Acute blood glucose (BG) decompensations (hypoglycemia and hyperglycemia) represent a frequent and significant risk for inpatients and adversely affect patient outcomes and safety. The increasing need for BG management in inpatients poses a high demand on clinical staff and health care systems in addition.This study aimed to generate a broadly applicable multiclass classification model for predicting BG decompensation events from patients’ electronic health records to indicate where adjustments in patient monitoring and therapeutic interventions are required. This should allow for taking proactive measures before BG levels are derailed.A retrospective cohort study was conducted on patients who were hospitalized at a tertiary hospital in Bern, Switzerland. Using patient details and routine data from electronic health records, a multiclass prediction model for BG decompensation events  was generated based on a second-level ensemble of gradient-boosted binary trees.A total of 63,579 hospital admissions of 38,250 patients were included in this study. The multiclass prediction model reached specificities of 93.7%, 98.9%, and 93.9% and sensitivities of 67.1%, 59%, and 63.6% for the main categories of interest, which were nondecompensated cases, hypoglycemia, or hyperglycemia, respectively. The median prediction horizon was 7 hours and 4 hours for hypoglycemia and hyperglycemia, respectively.Electronic health records have the potential to reliably predict all types of BG decompensation. Readily available patient details and routine laboratory data can support the decisions for proactive interventions and thus help to reduce the detrimental health effects of hypoglycemia and hyperglycemia. Diabetes is one of the most common lifestyle diseases worldwide (affecting approximately 537 million people in 2021), particularly among older adults (aged >65 years), with numbers on the rise .The hallmark of diabetes is loss of control over blood glucose (BG) levels. Failure to maintain BG levels within the ranges normally set by functional glucose homeostasis in nondiabetic people manifests as hyper- and hypoglycemia, where BG levels decompensate, that is, exceed or fall below a critical threshold, respectively.Both hypoglycemia and hyperglycemia have been associated with numerous complications in inpatients. This includes an increased length of stay , diabetiThe environment of inpatients  is usually well-controlled; nevertheless, the maintenance of BG levels in a normoglycemic range is demanding. It is complicated by the fragile health status of the inpatient, stress (including postoperative stress), prolonged fasting, changes in diet and meal timings, and inadequate dosing of or changes in the type of antidiabetic drugs administered to name a few main troubles ,15. StanThe combination of continuous glucose monitoring (CGM) systems and subcutaneous insulin pumps with automated insulin delivery (closed-loop) systems is a recent promising development -19, whicAn alternative approach to continuous BG measurements is the prevention of BG decompensation by the detection of early signs or patterns associated with it, thereby avoiding the immediate and long-term adverse effects of hypoglycemia and hyperglycemia . To dateThis study investigated whether readily available standard laboratory results and patient information could be used to reliably predict both hypoglycemia and hyperglycemia in inpatients with a clinically relevant prediction horizon.The data set contained anonymized hospital admission data collected during the routine management of adult (aged ≥18 years) inpatients of the 6 hospitals of the Insel-Gruppe  from January 1, 2014, to December 5, 2019. Data were retrieved as is; that is, no extra data were collected for this retrospective cohort study. Data of patients whose BG levels had been assessed at least once were included if they met ≥1 of the following inclusion criteria:Diagnosis of diabetes or diabetes-related syndromes , includAdministration of an antidiabetic drug falling into code category A10 (or subcategories thereof) of the Anatomical Therapeutic Chemical Classification System1c value of ≥48.0 mmol/mol  or ≥6.5% Extreme BG levels regardless of any formal diagnosis of diabetes, including a BG level of <4.0 or ≥11.1 mmol/L measured at any time, a fasting venous BG level of ≥7.0 mmol/L, a 2-hour value of ≥11.1 mmol/L during an oral glucose tolerance test, or an HbAThe rationale behind these 3 inclusion criteria was to include a broad range of patients with potential indications of dysglycemia. The fact that BG level tests belong to the routine panel of laboratory tests in inpatients further helped reduce potential cohort bias. The unfiltered inclusion of all patients’ BG measurement data was not possible because of the limitations set by the Swiss Human Research Act.In total, the patient cohort comprised 38,250 patients  who had undergone 63,579 hospital admissions (cases), during which at least 1 laboratory analysis of 52 parameters was performed .The types of BG decompensation are defined by BG levels of <3.9 mmol/L   or >10, BG level intervals were assigned category numbers of 0 to 4, with category 0 representing cases not showing BG decompensation . These cBefore use, the data sets were cleaned and preprocessed to remove erroneous entries and unreasonable, unlikely, or even impossible values.incompatible with human life were published only for a relatively small number of analytes [For patient variables, values outside the following (reasonable) limits were set to “N/A”  as they are most likely the result of errors during data input: ages 18 to 130 years, body height 100 to 250 cm, and weight 25 to 400 kg. For laboratory measurements, negative values were removed . Values generally analytes , and meaanalytes , plasma analytes , potassianalytes , and sodanalytes .Isolation Forest algorithm [sklearn.ensemble. IsolationForest module; version 0.21.3) and were flagged. These binary outlier flags were used as additional variables to label potentially severe cases.Other putative outliers were identified using the lgorithm  , information on the previous and current administration of antidiabetic drugs, previous incidents of BG decompensation, history of diagnoses, and stay in ICU , which is a score indicating how influential each variable was during the construction of the tree ensemble, was determined during model training [The best models with respect to precision , sensitivity , area under the curve of the receiver operating characteristic curve (AUC ROC), and informedness were retained. The training . The seltraining ,35.Subsequently, multiple binary models were assembled into a second-level ensemble to build a multiclass classifier. The composition of this second-level ensemble was optimized for average precision using a genetic algorithm ,37, as tideal results). For multiclass classification, a case-specific bit string for the votes of all binary classifiers of the second-level ensemble was created. The label of the ideal class-specific bit string with the minimal Hamming distance to the predicted case-specific bit string was chosen as the predicted case label.Each multiclass is described by a  combination of predictions of all binary classifiers : hypoglycemia>severe hyperglycemia>moderate hyperglycemia>nondecompensated case>mild hyperglycemia. Mild hyperglycemia was assigned the lowest priority to reduce false alarms.This study was approved by the Bernese cantonal ethics committee  and registered with the Business Administration System for Ethics Committees of the canton of Bern (KEK/NZE file number: Req-2018-00335).Methods section) are summarized in For this study, we analyzed clinical data from 38,250 inpatients who had undergone 63,579 hospital admissions between January 1, 2014, and December 5, 2019, during which at least 1 laboratory analysis was performed. Of the 38,250 patients, 16,842 (44.03%) were women , and 21,408 (55.97%) were men . Specific details for the different categories of dysglycemia . The likelihood that patients with some form of BG decompensation were admitted to the ICU increased approximately 5-fold.The patients showing hypoglycemia included significantly younger patients compared with other categories, and similarly, patients presenting with hypoglycemia were less obese . Adding additional binary classifiers (beyond 2klog) is, in principle, redundant; however, additional bits can act as error-correcting codes .fitness value) during the optimization process.As the number of potential ensembles built from binary models grows exponentially, their composition was optimized using a genetic algorithm ,37, asseThe multiclass classifier ensemble with the best performance comprised binary model types A, B, G, H, and I (compare An overview of the true decompensation categories versus the model predictions (confusion matrix) is shown in The performance metrics for each class are summarized in When the different types of hyperglycemia were considered separately, mild, moderate, and severe hyperglycemia were correctly predicted in 46.69% (2411/5164), 31.22% (797/2553), and 36.87% (774/2099) of the cases in relation to the true category, respectively . For eacNondecompensated cases or cases showing hypoglycemia and severe hyperglycemia were predicted reasonably, albeit fairly conservatively, with lower sensitivity. The correct distinction between hyperglycemia types was more challenging. From a clinical perspective, this is understandable as these cases form a continuum. Nevertheless, a warning of any kind of hyperglycemia makes no difference in terms of the measures taken; hence, a classification of hyperglycemia was assumed to be sufficient, as long as this is indeed the underlying condition.The median look-back window was 4.4 (IQR 1.8-9) days, 1.9 (IQR 0.4-5.7) days, 1.0 (IQR 0.3-2.4) days, 1.5 (IQR 0.6-3.7) days, and 1.8 (IQR 0.7-4.4) days for control class, hypoglycemia, and mild, moderate, and severe hyperglycemia, respectively. The median prediction horizon was 7 (IQR 3-15) hours for hypoglycemia and 4  hours for all hyperglycemia types. In a clinical setting, such a prediction horizon would allow sufficient time for proactive interventions before BG decompensation occurs.If the multiclass classifier is converted (reduced) to a binary classifier, it correctly predicts 67.12%  of decompensated and 93.66%  of nondecompensated cases, corresponding to sensitivity  and specificity (selectivity), respectively. In terms of precision  and balanced accuracy, the model achieved 80.5% and 80.5%, respectively.Methods section for details) varied slightly across models, they all pointed in the same direction. A set of 12 variables encompassed the 10 most important variables for all 5 binary models. Not unexpectedly, quantitative readouts of glucose measurements had the highest importance; however, soft variables, such as information on recent decompensation events or time since admission, were also critical.Notably, across all predictions, a relatively small set of variables had a comparably large impact on the individual binary models constituting the multiclass classifier . AlthougIn this study, we set up a prediction model for hypo- and hyperglycemia from routine inpatient clinical data. We used anonymized EHRs of 63,579 hospital admissions of 38,250 patients between January 2014 and December 2019 to derive variables from measurements of common laboratory analytes, as well as patient information, drug administration, and diagnosis history. The data were characterized by a high degree of missingness, particularly for many of the variables originating from less common laboratory tests. To address this issue, we created a second-level ensemble comprising binary decision tree models that could deal with incomplete data. With respect to the overall main categories of interest (nondecompensated cases and hypo- or hyperglycemia), our classifier achieved 93.7% , 59% (1093/1853), and 63.6% (6240/9817) correct predictions, respectively. When converted to a binary classifier, it reached correct classification rates of 93.7%  and 67.1%  for decompensated and nondecompensated cases, respectively. The median prediction horizon was 7 and 4 hours for hypo- and hyperglycemia, respectively.In our modeling approach, the variables were derived rather than directly taken from the EHRs. This increases the effort in an applied clinical setting as the variables need to be updated when new measurements are added to a patient’s EHR. This concerns both the summary statistics of each analyte and variables related to patient history , which may change during hospitalization. However, an automatic update from clinical data warehouses should solve this issue. The ultimate aim should be to allow integration into a real-time alert system.Data were not specifically collected for our retrospective study; hence, our data set may show a potential bias in terms of the timing of blood sampling; for example, hours during the day with higher staffing levels or before meals may be somewhat overrepresented. Hypoglycemia, in particular, may occur at night or in the early morning hours when no measurements are performed. Despite this potential bias in the training data, our model featured a promising prediction horizon. With 7 and 4 hours for hypo- and hyperglycemia, respectively, it provided sufficient time to initiate measures and prevent BG decompensation and its adverse effects. The difference between hypo- and hyperglycemia may be explained by more deliberate monitoring of BG levels in potential hypoglycemic patients by clinical staff.The main strength of our model’s performance lies in the distinction between the extreme ends of the decompensation scale . However, the discrimination rate of different types of hyperglycemia, was rather moderate, particularly the rate of correct classification of moderate hyperglycemia (31.2%). In part, this may be because the categorization of different types of hyperglycemia, and the overall distinction into 5 categories in our model, had a clinical relevance rather than a computational one. Different types of hyperglycemia are defined by clinical practice guidelines ,27 and ftrigger a BG test by clinical staff. False positives cause an extra workload for clinical staff but are also noncritical for a patient and occurred at a low rate (6.3%). False-negative predictions are more problematic as they may possibly result in the noninitiation of a BG test or countermeasures for BG decompensation. The false-negative rate of our model (32.9%) is suboptimal, meaning that it classifies too conservatively and misses too many decompensated cases. However, in light of these cases being missed completely without decision support, this is a step in the right direction.This does not affect the model’s usefulness drastically when taking into account the intention behind a model like ours, namely serving as decision support for adjustments of patient monitoring or therapeutic strategies (not triggering any treatment such as administration of insulin or glucose). Regarding the potential consequences of misclassification for a patient, mix-ups of hyperglycemia types are clinically irrelevant, and similarly, confusion of hypoglycemia and hyperglycemia has no drastic consequences—they would all Methods section), in contrast to other popular methods such as logistic regression, support vector machines, and neural networks, which require complete data sets.Despite having a common denominator—diabetes or diabetes-related comorbidities—patients in our cohort were diagnosed with various primary and secondary diagnoses. Consequently, a plethora of different analyses have been conducted, with some tests done routinely; for example, the assessment of blood count, and other, more specific ones, were missing in most cases, such as analyses related to iron metabolism. Our prediction model, a second-level ensemble using derived variables, deals well with this sparse data (shown in the Methods section). However, this is not necessarily disadvantageous. A cohort without preselection may lead to trivial models calling for the (nondecompensated) group with an overwhelming frequency, yielding a low overall classification error but limited clinical utility [Akin to other studies , the pat utility . The actNotably, our model uses routine clinical data from standard laboratory tests and patient information, all of which are readily available in hospital settings. This is beneficial as these variables—assuming a proper in-house information flow—are available for free, both in terms of cost  and effort (once the information is entered). However, such data collected during routine management usually do not feature fixed sampling times or a common set of analyses, which complicates alignment between cases. Given the absence of periodicity in the data, our approach was to mimic a physician’s intuitive assessment of the information present across a patient’s health record  rather than individual data points.This could ensure broad applicability, for example, in contrast to models based on expensive specialized tests  or even An increasing number of prediction studies are using the growing amount of patient data available in EHRs . A multiclass model offers the advantage of overcoming the vagueness associated with a binary model in a setting of >2 classes. For example, the prediction of Notably, our model performed reasonably well when reverted to a binary model. Although it may be counterintuitive to first build a multiclass classifier and then revert it to a binary classifier, this approach takes advantage of the fact that ensembles tend to outperform individual models  and can In the next step, it would be interesting to assess the multiclass classifier in a follow-up retrospective cohort study for validation purposes using an independent data set. Optimizing the sensitivity and reducing the false-negative rate should be an additional focus to make the model more applicable for clinical use. Further down the road, the incorporation of the model into an alert system or even actionable artificial intelligence -19 couldOur multiclass prediction model based on derived variables can classify both hypo- and hyperglycemia with reasonable sensitivity.Given the serious adverse health effects of hypo- and hyperglycemia and the associated poor outcome of BG decompensation in inpatients, it is important to prevent dysglycemia whenever possible. Prediction models such as ours may support clinicians in inpatient management by proactively pointing out the necessity for adjustment of patient monitoring or therapeutic strategies. Therefore, this study may serve as a step toward a real-time alarm system and actionable artificial intelligence, which may aid in reducing BG decompensation in inpatients.


No recurrence, testicular ascent or atrophy, or mortality was observed in either group during the 2-year follow-up period. Conclusions: Single-incision laparoscopic herniorrhaphy is a safe and effective operation for inguinal hernia repair in infants, even those with prematurity, lower body weight at the time of surgery, or cardiac and/or pulmonary comorbidities. Comparable results revealed no significant differences in perioperative complications despite younger ages and lower body weights.Background: As surgical techniques progress, laparoscopic herniorrhaphy is now performed more often in premature babies. The aim of this study was to analyze the outcomes of newborns and infants who underwent single-incision laparoscopic herniorrhaphy (SILH) at our center. Methods: We retrospectively reviewed patients younger than 12 months old who received SILH at our department from 2016 to 2020. SILH involved a 5 mm 30-degree scope and 3 mm instruments with a 3-0 Silk purse-string intracorporeal suture for closure of the internal ring. At the time of surgery, Group 1 newborns, whose corrected age was 2 months and below, were compared to the Group 2 infants, whose age was above 2 months. We assessed the patients’ characteristics, anesthesia, surgical data, and complications. Results: A total of 197 patients were included (114 newborns in Group 1 and 83 infants in Group 2). The mean age and body weight in Group 1 were 1.2 months and 3.8 kg, respectively, whereas in Group 2, they were 3.2 months and 6.7 kg, respectively. There were no significant differences in operative time (Group 1 = 34.1 min vs. Group 2 = 32.3 min,  In the 1990s, Schier F. first reported the laparoscopic approach for inguinal repair in children, and it has now become a commonly used technique ,3. The tSeveral laparoscopic techniques were introduced and classified as internal ring suturing either extracorporeally or intracorporeally. The extracorporeal technique involves suturing with a needle inserted percutaneously, and the knot is tied outside the fascia. The intracorporeal technique involves suturing of the internal ring using various methods, including purse-string and Z-type. Percutaneous internal ring suturing is one of the extracorporeal techniques, and the operative time is less than that of intracorporeal techniques . The leaA retrospective cohort study of SILH was performed by two experienced pediatric surgeons at Changhua Christian Hospital. A total of 197 pediatric patients underwent hernia repair using the SILH technique from March 2016 to August 2020. The inclusion criteria were newborns and infants under the age of 12 months at the time of SILH, and if complications occurred, they underwent full follow-ups until resolution. The exclusion criteria included loss of follow-ups before the resolution of complication. Newborns whose corrected age was 2 months and below were assigned to Group 1, and infants whose corrected age was above 2 months were assigned to Group 2. This study was approved by the Institutional Review Board of our hospital on 2 February 2020, which waived the need for patient consent. Patient data including gender, prematurity, corrected age and body weight at the time of surgery, preoperative hemoglobin, side of inguinal hernia repair, anesthetic comorbidities (cardiac defects and lung disease), anesthetic time (measured as time from induction to extubation) and concurrent umbilical hernia were collected. Outcome measures included perioperative complications, omphalitis, surgical site infection, postoperative hydrocele, testicular ascent or atrophy, and recurrence of hernia. Our primary outcome was hernia recurrence; secondary outcomes included anesthesia time, perioperative complications, and cPPV.2. A 5 mm 30-degree laparoscope was inserted to examine the patency of the processus vaginalis bilaterally . A p < 0.01, two-sample t-test). There was no significant difference in laterality or umbilical hernia.A summary of patient demographics and outcomes is listed in Cardiac comorbidities included atrial and/or ventricular septal defects, and the main pulmonary comorbidity was chronic lung disease. In Group 1, there were 14 patients with significant comorbidities ; in Group 2, there were 12 patients with significant comorbidities .No recurrence or MCIH was detected at a mean follow-up of 24 months .p = 0.07)).There was no significant difference in mean anesthetic time between the two groups (80 (range 52 to 143) minutes in Group 1 compared with 76.3 (range 52 to 112) minutes in Group 2 .The overall incidence of cPPV is 67.9%, which is higher than in previous studies. cPPV was found in 64 cases (56.2%) in Group 1 and 48 cases (34.1%) in Group 2; these values were significantly different  ,9,10,11.In the 1990s, El-Gohary and Schier F described the laparoscopic approach dealing with inguinal hernia in girls with inverted ligation or Z-sutures . In 2002Since 2010, applications of LIHR in preterms and newborns have been reported by many authors. LIHR seems to be a safe, feasible, and effective procedure for preterms with a low recurrence rate ,14,15,26LIHR is now being used worldwide with many refinements, and many centers have adopted the minimally invasive approach as the first choice for inguinal hernia repair in newborns. There were only a few studies considered comparing the specific subset group of newborns ,28. TherIn our center, we have performed single-incision laparoscopic herniorrhaphy (SILH) to manage pediatric inguinal hernias since September 2015. Initially, we only performed it in girls at ages above 2 years. As more experience was gained, we applied this technique to boys, infants, and then premature infants. There are some points to be highlighted with our laparoscopic approach: (a) the single-incision wound allowed a 5 mm laparoscope and 3 mm instruments to work together well in a small space with good cosmesis a–c; (b) When performing laparoscopic hernia repair, cPPV can be found and closed simultaneously. The incidence of cPPV is age-dependent. Rowe et al. reported a 64% rate of cPPV identified at the time of inguinal hernia repair in infants younger than 2 months, and Saad et al. reported a rate of 44% in infants younger than 1 year ,32. TherAnesthesiologic issues were reported in the literature ,35. We oThe optimal timing of hernia repair in younger and smaller infants or preterm babies is debatable. The foreseeable complications of intra- and post-operation versus incarceration must be considered. Delayed repair may increase incarceration. Sulkowski reported that delayed repair in 667 patients displayed a 9.5% incarceration rate, whereas early repair had a higher reoperation rate within 1 year . Some stThere were some studies that reported long-term follow-up of laparoscopic inguinal hernia repair in children with modifications and refinements. Matias Bruzoni reported transfixation suture ligation in 166 patients with a 1.8% recurrence rate in a median 24-month follow-up, and the study concluded that this repair can be adopted by surgeons with basic laparoscopic skills and result in good outcomes with acceptable recurrence rates . Denise We did not encounter major perioperative complications, but we did encounter some minor ones. Omphalitis was observed in 5.3% of cases, more in newborns than in infants. This could be due to the short time since the separation of the umbilical cord, causing fragile skin and subcutaneous tissue with stich reactions . One recFinally, it was reported that open inguinal hernia repair is one of the most common risks for male infertility . We shouThere are some limitations to this study. Retrospective selection bias cannot be avoided. All operations were performed by two laparoscopic surgeons, regardless of age and sex. The other limitation was a small number of patients with a short follow-up time. Because most recurrences and morbidities due to the operations usually present within the first postoperative year, we believe that the data may be reliable in terms of recurrences and postoperative complications.The SILH technique is a safe, feasible, and effective operation for minimally invasive inguinal hernia repair in infants, including those who are premature, have a lower body weight at the time of surgery, and have cardiac and/or pulmonary comorbidities. A prospective, randomized controlled trial in infants comparing outcomes following laparoscopic versus open inguinal hernia repair will be needed in the future.


Nitrogen (N) is an important nutrient for the growth and development of rice. The application of N fertilizer has become one of the inevitable ways to increase rice yield due to insufficient soil N content. However, in order to achieve stable and high yield, farmers usually increase N fertilizer input without hesitation, resulting in a series of problems such as environmental pollution, energy waste and low production efficiency. For sustainable agriculture, improving the nitrogen use efficiency (NUE) to decrease N fertilizer input is imperative. In the present review, we firstly demonstrate the role of N in mediating root architecture, photosynthesis, metabolic balance, and yield components in rice. Furthermore, we further summarize the current agronomic practices for enhancing rice NUE, including balanced fertilization, the use of nitrification inhibitors and slow-release N fertilizers, the split application of N fertilizer, root zone fertilization, and so on. Finally, we discuss the recent advances of N efficiency-related genes with potential breeding value. These genes will contribute to improving the N uptake, maintain the N metabolism balance, and enhance the NUE, thereby breeding new varieties against low N tolerance to improve the rice yield and quality. Moreover, N-efficient varieties also need combine with precise N fertilizer management and advanced cultivation techniques to realize the maximum exploitation of their biological potential. However, the NUE is only 28%~35%, which is 15%~20% lower than that of the global average NUE [Rice, a grain crop, is the principal food source for more than half of the world’s population ,2. Due trage NUE . TherefoNitrogen (N) is a crucial component for the synthesis of nucleotides, amino acids, and chlorophyll . The intThe efficient employment of N in agricultural production is crucial for yield and quality, environmental safety, and economic concerns . The useRice plants undergo a shift from vegetative to reproductive growth to produce a harvestable crop. Nitrogen is the primary component responsible for overall crop growth and development because it increases the number of leaves, individual leaf area, leaf area index (LAI), number of internodes, and internode length. N deficiency symptoms are first found in old leaves, and eventually become chlorotic and die . N defic3 species, indicating that rice assimilates a high amount of N per plant at the leaf level [Photosynthesis is vital for plant growth and crop yield ,20. Incraf level . In photaf level . These faf level . 2-assimilating ability and Rubisco remobilization in old leaves. Nitrogen deficiency will shorten the leaf life span and decrease the accumulation of the assimilation product, and the rates of senescence and loss of photosynthetic capacity are more rapid than those under abundant N. Conversely, the contents of Rubisco and soluble protein (per unit of chlorophyll) increase with the increase in plant N content. Therefore, extending the effective life span of leaves via N application or breeding is a tried-and-true method for increasing rice yield. The ratio of Rubisco to chlorophyll in rice is relatively stable across a certain range of N application, but is increased with the further increase in leaf N content. Furthermore, increased N supply has a more profound effect on the increase in the ratio of Rubisco to chlorophyll than on the ratio of ATP synthase to chlorophyll [Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco), an essential but rate-limiting component of photosynthesis, is central to the photosynthetic process ,25,26. Rorophyll ,27. Nitrogen is taken up by the roots, and assimilates are transported from the overground tissues to the roots to support regular growth and development . The rooThe signals from ammonium, nitrate, and nitrogen-containing metabolites including aspartate, glutamate, and glutamine, as well as the signals from C metabolism, constitute a complicated regulatory network involved in the C–N interaction . AdditioThe number of panicles or heads, the number of spikelets per panicle or head, the weight of 1000 spikelets, and the sterility or number of filled spikelets per panicle or head are the yield components that determine grain yield in cereal crops . The numThe timing of N availability is crucial for rice growth and development because it influences all yield components, including number of tillers, number of productive tillers, grain number per ear, 1000-grain weight, and grain N content. The uptake of N after anthesis accounts for approximately 50% of the final grain N content in rice . The ricThe measurement of NUE is important for assessing the fates of applied chemical fertilizers and their contribution to increasing crop yields ,38. NumeSustainable agricultural development requires taking advantage of advanced agronomic practices to ensure the more efficient use of N fertilizers, and thus reducing environmental pollution risks. Three main factors that influence the use efficiency of fertilizer N are crop demand, supply ability of plant-available N from the soil and fertilizer, and N loss from soil–plant systems ,31. In tRice NUE is closely related to N uptake, N accumulation, and transport . The morAn appropriate N management strategy is essential to increase NUE and crop yields ,47. ScieNew N fertilizer species can significantly reduce N fertilizer loss, but higher production costs and sales prices seriously restrict their popularization and application. In the future, soil-testing formula for fertilization with N, phosphorus and potassium must be used to improve crop yield and fertilizer utilization. Cultivated land is dominated by small fields for rice planting. Therefore, it is essential to develop economically feasible mechanical tools and promote the popularization and application of deep fertilization, which will greatly improve NUE and crop yields.Using N fertilizer excessively will not only make it difficult to continue to increase crop yield, but also reduce fertilizer use efficiency, resulting in the deterioration of the ecological environment. There are a large number of transporters involved in N uptake and utilization which play an important role in determining rice yield and quality. It is of great significance to investigate the mechanisms of N uptake, transport, and assimilation processes in rice, and to explore the genes of highly efficient N utilization for reducing both N fertilizer input and the cost of rice production, and increasing sustainable agricultural development.Therefore, we provide a thorough summary of the currently reported genes on NUE, paying particular attention to N uptake, assimilation, and transport, as well as transcriptional control of N signaling in rice . Thus faNPF genes affects nitrate uptake, distribution, and long-distance transport from root to stem in rice [OsNRT1.1B is a NRT1 family gene localized at the plasma membrane which is induced by high nitrate concentration. There is a variation between threonine and methionine at position 327 of OsNRT1.1B which is specific to indica and japonica, thus resulting in the different absorption capacity for nitrate in them. The NIL family with indica OsNRT1.1B showed higher yield and N use efficiency. The variation in OsNRT1.1B greatly explains the difference in nitrate utilization between indica and japonica, and has potential utility value for improving NUE in japonica [Nitrate is not only the main inorganic N source in plants, but also acts as signal molecules to activate the expressions of a series of genes, thus improving NUE. Nitrate transporter 1 (NRT1)/peptide transporter (PTR) exist widely in plants. They are generally known as the NPF family due to high homologous sequences. Several studies have reported that the proteins encoded by NPF family genes have some functional commonalities, such as OsNPF2.2, OsNPF2.4, OsNPF4.5, OsNPF7.2, and OsNRT1, belonging to low-affinity nitrate transporters. The knockdown or overexpression of  in rice ,53,54,55japonica . OsNRT2.3 during alternative splicing and are mainly expressed in the phloem of the plant. OsNRT2.3a encodes a phloem protein at the amino-acid position 516, responsible for long-distance nitrate transport from root to stem [OsNRT2.3B encodes a phloem plasma membrane protein at amino-acid position 486, which maintains intracellular pH buffering capacity to increase nitrate uptake [3--N distribution in the shoots [In addition to NRT1, NRT2 mainly participates in nitrate uptake and transport, and is an important nitrate transporter. OsNRT2.3A and OsNRT2.3B, as two members of the high-affinity nitrate transporter family, are two transcripts produced by  to stem ,58. OsNRe uptake . OsNRT2.e shoots . The nite shoots .4+-N than NO3--N because the absorption and assimilation of NH4+-N require less energy. However, excessive NH4+-N uptake will cause ammonium toxicity to plants, so ammonium uptake and metabolism are strictly regulated by ammonium transporter (AMT). In recent years, a total of 10 OsAMT genes have been identified in rice by genetic engineering and forward genetics methods. According to their homology, they are divided into five classes: OsAMT1 , OsAMT2 , OsAMT3 , OsAMT4 and OsAMT5 .The main N sources of plant uptake are ammonium and nitrate. Plants prefer to absorb NHOsAMT1 family, which shows a high homology of amino acid sequences and high affinity for NH4+-N uptake [OsAMTl.1 is expressed in both root and shoot, and endogenous glutamine has a feedback regulation effect on it [4+-N by rice under low-N conditions. The growth and N accumulation of single gene mutants exposed to low NH4+-N were not affected. The stem growth and N content of the amt1;1/1;2 double-mutant decreased by 30%, while the growth of the amt1;2/1;3 double-mutant was not affected. The amt1;1/1;2/1;3 triple-mutant had the most significant phenotype, with a 59% inhibition of shoot growth and a 72% reduction in N accumulation [Thus far, studies mainly focus on the three genes of the rice N uptake ,63. OsAMN uptake . OsAMTl.ct on it . Furthermulation .NLP genes, named OsNLP1-OsNLP6, were identified in rice based on genomic data analysis [OsNLP1, OsNLP3 and OsNLP4 could directly bind to the promoter regions of many N-uptake and assimilation genes, then coordinate the expression of these genes, and thus promote N uptake and utilization. The expression of OsNLP3 and OsNLP4 were induced by low NO3--N, but most of the proteins were localized in the cytoplasm and few were localized in the nucleus; thus, the expression of some N uptake and metabolism genes was weakly up-regulated [OsNLP1 was also induced by N starvation, but it was specifically localized in the nucleus and constitutively regulated N uptake and metabolism [3--N conditions, nitrate facilitated the transport of OsNLP3 and OsNLP4 from the cytoplasm to the nucleus, and strongly upregulated the expression of N uptake and metabolism genes, so promotes N uptake and utilization [4+-N was used as the sole N source, a small amount of OsNLP4 proteins was localized to the nucleus in a much slower manner, and regulated N utilization together with OsNLP1 [At present, several genes related to NUE have been identified in the NLP (nodule inception-like protein) family. Six analysis . Recent egulated ,68. The tabolism . Under hlization ,68. Howe3--N conditions, SPX4 formed a complex with NLP3 which prevented NLP3 from entering the nucleus, and then inhibited the expression of N-responsive genes and N utilization. For high NO3--N conditions, nitrate can promote the formation of an NRT1.1B–SPX4–NBIP1 complex. The ubiquitin ligase NBIP1 accelerated the ubiquitination and protein degradation of SPX4, and then released NLP3 into the nucleus, which activated the expression of N-responsive genes and the efficient utilization of N fertilizer [OsNLP3 is a key transcription factor in nitrate signaling transduction and is regulated by phosphate signaling repressor SPX4. Under low NOrtilizer .ANR1 is a key functional gene that has been verified to regulate lateral root development in Arabidopsis through the nitrate signaling pathway. Rice has five homologue genes of ANR1: OsMADS23, OsMADS25, OsMADS27, OsMADS57, and OsMADS61. Among these genes, OsMADS25, OsMADS27 and OsMADS57 are closely associated with N-signaling, which are mainly located at nucleus. They affected root architecture and NO3--N accumulation by regulating the nitrate transporters [In addition to those genes mentioned above, there are other genes involved in N uptake and transport in rice. The MADS-box family transcription factor plays an important role in the regulation of plant growth and development. sporters ,72,73.OsGS1;1, OsGS1;2 and OsGS1;3. OsGS1;1 is mainly responsible for rice growth and grain filling [OsGS1;2 mainly affects plant height and the number of tillers and spikes [FLO6 and the OsGS1;3 promoter, thereby regulating starch and protein synthesis, respectively, and thus regulating the accumulation of seed storage materials [During the growth and development of rice, three homologous genes encoding cytoplasmic glutamine synthetase are required, including  filling . OsGS1;2d spikes . In deveaterials .OsMYB61 regulates cellulose biosynthesis and NUE, and the introduction of indica OsMYB61 into japonica varieties shows an effect of increasing yield, especially under N deficiency; its expression is controlled by GRF4 [Growth-regulating factor 4 (OsGRF4) is a key component of the GA signaling pathway and interacts with DELLA proteins. GRF4 is a positive regulator of the plant carbon–nitrogen metabolism, which can promote N uptake, assimilation, and transport, as well as photosynthesis, carbohydrate metabolism, and transport, but DELLA limits these processes. GA can promote the degradation of the DELLA protein, and then enhances the transcriptional activity of GRF4, so as to achieve the synergistic regulation of photosynthetic carbon fixation capacity in the leaves and N-uptake capacity in the roots, thus maintaining the balance of the C–N metabolism in plants . OsMYB61 by GRF4 .OsGOGAT1, OsTCP19, OsDREB1C, and so on [Recently, more and more N-efficient genes have been reported, such as nd so on ,79,80. TNitrogen is an important element in plant growth, development, and yield formation. Improving plant NUE can efficiently reduce the application rate of N fertilizer and agricultural costs, thereby mitigating environmental pollution and ensuring food security. The agronomic strategies to improve NUE include screening rice varieties with high NUE, developing and applying new N fertilizers, optimizing the period and method of fertilization, scientifically using nitrification inhibitors and urease inhibitors, and popularizing and applying new technologies of fertilizer saving. These scientific and rational management measures of N fertilizer will contribute to realize food security and sustainable development in agriculture.4+- and NO3--related transporters have been continuously identified in rice. Currently, the breeding of high NUE cultivars mainly relies on traditional breeding methods. Although many N-efficient genes have been identified, the successful application to crop production is still rare. Therefore, in the future, the breeding of N-efficient varieties with real practical value by using molecular marker-assisted breeding technology is still an important research topic.Improving the NUE of rice includes not only N uptake, but also N transport and the allocation between sink and source. At present, some progresses have been obtained for exploring the physiological and molecular mechanisms of highly efficient N utilization in rice. Recently, many NHIn recent decades, with the development of multi-omics technologies, N uptake and utilization by rice have been systematically studied through transcriptomics, proteomics, and metabonomics, so as to improve the NUE of rice. In addition, it is necessary to further combine these results with precise field management and cultivation techniques to maximize the exploitation of the biological potential of new varieties.


This study investigated the effects of peripheral neuropathy symptoms, self-care ability, and disturbances to daily life on quality of life (QoL) among gynecological cancer patients undergoing chemotherapy.The participants included 144 patients with gynecological cancer undergoing anticancer chemotherapy at a tertiary hospital in Seoul, South Korea, from December 1, 2021 to January 28, 2022. Convenience sampling was used to recruit patients who had received 4 or more cycles of chemotherapy using a paclitaxel-platinum regimen, and a self-reported questionnaire was used to collect data. Descriptive statistics, the t-test, analysis of variance, Scheffé test, Pearson correlation coefficients, and multiple regression analysis were performed.p<.001) with an explanatory power of 56.7%. Self-care ability , disturbances to daily life , the duration of peripheral neuropathy symptoms , and regular exercise  were found to significantly affect QoL.Most of the participants had ovarian cancer (70.1%) or endometrial cancer (14.6%), and the most common number of treatment cycles was 6 to 10 (29.2%). The mean QoL (60.83±19.89) was greater than the midpoint. The regression model analyzing the patients’ QoL was statistically significant (F=15.38, Efforts to improve the self-care ability of gynecological cancer patients who have experienced peripheral neuropathy after receiving chemotherapy and mitigate disturbances to their daily life can improve their QoL. Healthcare professionals should identify peripheral neuropathy symptoms and examine the effects of the symptoms on patients’ daily lives. Improving the self-care ability of patients and alleviating their limitations in daily life may improve QoL. Due to advances in medical technology, physicians are increasingly able to diagnose and treat cancer early and properly, and the survival rate of cancer patients is subsequently increasing, with an estimated global number of cancer survivors of 19.3 million people as of 2020 . In addiIn particular, the factors that affect the QoL of gynecological cancer patients include lower limb lymphedema, depression, sleep disorders, recurrence, peripheral neuropathy, distress, changes in subjective health status, and physical changes -12. The Although lymphedema experienced by gynecological cancer patients also causes difficulties related to activities of daily living , persistFew studies, however, have analyzed the effect of self-care ability on QoL among gynecological cancer patients. While previous studies analyzing the QoL of gynecological patients have mainly investigated psychological factors -12, furtPrior studies showing that the disease-related characteristics and restricted activities of gynecological patients are factors that affect QoL and the theoretical basis that improved self-care ability can raise QoL were considered in this study. Therefore, we attempted to identify the relationship between peripheral neuropathy symptoms, disturbances to daily life, self-care ability, and QoL among gynecological cancer patients and provide basic data for the development of intervention programs to improve the QoL of gynecological cancer patients.The purpose of this study was to identify the impact of peripheral neuropathy symptoms, self-care ability, and disturbances to daily life on the QoL of gynecological cancer patients undergoing chemotherapy. The specific purposes were as follows:(1) Analyze the peripheral neuropathy symptoms, self-care ability, disturbances to daily life, and QoL of gynecological cancer patients(2) Identify differences in the QoL of gynecological cancer patients according to their general characteristics and disease-related characteristics(3) Identify the relationships between peripheral neuropathy symptoms, self-care ability, disturbances to daily life, and QoL in gynecological cancer patients(4) Identify the factors that influence the QoL of gynecological cancer patientsEthics statement: This study was approved by the Institutional Review Board of Asan Medical Center (2021-1563). Informed consent was obtained from the participants.https://www.strobe-statement.org).This is a correlational study investigating the relationship between peripheral neuropathy symptoms, self-care ability, disturbances to daily life, and QoL of gynecological cancer patients undergoing chemotherapy. This study was written according to the STROBE reporting guidelines  adults aged 19 years or above, (2) diagnosed with gynecological cancer , and (3) participants who received four or more concurrent cycles of paclitaxel and platinum-based drugs, basd on a study that showed peripheral neuropathy frequently occurs after four or more doses of paclitaxel and platinum-based drugs. The exclusion criteria were (1) participants who experienced peripheral neuropathy before undergoing chemotherapy and (2) participants for whom the exact reasons for peripheral neuropathy were unknown due to spinal and brain metastases.The sample size for this study was calculated using G*Power 3.1.9. Based on a prior study , the minPermission was obtained from the developer and adapter before using any of the instruments included in this study.QoL was evaluated using the Korean version of the Functional Assessment Cancer Therapy-General developed by Cella et al.  for measPeripheral neuropathy symptoms were evaluated using an instrument developed by Tofthagen  and tranSelf-care ability was evaluated using an instrument developed by Geden and Taylor  and reviDisturbances to daily life were evaluated using an instrument developed by Tofthagen et al.  and tranGeneral characteristics included six items on age, marital status, education level, economic status, living with family, and regular exercise, and disease-related characteristics, which included type of cancer, the first instance of chemotherapy-induced peripheral neuropathy (CIPN), and the duration of CIPN (3 items), were investigated using a structured questionnaire. In addition, three further items were investigated using electronic medical records and included the number of types of chemotherapy the patient had undergone, the number of chemotherapy treatments received, and the cumulative amount of anticancer agents administered.Data were collected using the convenience sampling method to identify patients undergoing chemotherapy in the gynecological ward and outpatient injection room of the hospital from December 1, 2021 to January 28, 2022. The researchers explained the purpose and procedures of the study and ensured the confidentiality of the data to the participants in person, after which their consent to participate in the study was obtained. Data were collected using questionnaires that were completed by the participants themselves. If it was difficult for patients to complete the questionnaire, the researchers read the questions aloud to the participants and recorded their answers. The questionnaire took approximately 20 minutes to complete, and the participants were provided with a small gift (KN95 masks) upon completion. After the questionnaires were completed, disease-related items were collected from electronic medical records.p<.05 for the following:Data were analyzed using IBM SPSS ver. 28.0  at a statistical significance level of • General characteristics, disease-related characteristics, peripheral neuropathy symptoms, self-care ability, disturbances to daily life, and the QoL of the participants were analyzed based on real numbers, percentages, means, and standard deviations.• Differences in the QoL of the participants according to general characteristics and disease-related characteristics were analyzed using the independent t-test and one-way analysis of variance, and post-hoc was conducted using the Scheffé test.• The correlations between peripheral neuropathy symptoms, self-care ability, and disturbances to daily life were analyzed using Pearson correlation coefficients.• The factors that affected QoL were identified by conducting multilinear regression analysis using the simultaneous input method.• To identify the factors that impact the QoL of gynecological patients, multiple regression analysis was conducted by loading the three variables  that showed significant differences in their correlations with QoL; also seven variables  that showed statistically significant differences related to QoL, and multiple regression analysis was conducted using the simultaneous input method.• The Durbin-Watson test value, which was calculated to test the assumption of the regression analysis, was 2.054, indicating no correlation between the independent variables. When multicollinearity was tested, the tolerance limit was .25–.83, which was larger than .1, and the variance inflation factor was 1.23–3.98, which did not exceed 10. These results indicated no problem related to multicollinearity.The participants’ mean age was 56.38±8.59 years, and the highest number of participants was aged 50 to 59 years . A total of 123 participants (85.4%) were married, 81 (56.3%) were high school graduates, and 50 (34.7%) had a mean monthly income of 1 million Korean won  to less than 3 million KRW. A total of 131 participants (91.0%) lived with their families, and 79 (54.9%) exercised regularly.For disease-related characteristics, the highest percentage of participants had ovarian cancer at 70.1% (n=101), while 21 (14.6%) had endometrial cancer, 20 (13.9%) had cervical cancer, and 2 (1.4%) had another form of gynecological cancer . The highest proportion of participants answered that they first experienced CIPN after 1 to 3 chemotherapy treatments . A total of 57 participants (39.6%) had fewer than 6 months of experience with CIPN, while 40 (27.8%) had over 2 years of experience with CIPN. The mean number of different types of chemotherapy administered was 1.97±1.31; most of the participants were administered 1 type of chemotherapy . The mean number of chemotherapy treatments was 13.81±11.91, and the highest number of participants received treatment 6 to 10 times at 42 (29.2%). The mean cumulative amount of paclitaxel administered was 1,734.35±1,184.03 mg/m2, and 44 participants had a cumulative capacity of 1,000 to 1,499 mg/m2, making up the largest proportion of participants at 30.6%.p<.001), education level , monthly family income , regular exercise , duration of CIPN experience , the number of types of chemotherapy , and the cumulative number of chemotherapy treatments . Post-verification using the Scheffé test showed that the QoL was lower for participants aged 60 years and above compared to those below 60 years of age among the participants with a monthly family income of less than 1 million KRW compared to those with a monthly income of 3 million KRW or more. QoL was lower for those with over 24 months of experience with CIPN, those who were administered 3 or more types of chemotherapy, and those who received 11 or more chemotherapy treatments  showing the lowest mean score. The mean score for CIPN symptoms among the participants was 42.53±19.73, with the highest score for sensory symptoms (30.93±13.93), followed by motor symptoms (11.60±7.37). The mean score for self-care ability was 144.33±28.79, and physical skills showed a relatively lower score compared to the other items. The mean score for disturbances to daily life was 56.24±34.09, with the highest mean score recorded for general activities (44.58±25.27) followed by manual dexterity (11.66±10.50) .p<.001), it had a mild negative correlation with QoL . While self-care ability had a mild negative correlation with disturbances to daily life , it had a moderate positive correlation with QoL . Disturbances to daily life had a moderate negative correlation with QoL   .p<.001), and the explanatory power related to QoL in this model was 56.7%.The QoL regression model of gynecological cancer patients undergoing chemotherapy was statistically significant , followed by the intensity of disturbances to daily life , the duration of CIPN symptoms , and regular exercise . In other words, a lower QoL corresponded to a higher intensity of disturbances to daily life, a duration of CIPN symptoms of less than 6 months compared to 6 to 24 months, a lack of regular exercise, and a low self-care ability  were found to influence QoL. The factor with the greatest influence was self-care ability (β=.39,  ability . The numThis study was conducted to analyze data from gynecological cancer patients undergoing chemotherapy to understand the relationship between peripheral neuropathy symptoms, self-care ability, and disturbances to daily life, and identify the factors that affect QoL.The QoL of gynecological cancer patients in this study was lower than in prior international and domestic studies conducted using the same instrument, which included QoL scores of 64.8 points , 78.8 poIn this study, QoL had a negative correlation with peripheral neuropathy symptoms and disturbances to daily life and a positive correlation with self-care ability. This is similar to the results of a study that found that peripheral neuropathy symptoms and disturbances to daily life worsened as the number of neurotoxic anticancer agents administered increased  and a stSelf-care ability had the largest impact on QoL, followed by disturbances to daily life, the duration of CIPN symptoms, and regular exercise. In a prior study of general cancer patients, higher self-care ability corresponded to higher QoL , which iThe second factor that affected the QoL of the participants was the impact of disturbances to daily life. Patients who received high doses of paclitaxel, a neurotoxic anticancer agent, constituted a high-risk group for peripheral neuropathy symptoms and faced many restrictions to their activities of daily living since their symptoms lasted for longer periods. In addition, cancer patients experience physical symptoms caused by the treatment process, including pain, fatigue, and a lack of concentration, even after treatment ends , which hThe duration of peripheral neuropathy symptoms was the third factor that affected QoL in this study. Peripheral neuropathy symptoms restrict motor and sensory functions and worsen the strength of disturbances to daily life, and symptoms worsen as the total amount of anticancer agents a patient is administered increases . When peRegular exercise was the fourth factor that influenced the QoL of the participants. In a previous study of cancer patients , the QoLBased on this study, to improve the QoL of gynecological patients undergoing chemotherapy, an exercise-based intervention program should be developed to alleviate patients’ peripheral neuropathy symptoms and reduce the impact of disturbances to their daily lives. Moreover, correct information about the disease should be provided, self-efficacy improvement programs should be adopted, community support systems should be established, and accessibility to available resources should be increased to improve patients’ QoL. The QoL of gynecological cancer patients will likely improve through these methods, and follow-up studies should be conducted that consider when patients’ symptoms change by analyzing changes in peripheral neuropathy symptoms according to the cumulative amount of anticancer agents administered in the chemotherapy process that also specifies the time at which nursing interventions were conducted.This study has limitations since the impacts of surgery, postoperative side effects, and recurrence on patients' QoL were not examined. Additionally, the results should be interpreted with caution since the data were from patients at a single hospital. Moreover, a total of 10 variables were analyzed using regression analysis in this study. When the sample size was calculated using G*Power 3.1.9 program with a significance level of .05, power of .85, a median effect size of .15, and 10 independent variables, the minimum sample size was 131 participants; however, when the power was set at .90, the minimum sample size was 147 participants. Thus, in future studies, the power should be increased by including more participants. This study makes meaningful contributions, however, as it showed that gynecological cancer patients who use neurotoxic anticancer agents have a high risk of peripheral neuropathy symptoms and identified the factors that influenced their QoL.In conclusion, to improve the QoL of gynecological cancer patients, alleviation of peripheral neuropathy symptoms and promoting activities of daily living should be sought through the programs that improve physical function and the rehabilitation process. Furthermore, patients’ self-care ability should be enhanced through forming support groups and strenthening self-efficacy. In terms of follow-up studies, we recommend conducting longitudinal studies on the development of web-based programs to expand support systems and improve accessibility and developing programs to improve physical function.


Staphylococcus aureus (MRSA) drugs from 2017 to 2021 at Istituto Giannina Gaslini by means of defined daily dose (DDD) adopted for adults by World Health Organization. We observed a statistically significant increase in the use of daptomycin and ceftaroline, combined with a decrease in the use of vancomycin. In the same period, we observed an increase in the proportion of bloodstream infections due to MRSA with vancomycin minimally inhibitory concentration (MIC mg/L) = 1, that represented the 100% of cases in 2021. This aspect was combined with the observation that in the 59% of cases, where vancomycin plasma concentrations were evaluated, it was not possible to achieve a ratio of the 24-h area under the concentration–time curve and MIC (AUC0–24/MIC) of vancomycin ≥ 400 mg/L. This study confirms that DDD can be used in pediatrics to monitor antibiotic consumption in relationship with infections epidemiology. Moreover, it describes the presence of vancomycin MIC creep for MRSA also in pediatrics and the difficulties in obtaining effective vancomycin plasma concentrations in children.Monitoring antibiotic use in the pediatric population is a challenge, especially when determining a relationship between specific pathogens, infections, and antibiotic use. We retrospectively analyzed the consumption of anti-methicillin-resistant  Staphylococcus aureus is a Gram-positive, coagulase-positive pathogen that frequently colonizes skin, skin glands, and mucous membranes of healthy individuals [Staphylococcus aureus (MRSA) presents an altered penicillin-binding protein (PBP) and is associated with decreased affinity for most semisynthetic penicillins [ividuals ,2. Methiicillins . Therefoicillins . Suscepticillins , but preicillins . In the icillins . Vancomyicillins ,6. Moniticillins , althougicillins .Although antibiotic consumption monitoring is one of many aspects of antimicrobial stewardship, until today, there is no consensus on the best approximation method in pediatrics. Recently, in our institution, a defined daily dose (DDD), as defined by the World Health Organization (WHO) Collaborating Center for Drug Statistics Methodology, based system for monitoring antibiotic consumption has been implemented . This prThe aim of the present study was to describe the consumption of anti MRSA antibiotics in bloodstream infections (BSIs) during a 5-year period in children admitted at a single center, and its relationship with patterns in MRSA antibiotic susceptibility and the possibility of achieving a therapeutic plasma concentration for vancomycin.The IRCCS Istituto Giannina Gaslini (IGG), Genoa, Italy, is a tertiary care children’s hospital in northern Italy serving as local pediatric hospital for the Genoa area, but representing a tertiary care referral hospital for Italy and many foreign countries.From January 2017 to December 2021, the consumption of anti MRSA antibiotics was retrospectively evaluated considering the amount of drug (in grams) dispensed by IGG Pharmacy service to the whole hospital wards of vancomycin, teicoplanin, daptomycin, ceftaroline, linezolid  . The numThe following data were extracted from the IGG Laboratory of Microbiology database and anonymously analyzed: positive blood cultures for MRSA with vancomycin MIC evaluated by means of Sensititre , vancomycin plasma concentrations corresponding to the same hospital admission code, if performed within 5 days following a positive blood culture, age at diagnosis of MRSA BSI, ward of admission as surrogate of underlying disease, and concomitant infection by SARS-CoV-2 in the period 2020–2021.0–24/MIC) of vancomycin ≥ 400, calculated as previously described [0–24 < 600.During the study period, vancomycin at a dose of 40 mg/kg/day divided in 2–4 doses or administered in 24 h continuous infusion (with a 10 mg/kg loading dose) was the standard initial therapy in absence of nephropathy or known previous severe adverse events of vancomycin. Plasma concentrations of the drug were routinely evaluated by means of commercial immunoassay, with dose increase up to 60 mg/kg/day if needed in order to obtain a ratio of the 24 h area under the concentration–time curve and MIC  (maximum 600 mg) q24h; for daptomycin, 10 mg/kg q24h; for ceftaroline, 12 mg/kg (maximum 600 mg) q8h; and for linezolid, 10 mg/kg q8h in patients < 12 years old or q12h (maximum 600 mg) for older subjects [Combination therapies  were performed in cases of severe infections requiring prolonged intravenous therapy in order to improve effectiveness and reduce the risk of resistance selection .Data were reported as absolute number and percentages for categorical variables and as median and 1st and 3rd quartile  for the continuous one. Percentages of MRSA MIC value, stratified as ≤0.5 mg/L or ≥1 mg/L, were calculated and trend over time (5-year period) was assessed by the chi-square statistic for the trend of proportions .The relationship between dispensed DDDs and year of observation (time) was analyzed by means of nonparametric local-constant Li-Racine kernel regression with a bandwidth of 0.5 . The nonp value < 0.05 was considered statistically significant. All analyses were performed using Stata .All tests were two-tailed and a This study was conducted in accordance with the Helsinki Declaration. According to Italian legislation, the study did not need ethical approval, as it was a purely observational retrospective study on routine collected anonymous data. Moreover, informed consent for participate in the study was not required since retrospective data were obtained by an anonymous microbiology database. In any case, consent to completely anonymous use of clinical data for research/epidemiological purposes is requested by clinical routine at the time of admission/diagnostic procedure.p = 0.086), During the study period, the median total vancomycin consumption was 1903.5 g, IQR (1603–2363.5) corresponding to a median number of DDDs of 952, IQR (802–1182), p = 0.027) was observed, On the contrary, a statistically significant increase in the use of daptomycin and ceftaroline across years . The most frequent wards of admission were the cardiovascular surgery, 11 cases (24.4%), and the intensive care unit, 10 cases (22.2%). Parity of cases, 6 (13.3%), was in hemato/oncology unit and in units admitting other immunocompromission/solid organ transplantation patients. The remaining 12 MRSA BSIs were diagnosed in neonatal or general pediatrics units, 8 (17.8%), and 4 (8.9%) in general surgery.p = 0.017) and it is noteworthy that in 2021 no isolated strain had MIC ≤ 0.5 mg/L.In 11 (24.4%) cases the MIC for vancomycin was ≤0.5 mg/L, while in the remaining 34 (75.6%) it was equal to 1 mg/L, 0–24/MIC ratio ≥ 400 mg/L, while in 19 (59.4%) vancomycin had to be substituted with another drug because of persistently insufficient AUC0–24/MIC ratio.Vancomycin plasma concentrations were available in 32 (71.1%) BSIs and the median concentration was 14.3 mg/L, IQR (10–18.8). In 13 (40.6%) cases, plasma concentrations allowed an AUCNo case was associated with SARS-CoV-2 infection. Moreover, analysis of hospital causes of death during the study period did not evidence any death due to MRSA bacteremia.This study allowed to identify different aspects useful for antimicrobial stewardship programs in a tertiary care pediatric hospital.First of all, we confirmed that DDD indicated by the World Health Organization ,11 can bS. aureus has been reported as MIC creep [The gradual increase in the value of vancomycin MIC for IC creep ,6, with IC creep ,18,19,200–24/MIC ≥ 400 in pediatric patients has been reported, with the recommendation of changes in dosing strategies in order to achieve target pharmacokinetic/pharmacodynamics parameters [We evaluated vancomycin plasma concentrations in more than two-third of cases and also found difficulties in achieving effective concentrations, and that presence of MRSA strains with increased MIC could have played a role in the increased use of daptomycin and ceftarline. The need for higher vancomycin doses to achieve a ratio of AUCrameters . Our datDuring the study period, we also observed a non-significant decrease in vancomycin use. This is probably related with the fact that vancomycin is used also for treatment of other Gram-positive, e.g., coagulase-negative staphylococci, beta-lactam-resistant infections, and even empirically in some clinical conditions. So, the use of alternative antibiotics for MRSA BSI probably changed only marginally the overall use of vancomycin. The use of teicoplanin and linezolid was marginal, and therefore we cannot estimate changes during time.COVID-19 has been an important driver of infections due to antibiotic-resistant bacteria, including MRSA, in Italy . HoweverOur study also indicates that currently knowledge of the local epidemiology of antibiotic susceptibility is critical for proper initial management of patients with suspected/confirmed infections such as BSI. Rapid microbiological diagnosis may be important for early identification of colonized patients with subsequent adoption of prophylactic strategies. Unfortunately, we did not collect data on the previous colonization of our MRSA BSI cases. Rapid microbiological diagnosis could also be useful for the identification of MRSA in blood cultures as it identifies the presence of resistance genes but unfortunately does not provide information on their expression and MIC of antibiotics. Therefore, it may be particularly useful in the presence of local epidemiological data (such as those collected in our center) to decide on initial  MRSA antibacterial therapy, which should be modified, if necessary, when MICs of different anti-MRSA antibiotics are available. The main limitations of the study are due to the retrospective and anonymous data collection and relate specifically to the unavailability of data on the presence of deep organ localization, the inaccurate definition of risk factors for BSI, and the fact that the final outcome was analyzed very roughly, only in terms of patients’ death. However, we believe that the final favorable outcome may be related to the use of drugs other than vancomycin, when necessary. In fact, the analysis of hospital causes of death, during the study period, reported no deaths due to MRSA bacteremia.0–24/MIC ratio does not achieve a therapeutic value (≥400) despite dose changes. These observations could be important for antimicrobial stewardship programs and for medical training of young clinicians regarding knowledge, attitudes, and practices on the use of antibiotics in the management of antibiotic-resistant pathogens, including MRSA [In conclusion, this study allowed us to become aware of two important events: the increase in BSI episodes due to MRSA with an increased MIC for vancomycin and the high proportion of MRSA BSI in which vancomycin AUCing MRSA . MedicalFurther studies are needed to investigate the presumed relationship between observed changes in the consumption of specific antibiotics and changes in the epidemiology of specific pathogens and infections.


Capra pyrenaica) populations. Mass treatment campaigns by administration of in-feed acaricides are used as a measure to mitigate the impact of mange in the affected populations. However, there are no data on ivermectin (IVM) pharmacokinetics in this wild caprine, and the treatment through medicated feed is not endorsed by evidence on its effectiveness. The aim of this study is to determine the pharmacokinetic profile of IVM in plasma samples of ibexes after the experimental oral administration of IVM, using high performance liquid chromatography (HPLC) with automated solid phase extraction and fluorescence detection. A dose of 500 μg of IVM per body weight was orally administered in a feed bolus to nine healthy adult ibexes . Blood samples were collected by jugular venipuncture into heparin-coated tubes at day 1, 2, 3, 4, 7, 10, 15, and 45 post-administration (dpa). The highest plasma concentration of IVM (Cmax = 3.4 ng/ml) was detected 24 h after the oral administration (T1), followed by a rapid decrease during the first week post-administration. Our results reveal that plasma IVM concentration drops drastically within 5 days of ingestion, questioning the effectiveness of a single in-feed dose of this drug to control sarcoptic mange. To the best of our knowledge, this is the first study on plasma availability of oral IVM in ibexes and in any wild ungulate species.Sarcoptic mange is considered the main driver of demographic declines occurred in the last decades in Iberian ibex ( Capra pyrenaica) is a wild ungulate native to the mountain ranges of the Iberian Peninsula and has recently been reintroduced in the French side of the Pyrenees. This caprine currently enjoys a favorable conservation status (“least concern” according to the IUCN), which allows sustainable hunting as a valuable game species. Besides its biological and ecological value, ibex trophy hunting and the associated related tourism represent a significant source of revenue for remote and disadvantaged rural communities in Spain , massive lethal control, and selective culling of clinically-affected animals  has been used against al signs . Oral adal signs , 8, 13; al signs . After oal signs . Moreoveal signs .The main findings related to domestic ruminants and the paucity of data concerning wild species recommend caution when extrapolating treatment protocols  from one species to another and, as a consequence, extended pharmacokinetic data in target animal species are much-needed to avoid drug misuse. Therefore, the aim of the present experimental study is to begin filling the existing knowledge gaps by exploring, for the first time, the pharmacokinetic profile of a single oral dose of IVM in Iberian ibexes.Nine adult healthy Iberian ibexes  were captured in Sierra Nevada Natural Space as part of the regular management of the species and transferred to the “Iberian ibex stock reservoir El Toril”, in Dílar, Granada , southern Spain . The ibead hoc formulated bolus containing 0.5 mg of IVM per kg of body weight was orally administered to each ibex. For this, specialized wildlife operators physically immobilized, blindfolded, and administered the boluses to the ibexes using commercial applicators. Blood samples (20 ml) were collected from the jugular vein into heparin-coated vacutainers just prior to drug administration (time 0) and 1 (T1), 2 (T2), 3 (T3), 4 (T4), 7 (T5), 10 (T6), 15 (T7), and 45 (T8) days after the bolus administration (dpa). Plasma was obtained immediately after the blood collection by centrifugation at 2,000 g for 20 mins and stored in 2 ml containers at −80°C until analyzed.After an acclimation period of at least 1 month in the experimental facilities, an IVM was analyzed in the plasma samples by high performance liquid chromatography (HPLC) with automated solid phase extraction and fluorescence detection following a validated method previously described . BrieflyA 100-μl aliquot of the derivatized samples was injected into the chromatograph. The mobile phase consisted of acetic acid 0.2% in water/methanol/acetonitrile (10:40:50) pumped at a flow rate of 1.4 ml/min through a column  with fluorescence detection. Fluorescence detection  was performed at 365 nm excitation and 475 nm emission wavelength. Recovery rate was calculated for each sample through internal standard recovery correction.A Linear Mixed Model  was fitted to explore the pharmacokinetics of plasma IVM concentrations  in the study ibexes. Time since drug administration was included as fixed factors whereas ibex identity as a random intercept term in the LMM . For thet = −11.11, p-value < 0.01) explained 61% of the plasma IVM concentration variability in the ibexes of the study. Moreover, the individual contribution to the observed patterns was 8% , a close relative of the Iberian ibex. Their protocol provided for the administration of an oral dose of 0.2 mg/kg of IVM for three consecutive days repeated three times at 2 week intervals. This protocol is clearly unfit for mass use under free-ranging conditions, since regular access of target wildlife to medicated feed is far from being guaranteed; nevertheless, the results are encouraging with respect to possible oral treatment options in Sarcoptes-exposed wild ruminants. Moreover, Leon-Vizcaino and colleagues (Ovis canadensis) experimentally infested with Psoroptes mites. The 0.5 mg/kg IVM dose in our study took into account the above findings, the lower antiparasitic efficacy of oral IVM when administered at the same dosage recommended via subcutaneous inoculation  were lower than those described in goats  after the oral administration of an IVM dose of 0.2 mg/kg , 31. By Several factors known to influence drug absorption and bioavailability may explain the interindividual variability in IVM plasma concentrations, observed in particular at T1-T4 . NeverthBoophilus spp)  , showinglus spp) , as showlus spp) .S. scabiei in Iberian ibex and other wild ungulate species should be further investigated, also considering that underdosing is a recognized driver for the development of resistance to endo and ectoparasiticides , two highly susceptible wildlife species to sarcoptic mange, suggesting that a better cooperation and a continuous debate between stakeholders, including veterinarians, wildlife carers and researchers, should be encouraged to achieve best treatment options for wildlife.Nonetheless, and similarly to IVM, numerous gaps in knowledge must be addressed before the in-field use of these alternative drugs may be considered a valid option . RecentlThere is therefore a need to further investigate the pharmacokinetics, pharmacodynamics, population target and environmental consequences of the administration of available macrocyclic lactones, isoxazolines and other candidate molecules, including long-acting formulations, before their in-field delivery become a management option to control sarcoptic mange in free-ranging wild ruminants.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.This study complied with all Andalusian, Spanish, and European legal requirements and guidelines regarding experimentation and animal welfare. Handling procedures and sampling frequency were designed to reduce stress and minimize the impact on the health of the subjects, as per European (2010/63/UE) and Spanish (R.D 53/2013) standards. The study was approved by the Ethics on Animal Welfare Committee of the University of Jaén and authorized by the Dirección General de Producción Agrícola y Ganadera of the Consejería de Agricultura, Pesca y Medio Ambiente of the Junta de Andalucía . The Sierra Nevada Natural Park staff also approved this study.BM, JG, JL-O, JE, AR, GM, PF, LR, MV, ES, BR, and RO conceptualized the project and agreed on the study design. RO prepared the IVM bolus. JG, JE, AR, and BR performed the IVM treatment and obtained blood samples from the ibexes. BM, GG, MP, and MR performed the laboratory analysis and elaborated the results. ES performed the statistical analysis. BM drafted the original manuscript. JG, JL-O, JE, AR, GM, PF, LR, MV, ES, BR, and RO contributed in shaping and revising the manuscript. All the authors have read and agreed to the final version of the manuscript.This project was funded by the Consejería de Medio Ambiente de la Junta de Andalucía , and by the Spanish Ministerio de Economía y Competitividad . The authors' research activities are partially supported by the Plan Andaluz de Investigación (RNM-118 group). MV is supported by a FI-GENCAT Fellowship  and ES by the Spanish Ministerio de Ciencia Innovación y Universidades (MICINN) through a Ramon y Cajal agreement (RYC-2016-21120). GM is a Serra Húnter Fellow.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


BRCA1 and BRCA2 genes. The scientific literature on BRCA1 and BRCA2 was searched in the Web of Science Core Collection database using the keywords “BRCA1” OR “BRCA2” (Title). The top 100 most cited papers were selected based on citations. The obtained data were exported into HistCiteTM, RStudio, and VOSviewer software for prerequisite analysis. The top 100 most cited papers on BRCA1 and BRCA2 were authored by 932 authors from 24 countries and published in 27 journals. These papers were cited 79,713 times, ranging from 441 to 4671 citations. The highly cited paper was cited 4671 times and published in Science (1994). The leading author, journal, publication year, institution, and country were Easton DF (n = 16), Nature Genetics (n = 11), 2002 (n = 11), University of Pennsylvania (n = 17), and the USA (n = 76), respectively. The results show that all the top 100 papers were produced in developed countries. The collaboration index among the authors was 9.49. The most frequently appeared keywords were ovarian-cancer, breast-cancer, mutations, gene, and familial breast. In recent times, the trend topics were patients, mutations, carriers, ovarian, and risk.This study aimed to identify, characterize, and map the important attributes of the top 100 most cited papers on  Certain factors play an important role in protecting against breast cancer development, including late menarche and more nursing duration.–4 Ovarian hormone exposure, the number of ovulatory cycles, and breast lobular differentiation are suggested to reduce the occurrence of breast cancer.–7 Researchers have evaluated the effects of reproductive factors on BRCA-related breast cancer, but the results are conflicting and differ by mutations either in BRCA1 or BRCA2.–10 Few studies suggest no impact of breastfeeding on breast cancer development, but few have reported its protective effect on breast cancer risk in BRCA1 carriers.–13 Breastfeeding did not show any impact on breast cancer risk in BRCA2 mutation carriers.Breast cancer, the most frequently diagnosed and reported cause of death, threatens women’s health in many countries. Breast cancer and recent trends in its research are topics of prime importance. The importance of quantitative and qualitative assessment of the available scientific literature in this field has increased. Such assessments can play a key role in funding concerning research projects and resource priority setting, as demonstrated in the Research Assessment Exercise.In 2020, 2.3 million women were diagnosed with breast cancer, and it caused 685,000 deaths worldwide. At the end of 2020, 7.8 million women living with breast cancer ranked it the most prevalent cancer globally. The present study aims to identify and analyze the top 100 most cited papers in BRCA1 and BRCA2 associated breast and ovarian cancers worldwide using comprehensive data analysis and bibliometric tools. Furthermore, this study can help researchers and policymakers devise policies regarding the diagnosis and treatment of breast and ovarian cancers.The bibliometric analysis introduces a review process that allows the published research to be better described, evaluated, and monitored. It covers quantitative and visual processes in scientific publications to define their characteristics and dynamics. Bibliometric studies are either evaluation or relational studies. Evaluation studies estimate the number of cited papers and total citations. Relational studies talk about the structure of a research issue, research profiling of authors, institutional affiliations, new research avenues, and scientific techniques employed. Appropriate interpretation is very important in bibliometric studies.A descriptive bibliometric study was conducted.https://clarivate.com/webofsciencegroup/solutions/web-of-science/), previously the Intellectual Property and Science business of Thomson Reuters, Philadelphia, Pennsylvania, USA  database hosted by Clarivate Analytics . The potential search keywords were entered in the database search engine using Boolean search operators “BRCA1” OR “BRCA2” in the title field without restrictions.The WoSCC database is the world’s oldest database.BRCA1- and BRCA2-related breast and ovarian cancer. The disagreements were resolved after a discussion with the third researcher. Only publications that focused on BRCA1 and BRCA2 causing breast and ovarian cancer were included in the final analysis. The top 100 most cited publications were identified based on the number of global citation score (GCS) in descending order, and publications that had more citations were ranked higher.Researchers in this study independently screened the retrieved documents to identify the top 100 most cited publications on A self-designed electronic data form was designed for data collection. After selecting the top 100 most cited publications, major key attributes were extracted from the data. For this purpose, the data were exported into Microsoft Excel 2019 to extract the required data and calculate the frequencies and percentages of the included publications. The following information was extracted: study title, year of publication, journal, authors name, institution, country, publication types, publication language, widely used keywords, and number of citations. The journals’ impact factor (IF) and quartile ranking (Q1–4) were obtained from Incites Journal Citation Reports 2020, released in June 2021 by Clarivate Analytics. The data were downloaded in 2 formats: plain text and comma-separated values.TM software. Furthermore, the data were plotted for visualization networks using VOSviewer software version 1.6.17 for windows. In addition, RStudio (biblioshiny package) was used to generate the cloud map, countries’ collaboration, and trend analysis.For data analysis, 3 different tools were used. OriginPro 2018 software was used to generate the relevant graphs. For citation analysis, the data were exported in to HistCiteThis study involved no animal and human subjects; therefore, no ethical approval was required.BRCA1 and BRCA2 were authored by 932 authors from 24 countries and published in 27 journals. These papers were published between 1994 and 2017. The GCS of these papers was 79,713 (797.1 citations per paper), ranging from 441 to 4671 citations. However, the overall local citation score was 588. The top 100 most cited papers were published in English, of which 93 papers were published as research articles. The overall collaboration among the authors was 9.49. The main facts about the top 100 most cited papers are presented in Table The top 100 most cited papers on BRCA1” published by Miki et al (1994) in Science and was cited 4671 times. The top 10 most cited papers along with their conclusion bottom lines can be seen in Table http://links.lww.com/MD/H319). Of the top 100 most cited papers, 15 papers were cited more than 1000 times, 58 papers from 500 to 999 times, and 27 papers from 441 to 499 times.The highly cited paper was “A strong candidate for the breast and ovarian cancer susceptibility gene R2) of published papers was 0.4.The most productive years were 2002 (n = 11), and 2001 (n = 10), while the most cited years were 1994 (n = 9124), and 2002 (n = 8054). In total, 56% of the most cited papers were published between 1994 and 2002. The annual scientific publication growth rate was found to be −4.27%. As shown in Figure Nature Genetics (n = 11), and Science (n = 10) were the top-ranked journals, while the most cited journals were Science , and Nature (n = 8752). The New England Journal of Medicine had the highest IF (91.253) as shown in Table The most prolific authors were Easton DF (n = 16) and Peto J (n = 11), while the most cited authors were Easton DF  and Narod S n = 14,422) as shown in Table ,422 as sThe institution with maximum published papers was the University of Pennsylvania (n = 17), followed by Memorial Sloan Kettering Cancer Centre n = 15), and the University of Cambridge (n = 15). However, the most cited institutions were the University of Cambridge n = 16,069), the University of Utah , and the University of Pennsylvania , as shown in Table , and the,069, theThe minimum number of occurrences of a keyword was fixed at 5, while the minimum cluster size was 10. Of the total KeyWords Plus (n = 411), only 45 met the threshold, and were plotted into 3 clusters, and each color represented a different cluster; red color , green color , and blue color , as shown in Figure The USA had the highest multiple country and single country corresponding author publications, 17 and 36, respectively, as shown in Figure BRCA1 and BRCA2 associated breast and ovarian cancer globally. Each year, 1.3 million breast cancer cases are diagnosed globally, which is the most common invasive cancer in females.BRCA1 and BRCA2 are among the most common genes implicated in the progression of breast and ovarian cancer. Therefore, it is important for the scientific community to identify and study the most influential papers in the field. This analysis can help fulfill the missing gaps, provide the recent and potential trends in this area, and direct attention to the critical aspects that have not been addressed yet. The outcomes of this study include the most prolific authors, most published journals, most active institutions, highly contributing countries, keywords and trend topics analysis, and citations count.This study is the first comprehensive bibliometric analysis of the top 100 most cited papers on Nature Genetics which published 11 articles, while Science published 10, and New England Journal of Medicine published only 5 articles among the top 100 cited articles. The IF of Nature Genetics is the lowest compared to the other 2 journals. This phenomenon indicates that the relevancy of a journal to the nature of study plays a vital role than the IF of a journal.In our analysis, the most published journal was In this study, the overall GCS was 79,713 (ranging from 441 to 4671 citations), while the local citation score was 588 (ranging from 1 to 43 citations). In the top 100 most cited papers, 5 papers were cited more than 2000 times (2144–4671 citations), 10 papers were cited more than 1000 times (1014–1635 citations), 58 papers were cited at least 500 times (500–986 citations), while the remaining papers (n = 27) were cited more than 400 times (441–494 citations).BRCA study tends more to the diagnosis while treatment is a crucial step after the diagnosis. Scientists may have focused on other aspects of the disease.Generally, papers published in relevant and reputed journals with important public health issues attract more readers and can be cited multiple times. In the current study, no smooth ascending or descending trend in the year-wise citations was observed. This variation may be due to the current trends in the field, as the The included studies were mainly based on experimental work, that is, research articles (93%). This indicates that the research emphasis has been directed toward diagnosis, treatment, and applications rather than literature-based work. All the 100 top-cited papers were published in English, which is the leading scientific language used globally for research dissemination.The University of Pennsylvania was the top leading institution in terms of publications, while the most cited institution was the University of Cambridge. In this category, universities remained on top while hospitals and centers remained on the bottom. This trend highlights the understandable fact of different objectives of universities and hospitals.–50 None of the resource-limited countries were involved in the highly influential studies as the main contributor or leader. This trend has various reasons, for which funding allocation by any country is the most important. In the USA, research and development is funded by a number of sectors, including the federal government, academia, businesses, nonprofit organizations, and state governments for a variety of purposes. As a result, in the 20th century, the USA has become a global leader in research and development.–52Among the countries involved in the top 100 cited papers, the USA was the leading country in terms of publications, citations, and collaboration. This trend is in line with many other studies in various research fields. Another study found that GD2 could be used as a monitoring target in clinical isolates from breast cancer patients.During the period between 2003 and 2007, studies were conducted on the topics related to patients, mutations, carriers, ovarian, and risk factors. However, an examination of the top 10 most cited studies indicates that 90% of the studies focused on diagnosis, while 10% focused on treatment. It is observed that after performing certain work on diagnosis, the scientist moved to treatment as the main aim of diagnosis is to use this information for treatment. This trend has shown a ray of hope that scientists have assessed this problem and are seriously working to solve it step by step.This study will not only be important for medical practitioners but also for policymakers for better decisions. More research needs to be carried out in this field, and researchers, especially from disease burdened countries, should be encouraged to carry out research and share their findings in peer-reviewed journals.This bibliometric study should boldly call out that the vast majority of the most influential papers originate from the USA, the UK, and Canada, clustering around well-known institutions. Interestingly, these contributions are well respected and deeply appreciated. However, it would benefit the community at large to have industry and individual government funding directed more towards high-quality research and peer-reviewed research publications in low-income countries.BRCA1 and BRCA2 in the community may lead to timely diagnosis and management. This can partially lead to a better quality of life for the patients and can help to reduce the occurrence of hereditary breast cancer in future generations.The most frequently appearing keywords were ovarian-cancer, breast-cancer, mutations, gene, and familial breast. In recent times, the trend topics were patients, mutations, carriers, ovarian, and risk. A better understanding of breast and ovarian cancer’s clinical features along with screening of This study has some limitations. Firstly, only the WoSCC database was utilized. Secondly, the search was limited to the title field. Thirdly, the self-cations of the authors were not excluded. Therefore, the above limitations may bias the frequency of publications frequency and citation score.Conceptualization: Shadi Alkhayyat, Muhammad Khan, Tauseef Ahmad.Data curation: Muhammad Khan, Tauseef Ahmad.Formal analysis: Tauseef Ahmad.Methodology: Shadi Alkhayyat, Muhammad Khan, Tauseef Ahmad.Project administration: Tauseef Ahmad.Software: Tauseef Ahmad.Validation: Muhammad Khan, Tauseef Ahmad, Haroon, Mukhtiar Baig.Visualization: Tauseef Ahmad.Writing – original draft: Shadi Alkhayyat, Muhammad Khan, Tauseef Ahmad, Haroon, Huma Tariq.Writing – review & editing: Muhammad Khan, Tauseef Ahmad, Huma Tariq, Mukhtiar Baig.Breast cancer is the most frequently diagnosed and reported cause of death in women. To characterize important attributes of the top 100 most cited papers in breast and ovarian cancer-related BRCA1 and BRCA2 genes. Overall, the papers included in the current study were cited 79,713 times (ranging from 441 to 4671). The most published journal was Nature Genetics. The most productive country was the USA. However, collaborations with developed countries are needed to promote breast cancer research in developing countries.