We report two cases of Japanese men who presented with proteinuria, eosinophilia, hypocomplementemia, and high serum immunoglobulin G4 (IgG4) concentration and were diagnosed with membranous nephropathy associated with IgG4-related tubulointerstitial nephritis on renal biopsy. The typical renal lesions of IgG4-related disease are tubulointerstitial nephritis, which improves remarkably with steroid therapy, and occasional glomerular changes. In our two cases, renal biopsy revealed IgG4-positive immune complex deposits in glomeruli in a pattern of membranous nephropathy and concurrent tubulointerstitial nephritis with IgG4 plasma cells. In both cases, proteinuria persisted with initial prednisolone treatment and was resolved only after the addition of mizoribine. We report the first two cases in which the combination of prednisolone and mizoribine was effective for treating membranous nephropathy associated with IgG4-related tubulointerstitial nephritis. Recently, attention has been drawn to immunoglobulin G4- (IgG4-) related diseases (IgG4-RD), an autoimmune disease involving multiple organs, including the pancreas, kidney, salivary and lacrimal glands, lung, lymph nodes, and retroperitoneum . It is cWe herein present two cases of membranous nephropathy with concurrent IgG4-TIN, both of which were successfully treated by a combination of prednisolone and mizoribine.μL), and normal serum creatinine level 1.0 mg/dL (88.4 μmol/L). Serum total IgG and IgG4 levels were elevated at 6989 mg/dL and 2750 mg/dL, respectively. An abdominal CT scan with contrast and kidney ultrasound showed no abnormalities and showed both kidneys at 9 cm.The patient was a 69-year-old Japanese man who presented with anorexia and weight loss. Five months prior to admission, he had visited a local hospital complaining of lower abdominal pain; colonoscopy revealed early-stage colon cancer, and he underwent endoscopic resection. The patient's persistent abdominal pain, anorexia, and weight loss of >10% after two months prompted a concern for recurrence of malignancy; however, computed tomography (CT), magnetic resonance imaging, and positron emission tomography scans showed no abnormalities other than mildly enlarged supraclavicular and para-aortic lymph nodes. He was referred to our tertiary medical center for further evaluation. His past medical history included hypertension, dyslipidemia, and glaucoma for 10 years. Physical examination was normal, except for mild hypertension (143/80 mmHg). Laboratory findings are listed in The renal biopsy tissue contained the cortex and medulla, with 27 glomeruli , and shoFollowing the renal biopsy, the patient was diagnosed with IgG4-TIN and concurrent membranous nephropathy and was started on oral prednisolone 55 mg/day (0.9 mg/kg/day) with an immediate decrease in serum IgG levels and increase in serum complement. Proteinuria, however, persisted for over 2 months, fluctuating between 1.5 and 4 g/day, and oral mizoribine 100 mg/day was added. The patient's proteinuria finally trended down after initiation of mizoribine, reaching 0.4 g/day. Mizoribine was subsequently discontinued after the patient developed hepatotoxicity and was switched to azathioprine 25 mg/day. Currently, 4 years after the initial diagnosis, the patient is administered prednisolone 1 mg/day and azathioprine 25 mg/day, maintaining normal complement, normal serum creatinine level, and negative proteinuria. There were no extrarenal manifestations of IgG4-RD during this follow-up period.μL), hypoalbuminemia, and hypocomplementemia (μmol/L). Both IgG and IgG4 levels were elevated at 6350 mg/dL and 1350 mg/dL, respectively. Kidney ultrasound showed normal sized kidneys with small cysts. An abdominal CT scan with contrast showed a small amount of pleural effusion and ascites, without any lesions in either kidney.An 80-year-old Japanese man with a history of myocardial infarction, osteoarthritis, and 40-pack-year smoking was admitted to a local hospital with pancreatitis of unknown etiology 4 months prior to admission. One month after discharge, he developed leg edema on both legs and other features consistent with nephrotic syndrome, prompting referral to our medical center. Laboratory findings indicated proteinuria (2.73 g/day), eosinophilia  reduced his serum complement and IgG levels, and proteinuria was resolved to some extent (0.3 g/day). Two months later, when the prednisolone dose was tapered, however, proteinuria recurred (2.6 g/day); mizoribine was added to his regimen, which resolved the proteinuria. He had another episode of proteinuria 10 months after the initiation of mizoribine, which was resolved with temporarily increased prednisolone dose. We followed up with this patient for 17 months after the initial diagnosis when he tested negative for proteinuria and had normal complement and serum creatinine levels, and, subsequently, we tapered the prednisolone dose to 10 mg/day with mizoribine 150 mg/day. There was no recurrence of pancreatitis or any other extrarenal manifestations of IgG4-RD during the follow-up period. supraclavicular and para-aortic lymph nodes on CT in Case 1 and a recent history of pancreatitis of unknown etiology in Case 2 were assumed to be secondary to IgG4-RD.While many studies have reported IgG4-RKD in the past decade, a proposal on diagnostic criteria has been only recently published , 13. IgGIt is unclear why most cases of IgG4-RKD show TIN, whereas some cases show concurrent glomerular lesions. Nishi et al. reviewed 37 cases of IgG4-RKD that presented with TIN, of which 10 cases 27%) had complicated glomerulonephritis, including mesangial proliferative glomerulonephritis, membranous nephropathy, membranoproliferative glomerulonephritis, and endocapillary proliferative glomerulonephritis 7% had co, 11, 12.Of the 15 cases in which the treatment and the outcome were reported, 13 cases were initially administered corticosteroid therapy based on the fact that typical IgG4-RD and IgG4-TIN improve remarkably with steroid therapy . HoweverIn the two present cases, we initially failed to control proteinuria with steroids alone but observed a decrease to 0 g/day as well as maintenance of renal function after adding mizoribine. Mizoribine is an imidazole nucleoside with immunosuppressive activity, which inhibits T-cell and B-cell proliferation . Its useWhile IgG4-RD is generally known to have a favorable response to steroid treatment, a poor response in cases of proteinuria with steroid therapy suggests that, although TIN subsides with steroids, the membranous nephropathy may linger. In such cases, it is justified to treat patients with immunosuppressants.In summary, we describe two cases of IgG4-TIN with concurrent membranous nephropathy that responded favorably to the combination of prednisolone and mizoribine. When renal function or proteinuria in IgG4-RKD does not respond well to steroid therapy, particularly when these conditions are associated with membranous nephropathy, the administration of immunosuppressants should be considered.


In the Abstract, the final sentence in the Conclusions subsection is incorrect. The correct sentence should read: “HIV suppression with treatment protects against the appearance of HSIL.”


Antimicrobial prophylaxis for urologic procedures is a major issue, as potential advantages of antibiotic administration should be carefully weighed against potential side effects, microbial resistance, and health care costs. This study aimed to review a six years trend of antibiotic use in urological surgeries at Muhimbili National Hospital (MNH) being an experience in a typical third world environment.This was a six years hospital based descriptive, retrospective study conducted of which all case notes of urological patients operated on in between January 2007 to December, 2012 were reviewed by using a structured data collecting tool. The data were analyzed using SPSS software.Male patients were the majority at 62% (450). The age range was 0 - 90 years, with a mean of 30 ± 22.09. Among the urological surgeries done at MNH 86.5% (628) received prophylactic antibiotics regardless of the type surgery done. Majority 63.7% (463) received antibiotics during induction. Ceftriaxone was the commonly given antibiotic regardless of the type of urological surgery done. Most of patients (86.4%) were given antibiotics for five days regardless whether it was for prophylactic or treatment intention.Antibiotic use is still a challenge at our hospital with over use of prophylactic antibiotics without obvious indications. Prolonged use of prophylactic antibiotics beyond five days was the main finding. Ceftriaxone was the most given antibiotic regardless of the urological surgery done and its level of contamination. Antibiotic stewardship needs to be addressed urgently to avoid serious drug resistances leaving alone the cost implication. Antibiotics are synthetic molecules that can destroy or inhibit the growth of microorganisms without harming the host. They can be used for prophylactic purposes to reduce the incidence of postoperative infection of which duration should not exceed 24hrs in many procedures given one hour prior to incision. Also antibiotics for treatment purposes are given when an established infection has been identified.Antibiotic prophylaxis is a brief course of antibiotics administered before or at the start of an intervention and used to minimize the infectious complications resulting from diagnostic and therapeutic interventions. While the rationale for the use of antibiotics is well accepted, possible side-effects and development of microbial resistance patterns are potential risks. Therefore, an antibiotic prophylaxis policy should be well considered and, ideally, based on high levels of evidence. Urology is a surgical speciality which has under-gone many changes in the last decade. Surgical procedures have mainly shifted from open to endoscopic and laparoscopic procedures, and nowadays, a greater number of elderly patients or carriers of temporary urinary derivations are being operated on. These developments can influence the choice of antibiotic prophylaxis policy. Although it is common practice to administer antibiotic prophylaxis in many urologic procedures, there is still little evidence for the use of antibiotic prophylaxis in most of these procedures. This is mainly due to the lack of well-designed studies as well as the lack of clear definitions of favourable outcome parameters. The question remains to what extent antibiotic prophylaxis is beneficial in the different urologic procedures. Various authors have addressed this issue in reviews in recent years –5. Also,This was a retrospective study at Muhimbili National Hospital (MNH)- medical record department from November 2013 to April 2014. All case notes of urological patients operated on in between January 2007 to December, 2012 was included in the study.All available case notes of operated patients in urology unit during the period of 2007 to 2012 were eligible for use in this study.Case notes with incomplete information were not considered in some of the analysis where such missing variable are imperative.A structured questionnaire was used to collect data from patient's case notes. An electronically generated medical detail of all operated patients was obtained per year. The details that were possible to obtain included the age, sex, file number, date of operation and type of operation. From this, patients who were operated under urology unit were identified and their case notes retrieved. Data coding was done, cleansed and entered into computer software for storage and analysis using SPSS version 18 statistical program. Frequencies were run for all categorical variables and patterns of surgery and their outcome described. Mean and standard deviation were used to summarize continuous variables.REF.No.MU/DRP/AEC/Vol.XVIII/22 of 30th October 2013 and a separate permission to conduct the study was also obtained from the Executive Director of Muhimbili National Hospital (MNH). Direct patient identifiers were not used except for file numbers during initial data collection; thereafter the questionnaires were coded for further analysis.Ethical clearance to conduct the study was obtained from the Institutional Review Board (IRB) at Muhimbili University of Health and Allied Sciences (MUHAS) This study was done at Muhimbili National Hospital which is the only national referral hospital located in the Centre of Dar es Salaam city, thus the findings may reflect a true image of the trend of antibiotic use in urological surgeries in Dar es Salaam and country. At large but incomplete documentation might impair the image.A total 726 case notes of patients who underwent urological surgeries during the study period of six years were reviewed. The age range was 0 - 90 years, with a mean of 30 ± 22.09 with male predominance giving a ratio of 6.4: 1. Cystoscopy 260 (36%) was the most commonly done urological surgery followed by prostatectomy 154 (21%) . Most ofIn this study we found that urological surgeries are predominantly done in male with a wide range of ages. Most of our patients 589 81.1%) were given antibiotics regardless of the type urological surgeries this is similar to the findings of others studies in Europe, United states and local studies that addresses the use of antibiotic prophylaxis in urologic interventions. Contrary to the recommendation from others studies that Antibiotics for most urologic interventions having only moderate to low evidence for the use of antibiotic prophylaxis, with the exception of TURP and prostate biopsy. Strong evidence supports the use of short-term prophylaxis for TURP, and this evidence is moderate to high for prostate biopsy. The main point of consideration when assessing the benefit of antibiotic prophylaxis is what to consider as a favourable outcome. In our study Eighty seven point four percent of clean contaminated urological surgeries were given prophylactic antibiotics also those who had clean urological surgeries 265 74.6%) were given antibiotics .1% were , 17. Our4.6% wereAntibiotic use is still a challenge at our hospital. Prolonged use of prophylactic antibiotics beyond five days was the main finding. Ceftriaxone was the most given antibiotic regardless of the urological surgery done and its level of contamination. Antibiotic stewardship needs to be addressed by adhering to antibiotics use guidelines and this will increase the quality of care and at the same time reduce both costs and the development of microbial resistance. Further research is needed because of lack of evidence that those patients with increased risk for infectious complications should receive antibiotic prophylaxis and why do clinicians give antibiotics empirically.


Expansion and cracking induced by the corrosion of reinforcement concrete is the major factor in the failure of concrete durability. Therefore, monitoring of concrete cracking is critical for evaluating the safety of concrete structures. In this paper, we introduce a novel monitoring method combining Brillouin optical time domain analysis (BOTDA) and fiber Bragg grating (FBG), based on mechanical principles of concrete expansion cracking. BOTDA monitors concrete expansion and crack width, while FBG identifies the time and position of cracking. A water-pressure loading simulation test was carried out to determine the relationship between fiber strain, concrete expansion and crack width. An electrical accelerated corrosion test was also conducted to evaluate the ability of this novel sensor to monitor concrete cracking under practical conditions. Reinforcement corrosion has become the major reason for the failure of concrete durability. It is estimated that maintenance costs for reinforced concrete structures is up to 100 billion dollars worldwide [Newly developed technologies, such as the anode ladder sensor developed by RWTH Aachen University  and the in situ. Lee [In recent years, the fiber Bragg grating (FBG) sensor has been extensively adopted as a new non-destructive evaluation technique for monitoring strain in structures under corrosive conditions . Saouma itu. Lee  used FBGitu. Lee  presenteitu. Lee . Zhao [1itu. Lee  demonstritu. Lee  approveditu. Lee ,16 also In this paper, we present an approach that combines BOTDA and FBG. BOTDA is used to monitor the progression of expansion and cracking induced by reinforcement corrosion, while FBG is used to identify the time and position of cracking. A water-pressure loading simulation test was used to establish a relationship between fiber strain, concrete expansion and crack width. An electrical accelerated corrosion test was also carried out to verify the effectiveness of the monitoring of concrete cracking under practical conditions.The interaction between incident light waves and acoustic phonons in optical fibers generates Brillouin scattered light as backscattered light, which propagates in the opposite direction of the incident light waves. When the strain or temperature varies, the Brillouin frequency will shift. The frequency shift has a linear relationship with both strain and temperature. The relationship among strain variation, temperature change and Brillouin frequency shift is expressed in Equation (1) . (1)ΔvB has a relationship with both temperature change (ΔT) and strain variation (Δε), but there is no coupling relationship between them. Free optical fiber sensors that are not bonded to a structure can be used as temperature compensation sensors by laying them beside the strain monitoring sensors, thus eliminating the influence of temperature on strain monitoring.The Brillouin frequency shift ΔvZ is the distance from the position where incident light is launched to the position where scattered light is generated, which can be determined by using Equation (2). c is the velocity of light in a vacuum, n is the refractive index of the optical fiber and t is the time interval between launching the incident light and receiving the scattered light at the launching end.τ) of the incident light. For a given pulse width τ, the spatial resolution ∆Z is expressed as: As a distributed testing technique, BOTDA’s main disadvantage is its limited spatial resolution. Spatial resolution is determined by the pulse width ( section .Bλ) that is reflected at the sensor is given by: Bn is the reflective index and Λ is the spatial pitch. When projecting a wide spectrum light source onto the optical fibers, the narrow band spectrum satisfying Equation (4) would be reflected back due to the effect of the gratings.FBG is a periodic and permanent modification of the core refractive index value along the optical fiber axis . The FBGBλ) and the changes of strain and temperature at the grating region (εg) can be expressed as: ερ is the strain-optic coefficient, ν is Poisson's ratio and α and β represent the thermal expansion and thermo-optic coefficients, respectively. Any changes in external parameters  would alter the grating characteristics and result in a shift of the reflected Bragg wavelength.The relationship between the reflective Bragg wavelength shift  free expansion stage: the corrosion products fill the voids around the steel/concrete interface or migrate away from the steel/concrete interface; (2) stress-initiated stage: as the total amount of corrosion products reaches the threshold value, the formation of corrosion products starts to create expansive stress on the surrounding concrete, which increases with the growth of corrosion products; (3) cracking stage: when the expansive stress exceeds the tensile strength of the concrete, cracks will initially emerge around the steel and subsequently propagate to the surface of the concrete . In this(1)Elastic deformation: concrete behaves as an elastic material, such that non-linear deformation is not considered.(2)Uniform corrosion: corrosion products arrange uniformly around the steel; therefore, the expansion stress acting on the concrete cover is uniform.(3)No leakage of corrosion products: corrosion products do not leak out from the concrete cover; therefore, expansion stress increases with increasing amounts of corrosion products.Concrete is under elastic deformation before cracking; therefore, elastic mechanics principles are used to explain the mechanism of corrosion-induced concrete expansion. In this paper, three main assumptions are considered: The mechanical model of reinforced concrete corrosion is illustrated in σ is the hoop stress of concrete, p is the internal pressure, b is the external diameter of the circular ring, a is the internal diameter of the circular ring, r is the distance from the analysis point to the center, ε is the hoop strain at the analysis point and E is the elastic modulus of concrete. From the equations above, it is clear that there is a linear relationship between corrosion-induced expansion (Δd) and concrete strain (ε).According to elastic mechanics theory, the mechanical equation for a circular ring bearing uniform internal stress is described in Equations (6)–(8). Therefore, one can estimate concrete expansion by monitoring hoop strain. In this paper, optical fibers were bent into a circular shape around a steel bar to record concrete expansion strain by BOTDA.As discussed in w is the total widths of all cracks, ε is the optical fiber strain, ΔL is the elongation length of the optical fiber due to cracking  and L is the gauge length . The illustration of crack detecting by BOTDA is shown as Elastic mechanics theory is inapplicable once concrete cracks have formed. Thus, there is no mechanical theory that explains the relationship between crack width and optical fiber strain. However, geometric analysis can be utilized to establish the relationship between crack width and optical fiber strain. The strain at positions where the optical fiber crosses a crack is greater than the strain at other positions. Therefore, crack width analysis can ignore the strain measured at all points other than the crack position. According to geometric analysis, the strain at positions where the optical fiber crosses a crack is given by: n) located in the spatial resolution is related to the position of both sample point (D) and optical fiber (2πRf). Therefore, the total crack width w is given by: iw is the width of each crack located in the spatial resolution and n is the total number of cracks located in the fiber whose length is equal to the spatial resolution. Therefore, the crack width can be calculated by the fiber strain of BOTDA. In iw) could be obtained. Two assumptions should be mentioned: (1) the number of cracks (n) is a known parameter; it can be obtained by logical analysis in the following sections; (2) the width of each crack iw is an average value.In Equation (11), the width of each crack ((1)The embedding of an optical fiber into the concrete should cause the least adverse effect on the concrete; therefore, the optical fiber should be as slim as possible. In this paper, a 900-μm tight-buffered optical fiber and 125-μm bare Bragg grating were selected for BOTDA and FBG, respectively.(2)As bare Bragg grating fiber is extraordinary brittle, effective methods need to be implemented to protect the grating. In this paper, the bare Bragg grating is pasted on the surface with tight-buffered fibers and covered by epoxy resin for protection.(3)Temperature compensation should be implemented to obtain precise results. Based on Equations (1) and (5), the measured strain is impacted by temperature in both BOTDA and FBG sensing technologies. In this paper, temperature compensation was achieved by setting up compensation samples cast with the same materials, embedded with the same sensors and placed in the same environment as the test samples. However, the compensation samples lacked a steel bar, so that no corrosion-induced concrete expansion or cracking occurred.According to the principles discussed above, several key points should be considered in the design of an optimal sensor: (1)Electrical accelerated corrosion test: distributed optical fibers and bare Bragg grating fibers were embedded into samples simultaneously in order to monitor concrete expansion by BOTDA and to identify cracks by FBG.(2)Water-pressure loading simulation test: distributed optical fibers alone were embedded into samples to establish the relationship between optical fiber strain and crack width.Reinforced concrete corrosion in natural environments is a long-term process, typically occurring over the course of decades. Therefore, electrical accelerated corrosion tests are commonly employed to study reinforced concrete corrosion. However, in these tests, the corrosion products permeate and contaminate the concrete surface, such that it is impossible to identify the initial crack or to measure the crack width. To avoid this issue, we conducted a simulation test based on water-pressure loading. The main purposes of the accelerated corrosion test and water-pressure test were as follows: The samples used in the water-pressure loading simulation test were circular rings with an external diameter of 85 mm and an internal diameter of 20 mm. After being wound with 2.0 m of optical fiber, the diameter of the optical fiber ring was 75 mm. A schematic of the water-pressure loading simulation test is shown in Water pressure was applied to the internal hole of the circular ring to simulate corrosion-induced expansion force. The expansion force was produced by pouring water into a hollow tube. An inlet opening was installed at one end of the tube, and a pressure gauge was installed at the other end of the tube. In the middle section of the tube, three osculums were arranged around the tube. The water outflow from the three osculums was sealed up by a heat-shrinkable sleeve and a water stop valve. The section of heat-shrinkable sleeve located inside the concrete tube was free, while the other sections were restrained by the steel tube. Thus, the free section could produce an expansion force on the surface of the concrete sample. The layout of the water-pressure loading simulation test is shown in A DITEST STA-R BOTDA (product of OMNISENS Switzerland) was used to monitor the strain of the distributed optical fiber. The spatial resolution was set as 500 mm, and the sampling point distance was set as 100 mm. BOTDA recorded the Brillouin frequency shift automatically during the experiment. Strain was calculated by Equation (1). Previous experiments revealed that cracking would begin once the pressure gauge reading reached 6.0 Mpa–7.0 MPa. This might result in brittle failure if no restraint measure were applied on the surface of the concrete sample. BOTDA cannot record the strain in such a short time; hence, a fastener was installed on the surface of the concrete sample to control the crack propagation. The simulation test occurred via a two-stage process: (1) the surface of the concrete sample remained free; the loading step was set as 1.0 Mpa and was then increased to 6.0 Mpa; (2) a fastener was fixed on the surface; the load was gradually increased until an initial crack was observed, after which the fastener was released step by step. The strain of the optical fiber is shown in The concrete sample employed in the electrical accelerated test was a cubic specimen with dimensions of 150 mm × 150 mm × 150 mm. The specification of the steel bar was HRB335 with a 20-mm diameter. The detailed configuration of the concrete sample is shown in The concrete cover was set as 40 mm. As wood formwork was applied to cast the cubic specimen. A hole with a 21-mm diameter was set at the bottom board of the wood formwork. Eleven holes with a 2-mm diameter were drilled at the other four surfaces of wood formwork, which acted as the anchor point for strings. In order to install the steel bar precisely, one end was inserted into the hole on the bottom board, while the other end was fastened by strings. Another network knitted by four strings provided an installation platform for corrosion monitoring fibers. The fibers were made into a loop 75 mm in diameter firstly, then placed into the network at the correct position and, finally, bonded to the string.2. The layout of the experiment is shown in In order to mimic actual conditions as closely as possible, four surfaces of the specimen were painted with epoxy resin. The other two surfaces adjacent to the steel bars were not painted, so that chloride ions could transfer into the concrete sample freely. Three specimens were used in the parallel electrical accelerated corrosion test. Only the distributed optical fiber sensor was embedded in the concrete cover of Specimen I and Specimen III, while the distributed optical fiber sensor and bare Bragg grating were embedded in Specimen II simultaneously. The embedding method for the sensors has been described in A DITEST STA-R BOTDA was used to monitor the strain of the distributed optical fiber. The parameters used were the same as that of the water-pressure loading simulation experiment. A MOI (company named Micron Optics) 125 static FBG was used to monitor the wavelength variation of the bare Bragg grating. A temperature compensation specimen without reinforced steel bar was placed in the same environment as Specimens I, II and III. No steel bar embedded means no expansion and cracking would occur in the temperature compensation specimen. Distributed optical fiber and bare Bragg grating were embedded the same way as Specimen II in the temperature compensation specimen. Thus, the Brillouin frequency shift and Bragg wavelength shift recorded by BOTDA and FBG were only related to the temperature change.In 8a, b, the temperature variation of BOTDA and FBG shares the same tendency. Since the specimens were immersed in water, the temperature variation did not have the same regularity with the change of environmental temperature. The shift values of distributed optical fiber and wavelength are used to acquire temperature compensation according to Equations (1) and (5). The strain of the distributed optical fiber and wavelength variation by considering temperature compensation are shown in In A water-pressure test and accelerated corrosion test were performed to monitor concrete expansion , ε is optical fiber strain and R is the correlation coefficient. Therefore, estimating crack width by fiber strain of BOTDA is feasible. It should be noted that the crack width is the summation of all crack widths around the specimen, shown as In the water-pressure test, two cracks appeared simultaneously, which exhibited an approximately symmetrical distribution. Thus, the relationship between average crack width and fiber strain is as follows:n in Equation 11 equals five. The theoretical relationship between average width and fiber strain is as Equation 18: Shown as By comparing Equation 17 with Equation 15, the maximal error of the crack is 31.5. This means that if the fiber strain were 2000 με, a 0.063-mm estimated error of the crack width would occur. Additionally, this error is acceptable.(1)Optical fibers are characteristically anti-corrosive and stable, rendering them suitable as candidates for sensors in corrosive environments. We present the theoretical principles underlying sensor function based on elastic mechanics and geometric analysis, and we show that the theoretical and experimental results matched reasonably.(2)Corrosion-induced concrete expansion can be monitored by BOTDA. A water-pressure test can be employed to obtain the threshold value for evaluating cracking, and this value may be used to evaluate the degree of expansion and to predict when cracking occurs.(3)Corrosion-induced initial cracking can be recognized by FBG. Using a bare Bragg grating embedded in concrete around the steel bar, cracking positions could be determined by analyzing the degree of wavelength decrease.(4)Corrosion-induced crack width can be detected by BOTDA. The coefficient between optical fiber strain and crack width can be obtained using theoretical equations and experimental parameters. Corrosion crack width can be estimated by analyzing the optical fiber strain from BOTDA.(5)In this paper, the familiar variation trend of fiber strain from BOTDA and wavelength from FBG are observed before cracking. This indicated that FBG alone may be able to monitor the whole corrosion process, thus the monitoring costs would become reasonable, because the equipment for BOTDA is extremely expensive. Furthermore, some calibration experiments should be carried out to establish the relationship between concrete strain and wavelength.In this paper, we present a novel sensor for reinforced concrete corrosion based on BOTDA and FBG. This sensor can monitor the entire corrosion process, including concrete expansion, and can detect the initial position and crack width. Based on the data from the two types of experiments carried out to evaluate this novel sensor, we conclude that: It should be noted that the threshold value for concrete cracking depends on the concrete mixture, while the cracking width coefficient depends on the test parameters of BOTDA. Thus, a calibration experiment should be carried out firstly before applying this novel sensor to a specific project. The experiments reported in this paper were conducted indoors; it would therefore be necessary to perform these experiments again on-site to study the performance of the sensor in a different setting.


Myofibrils were activated isometrically along the descending limb of the force–length relationship (mean ± 1 standard deviation (SD) = 2.8 ± 0.3 µm sarcomere−1). Once the I-state was reached, myofibrils were shortened to an SL on the plateau of the force–length relationship (2.4 µm sarcomere−1), and then were actively stretched to the reference length (2.9 ± 0.3 µm sarcomere−1). We observed RFE in all myofibrils (39 ± 15%), and saw varying amounts of non-uniformity (1 SD = 0.9 ± 0.5 µm) that was not significantly correlated with the amount of RFE, but through pairwise comparisons was found to be significantly greater than the non-uniformity measured for the I-state (0.7 ± 0.4 µm). Three myofibrils exhibited no increase in non-uniformity. Active stretching was accompanied by sarcomere popping in four myofibrils, and seven had popped sarcomeres in the I-state. These results suggest that, while non-uniformities are present with RFE, they are also present in the I-state. Furthermore, non-uniformity is not associated with the magnitude of RFE, and myofibrils that had no increase in non-uniformity with stretch still showed normal RFE. Therefore, it appears that SL non-uniformity is a normal associate of muscle contraction, but does not contribute to RFE following active stretching of isolated skeletal muscle myofibrils.The sarcomere length non-uniformity theory (SLNT) is a widely accepted explanation for residual force enhancement (RFE). RFE is the increase in steady-state isometric force following active muscle stretching. The SLNT predicts that active stretching of a muscle causes sarcomere lengths (SL) to become non-uniform, with some sarcomeres stretched beyond actin–myosin filament overlap (popping), causing RFE. Despite being widely known, this theory has never been directly tested. We performed experiments on isolated rabbit muscle myofibrils ( RFE iA popular mechanism thought to be responsible for RFE is the sarcomere length non-uniformity theory (SLNT) ,25. PropThe SLNT has been expressed as a mathematical model, which incorporates predictions regarding RFE following active stretch of muscle ,25. The Despite extensive research regarding RFE in skeletal muscle, the detailed and specific assumptions and predictions of the SLNT have not been tested directly. Specifically, SL changes (prediction 1) and distributions (prediction 2) have not been quantified and directly compared for the I- and FE-states in the same myofibril. In addition, the idea that sarcomeres pop during active stretching (prediction 3), and not during isometric contractions, even if the isometric contractions occur on the descending limb of the force–length relationship, has not been tested systematically –29. Furt2.2.1.® camera  attached to the microscope was used to record all of the experiments on StreamPix 5 video imaging software  at 30 Hz . Myofibril length changes were delivered through a custom-written software program  that controlled radial piezo-tubes  that held the needle, which was attached to the myofibril at one end. The myofibrils were attached to one of a pair of cantilevers for force measurement at their opposite end.Eight six-month-old female New Zealand White rabbits were euthanized by an intravenous injection of sodium pentobarbital according to a protocol approved by the Life and Environmental Sciences Animal Care Committee of the University of Calgary. Isolation of single myofibrils was accomplished as previously published ,26,30,31n = 12) with a good striation pattern  and 5–23 sarcomeres in length, were activated via a specialized jetted fluid (Jacuzzi) technique at a mean SL of 2.8 ± 0.3 µm. The Jacuzzi delivered the calcium-based activating solution  directly to the myofibrils. The myofibrils reached the I-state contraction prior to being rapidly shortened (0.8 µm s−1 sarcomere−1) to an average SL of 2.4 µm, where they were held for 10 s. The myofibrils were then slowly stretched (0.1 µm s−1 sarcomere−1) back to a mean length of 2.9 ± 0.3 µm sarcomere−1 and allowed to reach the FE-state (a). The active shortening phase of the experimental protocol brings the sarcomeres to the initial length required prior to active stretch. By performing this shortening step quickly and following it by a 10 s pause, any history-dependent effects are gone, and so the protocol is equivalent to deactivating the myofibril, bringing it back to the initial length and then reactivating it [Myofibrils  [−1). Forces were normalized to the cross-sectional area, calculated using the diameter of each myofibril at optimal length (2.4 µm sarcomere−1) and expressed in units of stress (nN µm−2) [b,c). The movement of the cantilever that allowed for the quantification of force resulted in small length changes in the myofibril upon activation; therefore, the I-state was defined as the time point following activation at which the mean SL and the myofibril stress were constant. Constant stress was determined visually from the force–time graph as the point when the total myofibril length and therefore, force reached a plateau following activation. The FE-state was defined similarly, following myofibril lengthening until the end of the protocol. Mean SL, standard deviation (SD) of the mean SL, and stress were determined for the I- and the FE-states for each myofibril. The SD of the mean SL was used to quantify the amount of SL non-uniformity, whereby an increase in SD was indicative of a more non-uniform distribution [R correlation was used to determine the relationship between individual SL in the I-state and the length change between the I- and FE-states. The second prediction of the SLNT was tested using a Wilcoxon signed ranks non-parametric test to compare SL non-uniformity (SD) in the I- and FE-states. The third prediction was analysed by determining individual SLs in each state to identify which sarcomeres had popped beyond myofilament overlap (SL ≥ 4.0 µm). A Fisher's exact test was then performed to determine if there was a difference in the number of popped sarcomeres between the I- and FE-states. The fourth prediction was analysed using a Spearman R correlation to identify the relationship between the increase in SD between the I- and FE-states and the amount of RFE. A significance level of 0.05 was used for all of the statistical tests.Individual SLs were defined as the distance between the centroids of adjacent A-bands, as identified using a custom-written MATLABick, MA) ,30,33–36nN µm−2) ,33–40. Aribution ,36. A Wi2.3.N,N,N′N′-tetraacetic acid  at pH = 7.0.Rigor solution: Tris (50 mM), sodium chloride (100 mM), potassium chloride (2 mM), magnesium chloride (2 mM) and ethylene glycol bis(2-aminoethyl ether)-N morpholino)propanesulfonic acid , potassium proprionate (64.4 mM), sodium sulfate (9.45 mM), magnesium proprionate (5.23 mM), potassium EGTA (2 mM), adenosine triphosphate  and creatine phosphate (10 mM) at pH = 7.0.Relaxing solution: 3-(Activating solution: MOPS (10 mM), potassium proprionate (45.1 mM), magnesium proprionate (5.21 mM), sodium sulfate (9.27 mM), sodium EGTA (1 mM), ATP (7 mM), creatine phosphate (10 mM), calcium chloride (0.75 mM) at pCa = 3.12 and pH = 7.0.3.a–c. The I-state exhibited an average stress of 89 ± 35 nN µm−2 (mean ± 1 SD), which was significantly less than the average stress produced in the FE-state , thereby exhibiting an average RFE of 39 ± 15%. The I-state stresses were comparable to values that have been observed previously [Individual myofibril results are presented in figure 2eviously ,34,36,393.1.r = 0.216; p = 0.011; For the 137 individual sarcomeres tested within the 12 myofibrils, a weak but significant correlation was found between SL in the I-state and the length change (3.2.p < 0.05), three of the myofibrils  did not demonstrate an increase in SL non-uniformity, one of which (myofibril 11) produced the greatest amount of RFE.Prior to myofibril activation SL non-uniformity was relatively small (mean SD = 0.1 µm). While there was a significant increase in non-uniformity (SD) from the I-state (0.7 ± 0.4 µm) to the FE-state .The SLNT predicts that active stretching of muscle results in sarcomeres being stretched beyond actin–myosin filament overlap ,25. Whil3.4.r = −0.309, p = 0.328; There was no significant correlation between the amount of RFE exhibited by a myofibril and the increase in SL non-uniformity (4.p = 0.011) between the change in SL between states and SL in the I-state was found, we feel that the strength of this relationship (r = 0.216) and the variability of the individual data . These data oppose the first prediction of the SLNT.Here, we provide the first systematic comparisons of individual SL measurements between purely isometric reference contractions (I-state) and isometric contractions following active stretch (FE-state) in the same myofibril where individual SL and forces could be measured continuously. The results allowed for systematic testing of basic assumptions and predictions of the SLNT. All myofibrils exhibited substantial RFE, averaging 39% [ual data  questionDespite a relatively large amount of non-uniformity present in the I-state, which has also been observed by other researchers , there wn = 9) exhibited popped sarcomeres in the FE-state, popping only accompanied the active stretch in four myofibrils. In the remaining five myofibrils, sarcomeres had already popped upon activation in the I-state at an average SL of about 2.8 µm. In addition, three myofibrils demonstrated RFE without popped sarcomeres. Force enhancement in the absence of popped sarcomeres has been observed previously [The third prediction of the SLNT requires that sarcomeres must pop in order for RFE to occur ,25. Whileviously . HoweverThe lack of a significant correlation between the amount of RFE and the increase in non-uniformity, as well as the observation of RFE in the complete absence of an increase in SL non-uniformity suggests that while SL non-uniformities are often, but not always, present in the FE state, the amount of non-uniformity does not appear to influence the magnitude of the RFE. This finding contradicts the fourth prediction based on the SLNT.It has been suggested that small variations in SLs along an isolated myofibril may be the result of differences in the number of contractile proteins , or the in vivo skeletal muscles. Active shortening preceding active stretching, if anything at all, should have resulted in increased SL non-uniformities in the FE- compared with the I-state [in vivo. However, a previous study that observed sarcomere behaviour in vivo in passive and purely isometric contractions found approximately 20% variation in SL [in vivo data. Therefore, it appears that SL non-uniformities observed in our isolated myofibril preparations agree well with those in whole muscle preparations. This agreement of course does not imply that results from myofibrils can be generalized to entire muscles, but it lends credence to the idea that similar observations to those made here would probably be made in whole muscle preparations. However, this will need to be confirmed with experiments where active stretching can be accomplished while simultaneously following a number of sarcomeres in situ. Such a study will require technical developments, as nobody has been able to make such measurements to date. Finally, the variability of the results regarding SL distributions and amount of RFE, despite the rigorous and standardized experimental protocol, leads to the conclusion that the phenomenon of RFE cannot be solely credited to the mathematical explanation provided by the SLNT.There are limitations of this study that need to be kept in mind when interpreting the results. The three most critical ones are the fact that stretching of myofibrils was preceded by active shortening, the average SLs were not perfectly identical in the I- and FE-state, and that the experiments were performed on isolated myofibrils instead of  I-state , therefoon in SL , which s5.Based on the findings of this study, we conclude that RFE is not simply a product of the development of SL non-uniformities during active stretch in the manner proposed by the SLNT. Our results oppose the mathematical basis of the SLNT. We observed RFE in the absence of an increase in SL non-uniformities from I- to FE-states and in the absence of popped sarcomeres ,25. SL n


Correct antibiotic treatment is of utmost importance to treat infections in critically ill patients, not only in terms of spectrum and timing but also in terms of dosing. However, this is a real challenge for the clinician because the pathophysiology  has a major impact on the pharmacokinetics of hydrophilic antibiotics. The presence of extra-corporal circuits, such as continuous renal replacement therapy, may further complicate this difficult exercise. Standard dosing may result in inadequate concentrations, but unadjusted dosing regimens may lead to toxicity. Recent studies confirm the variability in concentrations, and the wide variation in dialysis techniques used certainly contributes to these findings. Well-designed clinical studies are needed to provide the data from which robust dosing guidance can be developed. In the meantime, non-adjusted dosing in the first 1 to 2 days of antibiotic therapy during continuous renal replacement therapy followed by dose reduction later on seems to be a prudent approach. This commentary discusses the findings of Beumier and colleagues  about beBut also when the kidneys fail, antibiotic dosing can be challenging. When kidney function deteriorates, standard dosing may lead to accumulation of a drug and therefore antibiotic doses are often adapted to the kidney function. Also, when renal replacement therapy (RRT) is indicated, antibiotic doses are often decreased.RRT does, however, affect antibiotic concentrations as antibiotics are also eliminated from the circulation. The rate at which this occurs is affected by the physicochemical characteristics of the drug and the type and intensity of RRT used, among other factors. Antibiotics with a small volume of distribution and low protein binding will be affected more. It can be expected that CRRT techniques are more efficient in removing antibiotics from the blood.Several studies have addressed this issue in recent years. Seyler and colleagues  found thCritical Care, Beumier and colleagues [In this issue of lleagues  report tWith these new data, drawing firm conclusions regarding antibiotic dosing during RRT remains difficult. However, it can be concluded that higher-than-standard dosing in this patient population is probably unwarranted. From previous studies, it seems that underdosing is more common during the first days of treatment and that overdosing may occur later (48 hours or later) when doses are not adjusted. This is probably due to the fact that factors other than RRT determine the concentrations in the first 24 to 48 hours of therapy, such as the enhanced volume of distribution, and elimination determines the subsequent concentrations. Furthermore, it should be kept in mind that the susceptibility of the microorganism is equally important; target attainment is in danger only when borderline susceptible microorganisms with higher-than-average MIC are involved.Clearly, more research using well-designed studies with prospective data collection is needed. Moreover, the impact of other RRT strategies such as intermittent hemodialysis and sustained low-efficiency daily dialysis needs our urgent attention. In the meantime, for patients undergoing CRRT, optimizing antibiotic therapy is as essential as in other patients. Though rarely suggested in CRRT, prolonged and extended infusion may be sufficient to overcome underdosing in many. In difficult cases, TDM - when available - could be a solution, although many questions surrounding the application of TDM remain unanswered. Most importantly, it is not clear what PK/PD target should be aimed for to treat infections during critical illness, but TDM could at least detect the extremes of concentrations and allow dose adaptation in case of severe under- and overdosing.CRRT: Continuous renal replacement therapy; MIC: Minimum inhibitory concentration; PD: Pharmacodynamics; PK: Pharmacokinetics; RRT: Renal replacement therapy; TDM: Therapeutic drug monitoring.The authors declare that they have no competing interests.


Immunoglobulin G4-related disease (IgG4-RD) is a systemic fibroinflammatory disorder affecting nearly all organs, including the kidney. Tubulointerstitial nephritis (IgG4-TIN) is the most common form of IgG4-related kidney disease (IgG4-RKD) and is the focus of this concise review.The study aims to describe when IgG4-TIN should be suspected and to summarize the diagnosis, treatment, and natural history of the disease.Ovid MEDLINE, Google Scholar, and PubMed were searched for full-text English language articles up to January 2016. References included in the manuscript were chosen at the authors’ discretion based on their relevance to the subject of the review.Characteristic radiologic findings Elevated serum IgG4 levelCharacteristic findings of IgG4-RD in other organsIgG4-TIN should be considered in patients presenting with abnormal urinalysis, abnormal kidney function, renal lesions on imaging, and elevated IgG, IgE, or hypocomplementemia. Diagnosis of IgG4-TIN requires a combination of histologic features  and at least one of the following:Other conditions such as lupus, vasculitis, diabetic nephropathy, and lymphoma must be excluded, as these can also present with IgG4+ plasma cells in the renal parenchyma. IgG4-TIN is generally responsive to steroids and B cell depletion with rituximab, but relapses are common and patients require close long-term follow-up.Available data on IgG4-TIN are from retrospective observational studies.IgG4-TIN is a distinct and emerging subtype of interstitial nephritis. Nephrologists must be aware of this entity and how to definitively diagnose and treat it. Prospective studies and ideally multi-center clinical trials are needed to study the epidemiology, treatment, and natural history of this disease. Immunoglobulin G4-related disease (IgG4-RD) is an emerging disease, which is difficult to diagnose, and remains under-recognized, particularly in patients with single-organ system involvement including IgG4-related kidney disease (IgG4-RKD). Tubulointerstitial IgG-RKD is the most common form of renal involvement and represents an important evolution in the understanding of tubulointerstitial nephritis. While many sub-classifications of glomerulonephritis exist, there are relatively few distinct subtypes of tubulointerstitial nephritis.Tubulointerstitial nephritis (IgG4-TIN) is an important emerging subtype of interstitial nephritis.Little is known about the epidemiology of this disease and what proportion of all TIN is represented by IgG4-TIN.Diagnosis requires that clinicians and pathologists recognize the clinical, radiologic, and histologic features and correlate findings with established diagnostic criteria.Research is needed in the epidemiology, treatment, and natural history of tubulointerstitial IgG4-RKD.IgG4-RD is a fibroinflammatory disease that can affect almost any organ, with nearly identical histopathologic findings in all tissues: a lymphoplasmacytic infiltrate of polyclonal lymphocytes, IgG4+ plasma cells, and eosinophils , 2, ofteIgG4-RD in general affects middle-aged to elderly patients with a slight male preponderance , 7 and cDefinitive diagnosis of IgG4-RD requires an adequate tissue biopsy demonstrating storiform fibrosis, mild to moderate tissue eosinophils, lymphoplasmacytic infiltrate, increased IgG4 levels , and an IgG4/IgG+ plasma cell ratio >40 % , 13. MeaDespite rising awareness, the epidemiology remains poorly understood and the true incidence and prevalence are likely underestimated , 7, 15. Many retrospective studies have revealed that IgG4-RD is responsible for many cases of “idiopathic” or unexplained disease in diverse organs. For example, one review of 26 patients with autoimmune hepatitis revealed that nine had characteristics suggestive of IgG4-RD . SubsequIgG4-RD can affect structures adjacent to the kidney, leading to acute or chronic kidney disease. The most common of such manifestation is retroperitoneal fibrosis leading to obstructive uropathy. Involvement of the renal pelvis in the form of IgG4 pyelitis has been reported but is rare. Intrinsic renal disease is encompassed by the term IgG4-related kidney disease (IgG4-RKD) , 22. In Patients with IgG4-RKD are demographically similar to those with IgG4-RD in general, most commonly middle aged to elderly with a male preponderance , 24. SomThe clinical presentation of tubulointerstitial IgG4-RKD is variable, and renal function may range from normal to severely compromised , 26. OutHistology is of primary importance to diagnosing IgG4-RKD. Of the many organs affected by IgG4-RD, the kidney is unique in having two distinct patterns of histologic involvement: TIN Fig.  and, lesIgG4-TIN should be considered in patients with AIN who do not have an obvious pharmacologic or infectious etiology, and it should be considered in patients with systemic symptoms potentially consistent with extra-renal IgG4-RD, and when there are findings of other organ involvement characteristic of IgG4-RD. Renal imaging showing low-attenuating lesions in the kidneys should also prompt suspicion of IgG4-TIN. When IgG4-TIN is suspected, the renal biopsy should be examined for a lymphoplasmacytic infiltrate, and if increased plasma cells are present, these should be stained for IgG and IgG4. These stains can also be performed on archived tissue samples from kidney and other organs, as many of these patients have chronic disease with previous “non-diagnostic” biopsies. Given the non-specific nature of the histologic appearance of IgG4-TIN, the pathologist should be specifically informed of a high degree of clinical suspicion for IgG4-RD in order to trigger appropriate immunohistochemical evaluation. Serum IgG, IgG subclasses, serum protein electrophoresis, complement levels, and imaging for multiple and bilateral low-attenuating renal lesions should also be considered.When a renal biopsy demonstrates TIN and increased IgG4+ plasma cells, other diagnoses to consider include pauci-immune glomerulonephritis, medication-induced interstitial nephritis, autoimmune TIN, lupus, Sjögren’s syndrome, and chronic pyelonephritis. Once pauci-immune GN is ruled out, the IgG4 stain has a sensitivity of 100 % and specificity of 92 % for IgG4-RKD . Other fThe treatment of IgG4-TIN mirrors the treatment of IgG4-RD in general. The 2015 International Consensus Statement for treatment of IgG4-RD advocates treating active disease urgently and that many patients with asymptomatic disease also require treatment to prevent or minimize future organ damage . GlucocoWith respect to prognosis, most patients’ renal function improves once treatment is initiated, and this tends to plateau after weeks to months or may slightly decline from its peak recovery , 42. As In summary, many patients will respond to steroids, with new or worsening diabetes as the most significant toxicity, and rituximab is a potent and well-tolerated treatment option both for steroid naïve and steroid-refractory patients. Other traditional steroid-sparing immunosuppressives have been used with variable success, and their role is not clearly defined. Many patients will require maintenance prednisone or re-treatment with rituximab, and our own practice is either to maintain steroid-responsive patients on a low dose of prednisone or for those patients who achieve a steroid-free complete response with rituximab, to monitor serum IgG, IgG4, and kidney function closely and plan for re-treatment at the earliest sign of relapse.Interstitial nephritis is a frequent finding in patients biopsied for acute or chronic kidney disease , 46. CauIgG4-RD, immunoglobulin G4-related disease; IgG4-RKD, immunoglobulin G4-related kidney disease; IgG4-TIN, immunoglobulin G4 tubulointerstitial nephritis; TIN, tubulointerstitial nephritis


Antibiotic overuse is driving the emergence of antibiotic resistance worldwide. Good data on prescribing behaviours of healthcare providers are needed to support antimicrobial stewardship initiatives. This study examined the differences in antibiotic prescribing rates of public and private primary care clinics in Malaysia.We used data from the National Medical Care Survey (NMCS), a nationwide cluster sample of Malaysian public and private primary care clinics in 2014. NMCS contained demographic, diagnoses and prescribing from 129 public clinics and 416 private clinics. We identified all encounters who were prescribed antibiotic and analyse the prescribing rate, types of antibiotics, and diagnoses that resulted in antibiotic.Five thousand eight hundred ten encounters were prescribed antibiotics; antibiotic prescribing rate was 21.1 % . Antibiotic prescribing was higher in private clinics where they contributed almost 87 % of antibiotics prescribed in primary care. Upper respiratory tract infection (URTI) was the most frequent diagnosis in patients receiving antibiotic therapy and accounted for 49.2 % of prescriptions. Of the patients diagnosed with URTI, 46.2 % received antibiotic treatment . Penicillins, cephalosporins and macrolides were the most commonly prescribed antibiotics and accounted for 30.7, 23.6 and 16.0 % of all antibiotics, respectively. More recently available broad-spectrum antibiotics such as azithromycin and quinolones were more frequently prescribed in private clinics.Antibiotic prescribing rates are high in both public and private primary care settings in Malaysia, especially in the latter. This study provides evidence of excessive and inappropriate antibiotic prescribing for self-limiting conditions. These data highlights the needs for more concerted interventions targeting both prescribers and public. Improvement strategies should focus on reducing inappropriate prescribing. Antibiotic resistance is a globally significant threat to public health . A recenWhere data are available on low- and middle-income countries’ antibiotic use in the community, they are usually at a sub-national level. For example, Hadi et al., in their systematic review of non-hospital antibiotic use, identified 11 studies from ten countries . Only onMalaysia has a dual public-private health system with 871 public primary care clinics and 5198 private primary care clinics , 12. PriThe NMCS is a primary care survey conducted by the Clinical Research Centre Malaysia that collected information on clinical activities and prescriptions from primary care clinics in Malaysia. The study was conducted in 2014 and a detailed description of the NMCS methods is described elsewhere . BrieflyFrom NMCS records, we identified patients who were prescribed at least one systemic antibiotic. Systemic antibiotic were defined from the ATC code J01  and P01AB01 . Our primary outcome measure was antibiotic prescribing rate in public and private primary care clinics. We also determined the types of antibiotics prescribed and common diagnoses that resulted in prescription of antibiotics.Data were analysed and adjusted for the cluster study design using the survey function in STATA version 13 , 20. PosThe NMCS received ethical approval from the Medical Research and Ethics Committee of the Ministry of Health Malaysia (NMRR-09-842-4718). A public notice was placed at each participating clinic to inform patients of the ongoing study and that data would be collected for research purposes only. Patients who do not want to be part of the study may opt out by informing the doctor and their data were not collected.NMCS 2014 recorded 27,587 patient encounters from 545 primary care clinics. Of these, 5810 resulted in antibiotic prescription, corresponding to an overall prescribing rate of 21.1 % . Thus, the antibiotic prescribing rate in public primary care clinics in Malaysia may be declining, while that of private clinics has remained relatively stable but at a high level. However, when compared with more developed countries, the antibiotic prescribing rates in Malaysia are still a cause for concern. For example, the URTI-specific antibiotic prescribing rate in Malaysia as seen in our study was 46.2 %, but the corresponding rates in the Netherlands and Hong Kong in 2010 were 17 and 5 %, respectively , 25.Antibiotic prescribing rates in Malaysian primary care are much higher in private clinics compared with public clinics. Antibiotic over-prescribing (in private more than public clinics) has also been observed in surveys undertaken in Pakistan, India and several African countries –28. In aHigher antibiotic prescribing in private primary care clinics is partly owing to the higher proportion of acute self-limiting illnesses, such as viral fever and common colds. Furthermore, several reasons may explain the higher antibiotic prescribing rates in private clinics, among them that private general practitioners are more responsive to the patient’s expectation for antibiotics and the financial incentive of medication overuse, including that of antibiotics, as well as suboptimal knowledge about the aetiology of URTI and lack of awareness of the emergence of antibiotic resistance. Several local studies have documented misconceptions about the effectiveness of antibiotic therapy for URTI among the Malaysian general public and their healthcare providers, together with a lack of awareness of the harm of antibiotic resistance , 31–34.Attempts to improve antibiotic prescribing practices in developing countries have been documented by several systematic reviews , 36. TheOur study has a number of important features. The large number of patient encounters obtained from clinics sampled across the country has allowed us to study clinical practice in primary care clinics. Moreover, our study used records from NMCS that collected data on patient visits in public and private clinics, allowing for comparison between the sectors. A limitation of the study is that the findings reflect practice observed in primary care settings; it does not include consultations within hospital outpatient or emergency departments. We also did not collect data from community pharmacies; hence, the supply of antibiotics to patients from community pharmacies was not considered. In Malaysia, antibiotic is not available over the counter and under the Malaysian Poisons Act the purchase of antibiotics requires prescription from physicians. However, dispensing separation has not yet taken place in Malaysia and very few prescriptions were filled at private pharmacies .This study has shown that antibiotics are frequently prescribed in primary care clinics and provides evidence of antibiotic prescribing for self-limiting conditions. Excessive and inappropriate antibiotic use in the Malaysian primary care setting, especially in private clinics, highlights the need for more concerted interventions targeting prescribers as well as general public. Improvement strategies should focus on reducing inappropriate prescribing. This should include simultaneous education of the public and healthcare providers via the mass media, professional societies and within the clinic setting. Improving prescribing habits in primary care is necessary to reduce the unnecessary use of antibiotics and limit subsequent antibiotic resistance.This study was reviewed and approved by the Medical Research and Ethics Committee of the Ministry of Health Malaysia. A public notice was placed at each participating clinics to inform patients of the ongoing study and patients who do not wish to participate may opt out from the study. Aggregate data was used, with no identifying personal details published.Not applicable.All the data supporting the findings are available within the manuscript, additional data available upon request.


To assess the patterns and predictors of AIDS-related mortality and identify its correlates among adult people living with HIV/AIDS (PLWHA) in China, a retrospective record-based cohort study was conducted among 18 years or older PLWHA, who had at least one follow up reported to the national database between January-1989 and June-2012. Cumulative Incidence Function was used to calculate AIDS-related mortality rate. Gray’s test was used to determine the variation in cumulative incidence across strata. The Fine and Gray model was used to measure the burden of cumulative incidence of AIDS-related mortality and strength of its association with potential correlates. Among 375,629 patients, 107,634 died during study period, of which 54,759 (50.87%) deaths were AIDS-related. Cumulative mortality rates of AIDS-related death at one, two, five, 10 and 15 years post-diagnosis were 5.7%, 8.2%, 14.3%, 22.9% and 30.9%, respectively. Among PLWHA, male gender, ethnic minority and having AIDS were associated with significantly higher mortality. Further, homosexual transmission, being on ART and increasing CD4-testing frequency were associated with lower mortality. To reduce mortality among PLWHA, efficient interventions targeting males, ethnic minority, heterosexually infected and AIDS patients should be combined with immunologic monitoring, enhancement of coverage of HIV-testing and ART. Despite remarkable progress in promotion of access to HIV prevention, treatment and supportive care, HIV epidemic in China continued to expand. At the end of the year 2011, an estimated 780,000 people were living with HIV/AIDS (PLWHA) in this country, about 48,000 persons became newly infected with HIV during this year and the number of reported HIV cases were increasing over years2Despite the well-established positive role of preventive approach in containment of the HIV epidemic, in China, much of the national response so far had only focused on ensuring greater access of PLWHA to antiretroviral treatment (ART). To strengthen the treatment and follow-up involving this population, the “National Free Antiretroviral Treatment Hand book” was issued in 2011with revised criteria for initiation of treatment, prioritizing drug resistance testing and management of switching drug regimens. These efforts cumulatively resulted in an increase in the estimated number of people currently receiving ART from 65481 in 2009 to 126448 in 2011 and those on ART were reported to have better likelihood of survival1Though PLWHA could expect a longer life expectancy by virtue of timely treatment and effective control of opportunistic infections5678Incomplete and inaccurate population level data on HIV mortality were additional points of concern in China. Burden and predictors of mortality among PLWHA remained understudied here owing to several logistic factors11The dynamics of mortality among HIV infected persons is complex and a function of many socio-demographic factors, routes of infection, disease status at the time of diagnosis and the quality of the received treatmentOur study aimed to evaluate the mortality rate among PLWHA since they were identified/reported and to evaluate the potential correlates of AIDS related and unrelated deaths in this population in China, by analyzing the data from a concurrent cohort study  which was monitoring mortality among PLWHA in China.The data used in this current article were obtained from the HIV/AIDS case reporting system (CRS) under the National Center for AIDS/STD Control and Prevention of the Chinese Center for Disease Control and Prevention (China CDC) between 1989 and 2013. The methods were carried out in accordance with the approved guidelines.Detailed information regarding the relevant databases is described elsewherePLWHA were considered eligible to be recruited for this concurrent cohort study if they were aged 18 years or older and had at least one follow up record since their initial reporting to the national database between January 1, 1989 and June 30, 2012. Frequency of CD4 testing for each participant was also calculated in every six months, and frequency of CD4 testing was defined as the cumulative number of CD4 testing at each year divided by two (every six months).After identification and reporting, all HIV cases were followed up by the local CDCs. The intervals of two follow up varied between three or six months, depending on the disease status. If already been progressed to AIDS, the patients were followed in every three months, otherwise, they were followed six monthly. Accordingly, during the follow up period, blood samples for CD4 count and viral load testing were collected in every 3 or 6 months from each patient. The patients were appropriately treated as per the criteria. Treatment was indicated for confirmed sero-positive WHO Stage III or IV clinical HIV cases and those who had any of the following: symptomatic disease, extra-pulmonary tuberculosis (TB), laboratory criteria of CD4 count below 350 cells/μl or in the absence of CD4 count results: total lymphocyte count below 1200 cells/μl)HIV/AIDS related mortality rate was estimated using the number of deaths among the cases within each follow-up period as the numerator and the cohort’s total person-years at risk within each follow-up period as the denominator. For those who died, half of the follow-up duration (between 2 follow-ups) was used as their contribution to the total person-time at risk.During follow up period, if one patient was died, the reason of death will be put into the follow up system. Per ICD 10, if the patients were died of AIDS, AIDS related opportunistic infections, AIDS-related tumors or AIDS-related syndrome, their death were coded as AIDS related death, otherwise, their death were coded as Non-AIDS related death.The National HIV Epidemiology Cohort was retrospectively analyzed to calculate the mortality rate and to identify factors associated with death among PLWHA in China. During the pulling of the data from the case report and treatment databases, all personal identifiers were removed before the data analysis.SAS version 9.4As depending upon the disease status (AIDS patients or Non-AIDS patients (HIV carriers) follow up and CD4 testing frequency varied over time , cumulative number of previous CD4 tests were calculated and disease status was assessed at every 6 mouths. Both of these parameters were thus regarded as time-varying risk factors.Bias due to competing risks could arise in this study if an event of failure in treatment would have resulted from one of the several causes and one of them precluded the others1415The study protocol, contents and procedures were reviewed and approved by the Institutional Review Board of the National Center for AIDS Prevention and Control, China CDC. Written informed consent was obtained from participants at the recruitment stage.Between January 1, 1989 and June 30, 2012, a total of 449,386 HIV positive cases were reported to the Chinese HIV/AIDS report system. Among these cases, 64,348 (14.32%) were excluded either due to lost contact after being reported to the systems , or because of the lack of confirmation of the HIV sero-positivity by Western Blot testing . Further, another 9,409 (2.09%) patients were excluded as they were aged less than 18 years . OverallAbout 70.0% of the eligible patients were male, 64.6% were aged less than 40 years during diagnosis while approximately 73.0% were ever married (18.6% were divorced or widowed). About three quarters (73.7%) of the patients belonged to Han nationality, and about half of the patients reported that they were farmers. In addition, about 40.0% of the eligible patients were either illiterate or attended elementary school only .When identified, about half of the participants already progressed to AIDS. For about half of the subjects, the possible transmission route was heterosexual, and 48% of the patients were already on ART .At the end of the study follow up period , among the recruited PLWHA, 10,987 (2.9%) were lost to follow up, 107,634 (28.7%) died, while the other 257,008 individuals were surviving. Among these 107,634 deaths during the study period, 54,759 (50.9%) were categorized as HIV/AIDS-related death, while the other 52,875 died from reasons  other than HIV .The mortality rates of AIDS-related death at one, two, five, 10 and 15 years after the cases were identified were 5.7%, 8.2%, 14.3%, 22.9% and 30.9%, respectively , Table 2th post-identification year, the mortality rates for all deaths and AIDS-related deaths reached 10.17/100 PYs and 5.08/100 PYs respectively.Mortality rate of the participants at each follow up year was presented in Current study did also show that the mortality rates among subjects infected through homosexual route were much lower than the overall mortality rate in the follow up period , with aHR of 1.21 (1.17–1.25) for Uygur, Zhuang, Yi or Dai and 1.20 (95% CI = 1.14–1.25) for others (other 51 ethnicity minority groups in China). Patients who had progressed to AIDS had significantly higher mortality rate than those who had not . Compared to those who got infected through heterosexual route, homosexuals had a significantly lower AIDS-related mortality rate (aHR 0.56 95% CI = 0.52–0.62). Being on ART was also associated with 65% reduction in the hazard of AIDS-related mortality among HIV patients . In addition, it was also observed that those whose CD4 testing frequency increased one time per 6 months was associated with 81% reduction in the hazard of AIDS-related mortality  .Regarding non-AIDS-related deaths, AIDS  were significantly associated with higher mortality rates. Uygur/Zhuang/Yi/Dai, aHR 0.86, 0.84–0.89) and other ethnic minority groups other than Uygur/Zhuang/Yi/Dai  were significantly associated with lower mortality rates. Being on ART was also associated with 71% reduction in the hazard of non-AIDS-related mortality among HIV patients . In addition, it was also observed that those whose CD4 testing frequency increased one time per 6 months was associated with 80% reduction in the hazard of AIDS-related mortality  .In China, the majority of studies on HIV mortality conducted till date only explored the influence of ART and related operational indicators1112Mortality rates during the first follow up year and results of competing risks model suggested that HIV patients who got infected through homosexual contact had a significantly lower rate of AIDS-related mortality compared to heterosexually infected patients. This finding corroborated with the observation from a previous study conducted in Denmark11This study also indicated that the overall survival rate dropped substantially at 20 years post-diagnosis. As few people were followed for a span of more than 20 years this observed reduction in the survival could be considered as a result of sparse data problem, although negative biological influence of long-standing HIV infection should also be borne in mind.It was also found that among PLWHA in China, minority populations had significantly higher AIDS-related mortality rates than HIV patients with Han ethnicity. A parallel scenario was also observed among African Americans compared to Caucasians in the USAIn this study, about half of the deaths were not related to AIDS. This probably indicated that in order to reduce the overall mortality among HIV patients, additional attention should be paid to the causes of death other than those traditionally been considered to be AIDS-relatedIt appeared that more frequent CD4 testing was associated with prolonged survival. This finding was concurrent with the results of a systematic review which reported that clinical and immunologic combined monitoring (include CD4 testing) was better than clinical monitoring alone in terms of a combined mortality and morbidity endpointThere were some limitations in this study. It was not possible to include CD4 count and viral load in the analysis because before 2003, HIV patients of China were rarely tested for CD4 count and viral load, and the routine use of these tests started only since 2010. Future sub-analysis should deal with this shortcoming, by limiting the analysis among the patients who got tested at baseline for CD4 count and viral load. As some data elements were based on self-report (e.g. the routes of transmission), current study might have suffered from some miss-classifications. Outcome misclassification, particularly misclassification between AIDS-related and unrelated death, could be another problem, as the outcomes were reported by different hospitals leading to non-standardized ascertainment of the cause of death. Most of the MSM patients were identified in recent years, hence the short follow-up period was a barrier for the complete analyses regarding the progression of HIV to AIDS in this population. Moreover, being a record-based study, this current investigation captured limited information of the patients; hence the scope to adjust for potential confounders was also limited. Beside these, identified number of patients at each year was used as a surrogate for the number of PLWHA who got tested for HIV; this number could have been influenced by both the epidemic situation and the coverage of testing. Last but not the least, both ART and CD4 count being time- dependent variables in nature, due to the missing data problem and the complexity of treatment regimes, we could not properly treat them as time-dependent, which might have resulted in the potential for some bias in the currently reported results.Even with these limitations, the results of this study revealed that a large proportion of PLWHA in China was suffering from the issues pertaining to very late diagnosis, and mortality rate in this population was very high. Among these patients, ethnic minority, male gender, AIDS and not receiving ART were associated with higher AIDS-related mortality. While targeted interventions to expand HIV testing services and coverage of ART should continue with emphasis, urgent attention to address the risk factors for non- AIDS-related mortality among HIV patients seemed to be the need of the hour in this country. In the era of universal treatment, more implementation research focusing on the promotion of HIV testing and case finding, reduction of the barriers of treatment, and enhancement of the treatment coverage and retention in care rate  were needed urgently.How to cite this article: Li, M. et al. Mortality among People Living with HIV and AIDS in China: Implications for Enhancing Linkage. Sci. Rep.6, 28005; doi: 10.1038/srep28005 (2016).


We report the case of a 50-year-old man with a multiorgan IgG4-related disease presenting in a temporal association with a profound and symptomatic idiopathic CD4 lymphocytopenia. Both clinical pictures improved after steroid treatment. Idiopathic CD4 lymphocytopenia has been associated with a number of autoimmune conditions but, to the best of our knowledge, this is the first case in which an association with the IgG4-related disease is reported.The IgG4-related disease is a fibroinflammatory disease characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and, often but not always, elevated serum levels of IgG4. Idiopathic CD4 lymphocytopenia is a heterogenic and rare syndrome characterized by the detection of a persistent absolute CD4 T cells count <300 cells/mm The IgG4-related disease is a fibroinflammatory disease characterized by tumefactive lesions, a dense lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, and often, but not always, elevated levels of IgG4 , 2.∗0405 and DRB1∗0401 increase the susceptibility in Japanese population, whereas DQB1-57 mutations are associated with disease relapse in Korean population). Bacterial infections with a molecular mimicry mechanism and autoimmunity are all considered potential initiating mechanisms.The IgG4-related disease has been described in several organs and tissues: pancreas, biliary tract, salivary glands, periorbital tissue, kidneys, lungs, lymph nodes, meninges, aorta, breast, prostate, thyroid, pericardium, and skin , 3. Histβ (TGFβ), appears to be overexpressed in IgG4-related disease. TGFβ may play a central role in the fibrosis process [3  in more than one occasion and no evidence of HIV infection in absence of immunodeficiency or therapy associated with depressed levels of CD4 T cells [Autoimmunity is widely regarded as the initial immunologic stimulus for the type 2 helper T (Th2) cell immune response that is predominant in IgG4-related diseases. Serum IgG4 from patients with IgG4-related disease binds to the normal epithelia of the pancreatic ducts, bile ducts, and salivary ducts. Potential autoantigens at these sites include carbonic anhydrases, lactoferrin, pancreatic secretory trypsin inhibitor, and trypsinogens. However, these autoantibodies are neither specific for IgG4-related disease nor known to be of the IgG4 subclass. Thus, their role in IgG4-related disease is unclear. Autoimmunity and infectious agents may act as potential immunological triggers of the disease . The pre process . Various process , 2, 7, 9 process –9. In th T cells . Idiopat T cells  found in T cells .ICL has been associated with a number of autoimmune conditions  but, to On August 2007 a 43-year-old patient presented with the sudden onset of cholestatic jaundice and the radiologic detection of two pancreatic masses, diffuse lymphadenopathy, and hepatomegaly. To exclude the presence of a lymphoma, the patient underwent exploratory laparotomy. A biopsy of liver and of a lymph node at the level of hepatic hilum and cholecystectomy were performed. Biopsy of pancreatic mass was attended but, for technical reasons, not successful. Histology showed the presence of chronic cholecystitis with hypertrophic reactive lymphadenitis, fibrosis of the cystic duct with strong intramural inflammatory infiltrate, signs of portal fibrosis, and cholestasis in the absence of alterations of the biliary tract. Consequently, a bile duct-duodenal anastomosis was packed in absence of a conclusive diagnosis. Mycoplasma pneumoniae and Chlamydia pneumoniae, Epstein Barr and cytomegalovirus infections, tubulointerstitial nephritis, severe lymphopenia, and marked reduction of CD4  in conjunction with the onset of fatigue, weight loss, night sweats, arthralgia, hemorrhagic rhinitis, multiple caries, and consequent extraction of 10 teeth. After the exclusion of HIV and malignancies , an idiopathic CD4 lymphocytopenia was diagnosed. Nevertheless, only a part of the signs was explained by CD4 lymphocytopenia.Three years later, a reduction of the number of the CD4 lymphocytes was once again reported , ANA were negatives, and CD4 were in the normal range.After 3 months of prednisone 50 mg/day, we observed an improvement of the renal function paired with a reduction of inflammation, IgG, and kidneys volume and the disappearance of the dilatation of chalices and renal pelvis.At the time of the submission of the present case report, the patient, treated with prednisone 5 mg/day, is in remission with stable GFR and normalization of IgG4 and CD4 lymphocytes. Mycoplasma, and Chlamydia, in absence of HIV and malignancies, is the consequence of the idiopathic CD4 lymphocytopenia. Only when considered together, the IgG4-related disease and the idiopathic CD4 lymphocytopenia explain the clinical presentation of the subject.The involvement of liver (cholestatic jaundice), pancreas (pancreatic masses and lymphadenopathy) and, subsequently, the respiratory system , urinary tract , and salivary glands  as well as the detection of hypocomplementemia, increased polyclonal IgG and IgG4 subclass, and the rapid improvement of symptoms and laboratory data after steroid therapy are indicative of IgG4-related disease. On the other hand, the history of opportunistic infections such as CMV, EBV,The HISORT criteria  reach a The renal involvement reported in IgG4-related disease is a tubulointerstitial nephritis with polyclonal infiltration of lymphocytes and plasma cells, a membranous nephropathy, and a calicopelvic dilatation secondary to retroperitoneal fibrosis –19. RaisThe simultaneous presence of a tubulointerstitial nephritis and hypocomplementemia is a laboratory feature in IgG4-related tubulointerstitial nephritis , 21. WhaThe ICL is commonly associated with several autoimmune diseases such as lupus erythematosus systemic, anti-phospholipid antibody syndrome, Sjogren's syndrome, polyarthritis/vasculitis, psoriasis, lichen planus, autoimmune vitiligo, Behcet syndrome, and Hashimoto thyroiditis as well as the atopic dermatitis, sarcoidosis, and idiopathic obliterative bronchiolitis . HoweverThe present case report describes the clinical history and follow-up of a IgG4-related disease presenting in association with an apparently idiopathic profound and recurrent decline in CD4+ cells. The major limitation of this study is that, despite the fact that both the HISORT  and RaisIn conclusion, we reported a case of a subject with a multiorgan IgG4-related disease presenting in a temporal association with a profound and symptomatic idiopathic CD4 lymphocytopenia. Both clinical pictures improved after steroid treatment.