Economic expansion and innovation: A comprehensive analysis of Pakistan's path to technological excellence.

To encourage technological and industrial innovation, nations worldwide implement "re-industrialization" and "manufacturing return." This study investigates the relationship between GDP growth, expenditure on research and development, and medium- to high-tech as a percentage of manufactured exports on technological innovation in Pakistan. We evaluated long-run and short-run causal relationships using the ARDL, bound-F test, and ECM regression. The study found a positive relationship between GDP growth and technological innovation in the short and long run. In the short run, with a one-year lag, the analysis reveals a positive and statistically significant relationship between technological innovation, medium-high-tech exports, and GDP growth. In the long run, R&D is positive and significant, while economic growth and technological innovation are positive but not statistically significant. There is a 0.38 percent chance that exogenous shocks will eventually lead to equilibrium in the long run. Based on the findings of this study, it is recommended to allocate resources to research and development, promoting collaborative initiatives, ensuring intellectual property rights, and developing a skilled workforce.

Icosapent ethyl modulates circulating vascular regenerative cell content: The IPE-PREVENTION CardioLink-14 trial.

BACKGROUND: REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) showed that icosapent ethyl (IPE) reduced major adverse cardiovascular events by 25%. Since the underlying mechanisms for these benefits are not fully understood, the IPE-PREVENTION CardioLink-14 trial (ClinicalTrials.gov: NCT04562467) sought to determine if IPE regulates vascular regenerative (VR) cell content in people with mild to moderate hypertriglyceridemia. METHODS: Seventy statin-treated individuals with triglycerides ≥1.50 and <5.6 mmol/L and either atherosclerotic cardiovascular disease or type 2 diabetes with additional cardiovascular risk factors were randomized to IPE (4 g/day) or usual care. VR cells with high aldehyde dehydrogenase activity (ALDHhi) were isolated from blood collected at the baseline and 3-month visits and characterized with lineage-specific cell surface markers. The primary endpoint was the change in frequency of pro-vascular ALDHhiside scatter (SSC)lowCD133+ progenitor cells. Change in frequencies of ALDHhiSSCmid monocyte and ALDHhiSSChi granulocyte precursor subsets, reactive oxygen species production, serum biomarkers, and omega-3 levels were also evaluated. FINDINGS: Baseline characteristics, cardiovascular risk factors, and medications were balanced between the groups. Compared to usual care, IPE increased the mean frequency of ALDHhiSSClowCD133+ cells (-1.00% ± 2.45% vs. +7.79% ± 1.70%; p = 0.02), despite decreasing overall ALDHhiSSClow cell frequency. IPE assignment also reduced oxidative stress in ALDHhiSSClow progenitors and increased ALDHhiSSChi granulocyte precursor cell content. CONCLUSIONS: IPE-PREVENTION CardioLink-14 provides the first translational evidence that IPE can modulate VR cell content and suggests a novel mechanism that may underlie the cardioprotective effects observed with IPE in REDUCE-IT. FUNDING: HLS Therapeutics provided the IPE in kind and had no role in the study design, conduct, analyses, or interpretation.

Reducing the risk of denosumab-induced hypocalcemia in patients with advanced chronic kidney disease: a quality improvement initiative.

Denosumab can improve bone health in advanced kidney disease (CKD) but is associated with hypocalcemia. We created a clinical care pathway focused on the safe provision of denosumab in advanced CKD that reduced the risk of hypocalcemia by 37% at our hospital. Similar pathways could be adopted and tested in other centers. PURPOSE: There is an increased risk of hypocalcemia with denosumab in advanced chronic kidney disease (CKD). We aimed to reduce the proportion of patients with advanced CKD who experienced denosumab-induced hypocalcemia at our center. METHODS: We conducted a quality improvement (QI) project of patients with CKD stage 3b or less (i.e., estimated glomerular filtration rate <45 mL/min/1.73m2 including dialysis) who were part of the Osteoporosis and Bone Disease Program at St. Joseph's Health Care London (Canada) between December 2020 and January 2023. Our intervention was a clinical care pathway which optimized CKD mineral and bone disorder (CKD-MBD) and 25-hydroxyvitamin levels; provided calcium and vitamin D prophylaxis; promoted multidisciplinary communication between bone and kidney specialists; and carefully monitored calcium post-denosumab injection. Our primary outcome measure was the proportion of patients with hypocalcemia (defined by albumin-corrected serum calcium <1.9mmol/L) at 60 days. Process measures included the appropriate provision of calcium and vitamin D prophylaxis. Balance measures included the development of hypercalcemia and hyperphosphatemia following prophylaxis. We used plan-do-see-act cycles to study four tests of change and presented results using descriptive statistics and run charts. RESULTS: There were 6 patients with advanced CKD treated with denosumab prior to the implementation of our care pathway (March 2015-October 2020; 83% receiving dialysis). At the time of their denosumab injection, 83% were using 500-1000 mg of calcium, and 83% used 1000-2000 IU of vitamin D3. Fifty percent developed denosumab-induced hypocalcemia. Following the implementation of our care pathway, 15 patients (40% receiving dialysis) were treated with denosumab. Ninety-three percent received calcium at a daily dose of 350 to 2250 mg and 87% received 1000-2000 IU of vitamin D3. Thirteen percent developed denosumab-induced hypocalcemia. There was no hypercalcemia or hyperphosphatemia. CONCLUSIONS: A clinical care pathway focused on the safe provision of denosumab in advanced CKD reduced the risk of hypocalcemia in patients treated in our hospital. Similar pathways could be adopted and tested in other centers.

Incidence of Vitamin D Deficiency and Its Association With Microalbuminuria in Patients With Type 2 Diabetes Mellitus.

Background Vitamin D (VD) deficiency is common in patients with type 2 diabetes mellitus (T2DM). VD deficiency and its associated factors are understudied in Pakistan. This study aimed to estimate the incidence of VD deficiency and its association with microalbuminuria in patients with T2DM. Methods This descriptive cross-sectional study was performed on 110 patients diagnosed with T2DM aged between 30 and 65 years in the outpatient department clinic of diabetes in Benazir Bhutto Hospital, Rawalpindi, for around eight months from November 2022 to June 2023. Non-probability sampling technique and established inclusion and exclusion criteria were used for patient recruitment. Ethical approval and informed consent were also waived before data collection. Data collection was done by an interview-based and self-designed questionnaire. Data analysis was carried out via descriptive statistics along with chi-square, independent-samples t-test, and Pearson correlation in Statistical Package for the Social Sciences (SPSS) version 25 (Armonk, NY: IBM Corp.). Results The means of the study population for age, serum VD, and UACR (urine spot for albumin-to-creatinine ratio) were 48.50±15.67 years, 28.16±15.34 ng/mL, and 29.69± 87.22 µg/mg, respectively. The incidences of VD deficiency and microalbuminuria in the study population were 43.64% and 28.20%, respectively. VD deficiency was significantly associated with age group (p=0.002), gender (p=0.008), and albuminuria status (p=0.004). The comparison of means of UACR between the VD deficiency group and the non-VD deficiency group was also significant (0.001). VD deficiency was higher among older age groups, female gender, and patients with microalbuminuria. A significant negative correlation between serum VD level and UACR (microalbuminuria) (p=0.002) was present. Conclusion VD deficiency incidence was notably high in the study population. Older age, female gender, and microalbuminuria were found to elevate the VD deficiency to a crucial level. Serum VD deficiency and microalbuminuria were significantly and negatively correlated. Therefore, VD level should be monitored intermittently in T2DM, so that we could prevent the progression of T2DM timely.

Deranged Liver Function Test After COVID 19 Vaccination: A Rare Presentation With Review Of Literature.

Word Health Organization declared COVID 19 infection as pandemic in 2020. Since then different countries had started working on vaccination. After multiple trials different vaccinations got approved. The first vaccine to be received in Pakistan was Sinopharm and was provided to nearly all health care professionals on priority basis. The safety profile of different vaccines were satisfactory and there were very few side effects reported till date. We are reporting the first case in Pakistan where a female health care professional developed vaccination induced deranged liver function test with delayed but complete recovery. Extensive workup was done to rule out all other differentials of deranged liver function test.

Bones of contention: Predicting and preventing fractures in patients receiving peritoneal dialysis.

Low bone density is common among those individuals receiving peritoneal dialysis. While cross-sectional studies support an association between low bone mineral density (BMD) and prevalent fracture, relying on bone density alone, particularly at the lumbar spine and in those with high degrees of hyperparathyroidism may underestimate fracture risk. Commonly used risk calculators in the general population have been shown to perform reasonably well in those receiving dialysis although they do not include any risk factors for high turnover bone disease that may play a role in increased fracture risk. The best options for decreasing fracture risk in patients receiving peritoneal dialysis are unclear. The evidence for bisphosphonates is limited to small studies of BMD, and concerns about drug accumulation have limited their use. Denosumab is more commonly used and has some evidence for improvement in BMD but carries with it a high risk of hypocalcaemia requiring rigorous prophylaxis. More research is needed to explore practical methods to identify those at risk of fracture and determine the efficacy of antiresorptive and anabolic therapies to decrease this risk.

Glucagon-like peptide 1 receptor agonists in end-staged kidney disease and kidney transplantation: A narrative review.

AIMS: Glucagon-like peptide 1 receptor agonists (GLP-1RA) improve glycemic control and promote weight loss in type 2 diabetes (DM2) and obesity. We identified studies describing the metabolic benefits of GLP-1RA in end-staged kidney disease (ESKD) and kidney transplantation. DATA SYNTHESIS: We searched for randomized controlled trials (RCTs) and observational studies that investigated the metabolic benefits of GLP-1RA in ESKD and kidney transplantation. We summarized the effect of GLP-1RA on measures of obesity and glycemic control, examined adverse events, and explored adherence with therapy. In small RCTs of patients with DM2 on dialysis, liraglutide for up to 12 weeks lowered HbA1c by 0.8%, reduced time in hyperglycemia by ∼2%, lowered blood glucose by 2 mmol/L and reduced weight by 1-2 kg, compared with placebo. In prospective studies inclusive of ESKD, 12 months of semaglutide reduced HbA1c by 0.8%, and contributed to weight losses of 8 kg. In retrospective cohort studies in DM2 and kidney transplantation, 12 months of GLP-1RA lowered HbA1c by 2%, and fasting glucose by ∼3 mmol/L compared with non-use, and in some reports, weight losses of up to 4 kg were described. Gastrointestinal (GI) side effects were most commonly reported, with hypoglycemia described with GLP-1RA in hemodialysis, particularly in those using insulin. CONCLUSIONS: GLP-1RA are growing in popularity in those with DM2 and obesity. In small RCTs and observational cohort studies modest glycemic and weight benefits have been described in ESKD and transplantation, but GI side effects may limit adherence. Larger and longer term studies of GLP-1RA remain important.

To repeat or not to repeat? Measuring bone mineral density during anti-resorptive therapy or a drug holiday.

An initial bone mineral density (BMD) measurement is used to diagnose osteoporosis and decide whether patients need treatment, but the utility of repeating this test in those on treatment or on a drug holiday (ie, during a pause in bisphosphonate treatment) is controversial. Here, we present evidence for and against the use of BMD monitoring in patients receiving antiresorptive therapy or on a drug holiday, and give our recommendations, arguing against a one-size-fits-all approach.

Graphene nanoparticles as data generating digital materials in industry 4.0.

One of the potential applications of 2D materials is to enhance multi-functionality of structures and components used in aerospace, automotive, civil and defense industries. These multi-functional attributes include sensing, energy storage, EMI shielding and property enhancement. In this article, we have explored the potential of using graphene and its variants as data generating sensory elements in Industry 4.0. We have presented a complete roadmap to cover three emerging technologies i.e. advance materials, artificial intelligence and block-chain technology. The utility of 2D materials such as graphene nanoparticles is yet to be explored as an interface for digitalization of a modern smart factory i.e. "factory-of-the-future". In this article, we have explored how 2D material enhanced composites can act as an interface between physical and cyber spaces. An overview of employing graphene-based smart embedded sensors at various stages of composites manufacturing processes and their application in real-time structural health monitoring is presented. The technical challenges associated with interfacing graphene-based sensing networks with digital space are discussed. Additionally, an overview of the integration of associated tools such as artificial intelligence, machine learning and block-chain technology with graphene-based devices and structures is also presented.

Hypocalcemia Risk of Denosumab Across the Spectrum of Kidney Disease: A Population-Based Cohort Study.

Denosumab can be used in patients with chronic kidney disease (CKD) but has been linked with cases of severe hypocalcemia. The incidence of and risk factors for hypocalcemia after denosumab use are not well established. Using linked health care databases at ICES, we conducted a population-based cohort study of adults >65 years old with a new prescription for denosumab or a bisphosphonate between 2012 and 2020. We assessed incidence of hypocalcemia within 180 days of drug dispensing and stratified results by estimated glomerular filtration rate (eGFR in mL/min/1.73 m2 ). We used Cox proportional hazards to assess risk factors for hypocalcemia. There were 59,151 and 56,847 new denosumab and oral bisphosphonate users, respectively. Of the denosumab users, 29% had serum calcium measured in the year before their prescription, and one-third had their serum calcium checked within 180 days after their prescription. Mild hypocalcemia (albumin corrected calcium <2.00 mmol/L) occurred in 0.6% (95% confidence interval [CI] 0.6, 0.7) of new denosumab users and severe hypocalcemia (<1.8 mmol/L) in 0.2% (95% CI 0.2, 0.3). In those with an eGFR <15 or receiving maintenance dialysis, the incidence of mild and severe hypocalcemia was 24.1% (95% CI 18.1, 30.7) and 14.9% (95% CI 10.1, 20.7), respectively. In this group, kidney function and baseline serum calcium were strong predictors of hypocalcemia. We did not have information on over-the-counter vitamin D or calcium supplementation. In new bisphosphonate users, the incidence of mild hypocalcemia was 0.3% (95% CI 0.3, 0.3) with an incidence of 4.7% (95% CI 1.5, 10.8) in those with an eGFR <15 or receiving maintenance dialysis. In this large population-based cohort, we found that the overall risk of hypocalcemia with new denosumab use was low but increased substantially in those with eGFR <15 mL/min/1.73 m2 . Future studies should investigate strategies to mitigate hypocalcemia. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Repair of Aerospace Composite Structures Using Liquid Thermoplastic Resin.

In this study, two types of carbon-fiber-reinforced plastic (CFRP) composite scarf geometries were created using two scarf angles, i.e., 1.43° and 5.71°. The scarf joints were adhesively bonded using a novel liquid thermoplastic resin at two different temperatures. The performance of the repaired laminates was compared with pristine samples in terms of residual flexural strength using four-point bending tests. The repair quality of the laminates was examined by optical micrographs, and the failure modes after flexural tests were analyzed using a scanning electron microscope. The thermal stability of the resin was evaluated by thermogravimetric analysis (TGA), whereas the stiffness of the pristine samples was determined using dynamic mechanical analysis (DMA). The results showed that the laminates were not fully repaired under ambient conditions, and the highest recovery strength at room temperature was only 57% of the total strength exhibited by pristine laminates. Increasing the bonding temperature to an optimal repair temperature of 210 °C resulted in a significant improvement in the recovery strength. The best results were achieved for laminates with a higher scarf angle (5.71°). The highest residual flexural strength was recorded as 97% that of the pristine sample repaired at 210 °C with a scarf angle of 5.71°. The SEM micrographs showed that all the repaired samples exhibited delamination as the dominant failure mode, whereas the pristine samples exhibited dominant fiber fracture and fiber pullout failure modes. The residual strength recovered using liquid thermoplastic resin was found to be much higher than that reported for conventional epoxy adhesives.

A secure and dependable trust assessment (SDTS) scheme for industrial communication networks.

Due to tamper-resistant sensor nodes and wireless media, Industrial Wireless Sensor Networks (WSNs) are susceptible to various security threats that severely affect industrial/business applications. The survival of sensor networks is highly dependent on the flourishing collaboration of sensor nodes. Trust management schemes seem to be realistic and promising techniques to improve security as well as cooperation (dependability) among sensor nodes by estimating the trust level (score) of individual sensor nodes. This research paper presents a well-organized and motivating secure, dependable trust assessment (SDTS) scheme for industrial WSNs to cope with unexpected behavior such as an on-off attack, bad-mouthing attack, garnished attack, etc., by employing robust trust evaluation components based on success ratio and node misbehaviour. SDTS incorporates an interesting trust evaluation function in which the trust range can be adjusted in accordance with the application requirement. SDTS include direct communication trust, indirect communication trust, data trust, and misbehavior-based trust to defend the multiple internal attacks. SDTS works according to the behavior of nodes, i.e., whether the sensor nodes are interacting frequently or not. Moreover, abnormal attenuation and dynamic slide lengths are incorporated in the proposed model (SDTS) to deal with various natural calamities and internal attacks. SDTS is compared against three recent state-of-the-art methods and found efficient in terms of ease of trust assessment, false-positive rate (2.5%), false-negative rate (2%), attack detection rate (90%), detection accuracy (91%), average energy consumption (0.40 J), and throughput (108 Kbps) under the load of 500 sensor nodes with 50% malicious nodes. Investigational results exhibit the potency of the proposed scheme.

Comparison of the Effectiveness of Intra-articular Infiltration of Hyaluronic Acid and Corticosteroids in the Management of Knee Osteoarthritis: A Prospective Comparative Study.

Background Knee osteoarthritis (KOA) is a chronic and progressive disease of the knee joint characterized by articular cartilage destruction. It is the most common cause of knee disability and pain globally. Various treatments are used for the management of KOA; however, the role of intra-articular injections in KOA management in Pakistan remains understudied. Therefore, this study aims to evaluate the effectiveness of intra-articular injections of hyaluronic acid (HA) and corticosteroids in the management of KOA. Methodology This randomized, prospective, comparative study was conducted among 88 patients diagnosed with KOA in the outpatient department clinic of orthopedics in Benazir Bhutto Hospital, Rawalpindi, from January 2022 to January 2023. For patient enrolment, structured inclusion and exclusion criteria and a simple random sampling technique were used. Before data collection, ethical approval and informed consent were obtained. Data collection was done via a self-structured and interview-based proforma. Data analysis was performed through descriptive statistics and independent t-tests using SPSS version 25 (IBM Corp., Armonk, NY, USA). Results KOA was more prevalent in women (60, 68.18%) than men (28, 31.82%). The means for study variables such as age, Visual Analog Scale (VAS) score, and Western Ontario and McMaster Universities (WOMAC) score were 58.08 ± 7.89 years, 7.66 ± 1.8, and 71.86 ± 8.90, respectively. The incidences of right-sided and left-sided KOA were 57 (64.77%) and 31 (35.23%), respectively. Likewise, the frequency of grade II KOA was 55 (62.50%), while the frequency of grade III KOA was 33 (37.50%). Differences in the mean scores of both VAS and WOMAC between study groups were statistically significant at the second-week, sixth-week, and third-month follow-up visits. However, the mean scores of VAS and WOMAC were lower in group B than in group A at the second-week follow-up visit, whereas the scores were lower in group A compared to group B after the sixth week and third month of intra-articular injections. Conclusions Intra-articular injections of both HA and corticosteroids were adequately effective in the management of KOA-associated pain and functional restrictions; nevertheless, the benefits of corticosteroids were acute and short-term, whereas the outcomes of HA were gradual and long-term.

Incidence of Microalbuminuria and Factors Affecting It in Patients With Type 2 Diabetes Mellitus.

Background and objectives Microalbuminuria prevalence is high in patients with type 2 diabetes mellitus (T2DM) all over the world and its prevalence is affected by several factors. In Pakistan, microalbuminuria and factors that play a role in its development in patients with T2DM are under-researched. This study aimed to determine the incidence of microalbuminuria and the factors affecting it in patients with T2DM. Material and methods This descriptive cross-sectional study was performed on 129 diagnosed patients with T2DM in the outpatient department of Benazir Bhutto Hospital, Rawalpindi, for approximately six months from August 2021 to January 2022. Patients were recruited in the study through a non-probability consecutive sampling technique and established inclusion and exclusion criteria. Ethical approval was obtained from the relevant hospital ethical review board (ERB). After explaining the study's aims, informed consent was also taken from all patients before the start of data collection. A self-structured and interview-based questionnaire was used for the collection of data. Descriptive statistics and a chi-square test were applied for the data analysis using Statistical Package for the Social Sciences (SPSS) version 25 (Armonk, NY: IBM Corp.). Results The incidence of microalbuminuria in the study population was 31.78%. The association between microalbuminuria and age (p = 0.002), gender (p = 0.003), duration of diabetes mellitus (p = 0.001), therapy type (p = 0.03), control of diabetes mellitus, (p = 0.001), and hypertension (p = 0.002) was statistically significant. Higher age group, male gender, longer duration of diabetes mellitus, oral hypoglycemic agents, poorly controlled diabetes mellitus, and history of hypertension, all were found to raise the incidence of microalbuminuria. Even though being overweight was also found to raise the incidence of microalbuminuria, the association between microalbuminuria and nutritional status was statistically insignificant (p = 0.05). Conclusion Microalbuminuria incidence is significantly high in the study population. The factors such as increasing age, male gender, longer duration of the diabetes mellitus, oral hypoglycemic agents, poorly controlled diabetes mellitus, and history of hypertension, all raise the incidence of microalbuminuria in patients with T2DM to a statistically significant extent. Screening of microalbuminuria patients with T2DM should be added to the routine investigations for diabetes mellitus for the early detection of renal and cardiovascular complications.

Risk Factors of Nephrolithiasis in a Tertiary Care Hospital in Rawalpindi: A Descriptive Cross-Sectional Study.

Background Nephrolithiasis (renal stones) is the most common urological disease. Its prevalence is high in every part of the world. Several factors lead to renal stone formation. In Pakistan, nephrolithiasis prevalence is also high as Pakistan is located in a region which is known as the salt belt. However, nephrolithiasis and its possible risk factors are under-researched in Pakistan. Objective This study aims to identify the risk factors for nephrolithiasis among admitted patients with renal stones. This may lead to a reduction in renal stone incidence and its allied complications by the prevention of risk factors that would have a major role in renal stone formation. Material and methods This descriptive cross-sectional study was performed among the 143 admitted patients with renal stones in the urology ward of Benazir Bhutto Hospital, Rawalpindi, for approximately six months from November 2021 to April 2022. Non-probability convenient sampling and developed inclusion and exclusion criteria were used for the recruitment of patients. After elaborating on the objectives, the study data were collected by interviewers through a self-structured questionnaire. Descriptive analysis was carried out using SPSS version 25.0 (IBM Corp., Armonk, NY). Results Nephrolithiasis was more prevalent among patients who had an age group range of 15-30 years (47.55%), male gender (56.65%), illiterate educational status (53.14%), lower socioeconomic status (66.43%), inadequate intake of water (61.53%), used tap water (56.64%), a habit of daily vegetable intake (65.04%), sedentary lifestyle (51.74%), family history of renal stones (57.34%), no diabetes mellitus (62.94%), no hypertension (52.45%), and overweight (48.23%). Conclusion In brief, the age group of 15-30 years, male gender, illiteracy, lower socioeconomic status, insufficient water intake, tap water, high vegetables, inactive lifestyle, family history of nephrolithiasis, and a high BMI all increase the risk of nephrolithiasis.

Diabetes and Ramadan: Practical guidelines 2021.

Fasting during Ramadan is one of the five pillars of Islam and is obligatory for all healthy Muslims from the age of puberty. Though individuals with some illness and serious medical conditions, including some people with diabetes, can be exempted from fasting, many will fast anyway. It is of paramount importance that people with diabetes that fast are given the appropriate guidance and receive proper care. The International Diabetes Federation (IDF) and Diabetes and Ramadan (DaR) International Alliance have come together to provide a substantial update to the previous guidelines. This update includes key information on fasting during Ramadan with type 1 diabetes, the management of diabetes in people of elderly ages and pregnant women, the effects of Ramadan on one's mental wellbeing, changes to the risk of macrovascular and microvascular complications, and areas of future research. The IDF-DAR Diabetes and Ramadan Practical Guidelines 2021 seek to improve upon the awareness, knowledge and management of diabetes during Ramadan, and to provide real-world recommendations to health professionals and the people with diabetes who choose to fast.

Denosumab in chronic kidney disease: a narrative review of treatment efficacy and safety.

People with chronic kidney disease (CKD) are at high risk of bone fractures. In this review, we summarize the complexity of fracture prevention in CKD, describe the usefulness of a medication called denosumab, and review its safety in this population. Our article will help doctors manage brittle bones in CKD and encourage researchers to conduct more studies to improve bone health in CKD. PURPOSE: Patients with CKD are at increased risk of fragility fractures and associated consequences. We discuss the complexity of fracture prevention in CKD, summarize the efficacy and safety of denosumab, and provide an approach to denosumab-induced hypocalcemia. METHODS: Using predefined terms, we searched PubMed, MEDLINE, and Google Scholar for studies on fracture prevention in CKD and the efficacy and safety of denosumab. We included observational studies, randomized controlled trials (RCTs), meta-analyses, evidence-based reviews, and clinical practice guidelines. RESULTS: The diagnosis of osteoporosis and prevention of related fragility fractures is complex in CKD, particularly in those with advanced and end-staged kidney disease (ESKD). Prior to initiating denosumab, it is important to assess for and optimize CKD-mineral and bone disorders (CKD-MBD). In observational studies and small RCTs, denosumab has been shown to improve bone mineral density and reduce bone turnover in CKD, but there have been no studies focused upon its fracture efficacy. Denosumab-induced hypocalcemia has also been reported, which disproportionately impacts those with ESKD. Risk factors for hypocalcemia with denosumab use in CKD include lower baseline serum calcium and 25 hydroxyvitamin D and both low and high bone turnover. Choosing the "right patient" for denosumab, supplementing with calcium and vitamin D, adjusting calcium dialysate, and close clinical monitoring are essential if considering this drug. CONCLUSION: With optimization of CKD-MBD, calcium and vitamin D supplementation, and close monitoring, denosumab can be considered in CKD. There are however opportunities to better understand its fracture efficacy and safety in an RCT setting.

Canadian national hypoparathyroidism registry: an overview of hypoparathyroidism in Canada.

PURPOSE: To evaluate the epidemiology, presentation and management of hypoparathyroidism in Canada. Hypoparathyroidism is associated with significant morbidity and poor quality of life. We present baseline results from the Canadian National Hypoparathyroidism Registry, a prospective observational study evaluating hypoparathyroidism in Canada. METHODS: Our study enrolled 130 patients with hypoparathyroidism. Patients were followed every 6 months with clinical and lab assessments. We present baseline data in this manuscript. RESULTS: Seventy percent (91/130) of patients had postsurgical hypoparathyroidism, 30% (39/130) of patients had nonsurgical hypoparathyroidism due to autoimmune, genetic or idiopathic causes, and a molecular diagnosis was confirmed in 11 of these 39 patients. Pseudohypoparathyroidism was confirmed in 4/39 patients, DiGeorge syndrome in 2/39 patients, Barakat syndrome with a mutation in the GATA3 gene in 1/39, and activating mutations of the CASR gene in 3/39 patients with nonsurgical hypoparathyroidism. Renal complications with nephrocalcinosis or nephrolithiasis were present in 27% (14/52) of patients with postsurgical disease and 17% (4/24) of patients with nonsurgical hypoparathyroidism. Basal ganglia calcification was noted on imaging in 15% (n = 5/34) of patients with postsurgical hypoparathyroidism and 37% (n = 7/19) of patients with nonsurgical hypoparathyroidism. CONCLUSIONS: Hypercalciuria was more commonly seen in those with renal complications of nephrocalcinosis, nephrolithiasis or CKD, and hyperphosphatemia was more commonly seen in those with basal ganglia calcification. Hospitalization occurred in 28% of those with postsurgical hypoparathyroidism and 46% of those with nonsurgical hypoparathyroidism. Hypoparathyroidism is associated with significant morbidity. Effective strategies to reduce the short-and long-term complications of hypoparathyroidism need to be developed and evaluated.

Study of the Effect of Different Hepatitis C Virus Genotypes on Splenomegaly.

Background Several recent studies have shown that the hepatitis C virus (HCV) and its different genotypes are a predominant and leading cause of cirrhosis and splenomegaly in different regions of the world. Advanced stage of cirrhosis leads to portal hypertension that causes splenomegaly. This complication may have many other manifestations such as anemia, infections, and bleeding disorders in severe stages. This study aimed to determine the effect of different HCV genotypes on the development of splenomegaly and to assess which HCV genotypes are more associated with it. Materials and methods A total of 483 conveniently sampled HCV patients were included in this descriptive cross-sectional study. Six genotypes (1, 2a, 2b, 3a, 3b, and mixed) were studied, and 80 patients for each of these genotypes were included. Data were collected from patient medical records regarding patient demographic details, HCV serology and genotyping, and sonographic size of the spleen. Results In total, splenomegaly was present in 14.1% (n=68) patients. The development of splenomegaly was significantly associated with old age, as 25.2% (n=26) of patients above 60 years of age (n=103) developed splenomegaly (P=0.005). Our study determined that splenomegaly was significantly related to HCV genotypes 3a, 3b, and 1 (P<0.001, P=0.017, and P=0.019, respectively). By taking mixed genotype as a reference, the odds of developing splenomegaly with genotype 3a were the highest (OR = 9.481; CI=95%). Conclusions Our study concludes that HCV genotype 3a, 3b, and 1, and age above 60 years have a significant association with splenomegaly. Genotype 3a has the highest risk of developing splenomegaly. Therefore, our study demands screening, early diagnosis, and prompt treatment of these particular HCV genotypes to prevent complications and risk of mortality.

Bisphosphonate and denosumab initiation in older adults in Ontario, Canada: a population-based cohort study.

We provide an update on how commonly prescribed osteoporosis therapies are being initiated in older adults in Ontario. Patients newly prescribed denosumab are older, more often female, and have more comorbidities than those prescribed bisphosphonates. Their characteristics, monitoring, and persistence with prescribed therapy differ from clinical trial participants. Real-world studies on oral bisphosphonates and denosumab might be valuable. PURPOSE: To provide a contemporary view on oral bisphosphonate and denosumab prescribing to older adults in routine care. METHODS: Using linked healthcare databases, we conducted a population-based cohort study of adults ≥ 66 years newly prescribed oral bisphosphonates or denosumab between February 2013 and March 2017 in Ontario, Canada. We captured their clinical characteristics, monitoring, and continuous use of prescribed therapies. We illustrate how "real-world" new users of bisphosphonates and denosumab differ from randomized controlled trial (RCT) participants. RESULTS: There were 107,847 individuals newly prescribed oral bisphosphonates (n = 59,996) or denosumab (n = 47,851) over the study period. Compared with new users of oral bisphosphonates, denosumab users were older (mean age 79.1 vs. 75.7 years), more often female (97.2 vs. 71.8%), from non-rural areas (93.9 vs. 89.9%), and resided in long-term care (10.9 vs. 3.3%). They had more comorbidities including dementia, falls, and fractures. Following their new prescription, denosumab users had more frequent testing of serum calcium. Duration of continuous use of denosumab was longer than bisphosphonates, and more bisphosphonate users had evidence of treatment discontinuation (56.7 bisphosphonate vs. 33.8% denosumab users discontinued therapy at 365 days). Compared with RCT participants, a higher proportion of "real-world" bisphosphonate and denosumab users had comorbidities including advanced kidney disease. CONCLUSION: The clinical characteristics and monitoring of new users of bisphosphonates and denosumab generally align with practice guidelines, product monographs, and drug reimbursement criteria. Given differences between real-world users and RCT participants, there may be a role for safety and effectiveness studies of bisphosphonates and denosumab in routine care.