would appear to be a major goal of preventive dentistry. Several subjective scoring procedures for estimating plaque have been described. In the prresent investigation, stained and unstained plaque scorres were compared with various physical characteristics of plaque such as dry weitht, wet weight, microscopic count, absorbance of dispersed plaque suspensions, nitrogen and carbohydrate content. An institutionalized population that exhibited moderate to severe gingivitis and heavy plaque accumulations was studied. Significant correlations between the gravimetric measurements and microscopic count with either gingivitis scores or the unstained plaque scores were found. The stained plaque scorre showed no correlation with plaque weight or gingivitis scores in this population.