Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

Anomalies of the fallopian tubes represent one of the most significant elements that might contribute to reproductive issues. They can be inherited or acquired; they are among the most important problems of the profession. Although there is much discussion regarding which therapies for each tubal disease are the most effective and result in the best long-term reproductive outcomes. During the evaluation of an infertile couple, certain anomalies of the fallopian tubes are frequently discovered. These abnormalities were thought, for a long time, to not have an influence on fertility; however, in recent years, researchers have discovered that they seem to play a crucial role in fertility problems. Couples in industrialized countries are postponing childbearing, which raises the risk of women developing tubal diseases before they are ready to become pregnant. These disorders may have a negative impact on a woman\'s ability to get pregnant. The goals of this study are to conduct research to gain a deeper understanding of the recent advancements that have been made in the field of tubal diseases and to carry out an evaluation of the medical conducts that have the best fertility outcomes. We searched both Medline and PubMed, paying special attention to the most relevant articles that have been added to either database over the course of the last six years.

Pelvic inflammatory disease (PID) is a syndrome that causes substantial morbidity, including chronic pelvic pain, to women globally. While limited data are available from low- and middle-income countries, national databases from the United States and Europe suggest that PID incidence may be decreasing but the rate of decrease may differ by the etiologic cause. Recent studies of women with PID have reported that fewer than half of women receiving a diagnosis of PID have gonococcal or chlamydial infection, while Mycoplasma genitalium, respiratory pathogens, and the constellation of bacteria associated with bacterial vaginosis may account for a substantial fraction of PID cases. The clinical diagnosis of PID is nonspecific, creating an urgent need to develop noninvasive tests to diagnose PID. Advances in serologic testing for Chlamydia trachomatis and Neisseria gonorrhoeae could advance epidemiologic studies, while the development of vaccines against these sexually transmitted pathogens could affect incident PID and associated morbidity.

OBJECTIVE: To describe the prevalence, clinical presentation and current treatment regimens of inflammatory bowel disease (IBD) in patients with primary immunodeficiency disorders (PIDs).
METHODS: A systematic review was conducted. The following databases were searched: MEDLINE, Embase, Web of Science, the Cochrane Library and Google Scholar.
RESULTS: A total of 838 articles were identified, of which 36 were included in this review. The prevalence of IBD in PIDs ranges between 3.4% and 61.2%, depending on the underlying PID. Diarrhea and abdominal pain were reported in 64.3% and 52.4% of the patients, respectively. Colon ulceration was the most frequent finding on endoscopic evaluation, while cryptitis, granulomas, ulcerations and neutrophilic/lymphocytic infiltrates were the most frequently reported histopathological abnormalities. Described treatment regimens included oral corticosteroids and other oral immunosuppressive agents, including mesalazine, azathioprine and cyclosporin, leading to clinical improvement in the majority of patients. In case of treatment failure, biological therapies including TNF- α blocking agents, are considered.
CONCLUSIONS: The overall prevalence of IBD in patients with PID is high, but varies between different PIDs. Physicians should be aware of these complications and focus on characteristic symptoms to reduce diagnostic delay and delay in initiation of treatment. Treatment of IBD in PIDs depends on severity of symptoms and may differ between various PIDs based on distinct underlying pathogenesis. An individualized diagnostic and therapeutic approach is therefore warranted.

Pharmaceutical continuous manufacturing is considered as an emerging technology by the regulatory agencies, which have defined a framework guided by an effective quality risk management. With the understanding of process dynamics and the appropriate control strategy, pharmaceutical continuous manufacturing is able to tackle the Quality-by-Design paradigm that paves the way to the future smart manufacturing described by Quality-by-Control. The introduction of soft sensors seems to be a helpful tool to reach smart manufacturing. In fact, soft sensors have the ability to keep the quality attributes of the final drug product as close as possible to their references set by regulatory agencies and to mitigate the undesired events by potentially discard out of specification products. Within this review, challenges related to implementing these technologies are discussed. Then, automation control strategies for pharmaceutical continuous manufacturing are presented and discussed: current control tools such as the proportional integral derivative controllers are compared to advanced control techniques like model predictive control, which holds promise to be an advanced automation concept for pharmaceutical continuous manufacturing. Finally, industrial applications of model predictive control in pharmaceutical continuous manufacturing are outlined. Simulations studies as well as real implementation on pharmaceutical plant are gathered from the control of one single operation unit such as the tablet press to the control of a full direct compaction line. Model predictive control is a key to enable the industrial revolution or Industry 4.0.

The management of lymphoma in patients with primary immunodeficiency (PID) is challenging because of its poor prognosis and complex therapeutic approaches. We conducted a systematic literature review of case-reports, case-series, and cohorts indexed in MEDLINE reporting the association of lymphoma and PID. One hundred and eighty-two articles were selected out of 787. We identified 386 cases. Median age at diagnosis of PID and lymphoma was 9.5 and 12 years old, respectively. T-cell deficiencies were the main PIDs associated with lymphoma (57%). The most prevalent lymphoma was diffuse large B-cell lymphoma (33.5%). Epstein-Barr Virus-driven lymphomas were mostly observed in innate immunodeficiencies (when reported). Complete response to treatment was observed in 65.8% of the cases. Death occurred in 38.2%. Few allogenic stem cell transplantations were performed (29 cases). Our detailed analysis of the literature provides a landscape of lymphoma\'s occurrence in PID. Devoted studies in specific sub-groups of patients at risk are needed to develop dedicated protocols.

Primary immunodeficiency diseases (PIDs) are a group of diseases that have been found to have an adverse impact on quality of life and health-related quality of life (HRQOL).
To systematically assess available evidence on the HRQOL of patients with PID.
We performed a literature search of all studies reporting HRQOL assessments in patients with PID published in English from inception to April 11, 2017, using MEDLINE and EMBASE.
Of 1699 articles, 37 met the inclusion criteria. HRQOL was assessed by using various generic instruments. Child Health Questionnaire - Parent Form 50 and short-form 36 were the most frequently used (for children and adults, respectively). No PID-specific HRQOL instruments were used for children. HRQOL is significantly lower in adults with PID (mean score difference, -24.46; 95% CI, -34.57 to -14.34) and children (-10.06; 95% CI, -12.95 to -7.17) compared with the reference population and lower than in patients with other chronic conditions. There is a general agreement between child- and parent-reported data, although parents report child school-related HRQOL as more impaired than do children (6.19; 95% CI, 0.38 to 11.99). Most studies were of low to moderate quality and had methodological limitations.
Available evidence suggests that patients with PID have a lower HRQOL than do healthy individuals and patients with other chronic conditions, including diabetes mellitus and juvenile idiopathic arthritis. No disease-specific instruments are available for children, and few options are available for adults. This finding highlights the need for developing PID-specific instruments that would allow for a more sensitive evaluation of PID impact on patient health and psychological well-being, school/work, and social activities.

BACKGROUND: Primary immunodeficiency disorders (PIDs) are a group of heterogeneous rare disorders, whereby the immune system is missing or not functioning adequately. For patients requiring treatment, the most common option is immunoglobulin replacement therapy (Ig). Treatment of PIDs is simultaneously associated with both improvements in health-related quality of life (HRQoL) and increased treatment burden.
OBJECTIVE: This review sought to review studies investigating the burden of Ig treatment, synthesize evidence in relation to administration routes (subcutaneous or intravenous) and instruments used, as well as make recommendations for clinical and research applications in this area for patients aged 16 years and older.
METHODS: We searched Medline, EMBASE, and The Cochrane Library. Sifting of titles was performed by two reviewers, and the assessment of full-text articles by three. From a database which contained 3,770 unique results, 67 full texts were reviewed. Eventually, 17 studies were found to meet the inclusion criteria, and included in this review. Due to data heterogeneity, a narrative, descriptive synthesis of the evidence was undertaken.
RESULTS: Most studies were carried out in the USA/North America, used a prospective observational design and involved patients with common variable immune deficiency. Four studies measured the burden of receiving IVIg therapy and 13 measured SCIg therapy. A wide range of measures, primarily designed to measure aspects of treatment satisfaction (e.g., life quality index or a slightly modified version) and HRQoL (e.g., The Short Form-36) had been used.
CONCLUSIONS: Lack of a parallel control group in most studies meant that changes in outcomes could be due to factors other than changes in the treatment regimen. However, overall, PID patients appeared to report little Ig treatment burden and were satisfied with either modality. However, patient preference appeared to be the delivery of the Ig treatment in the patient\'s home and SCIg was preferred after switching from IVIg therapy. Individual differences appeared to affect treatment preference and therefore understanding the decision support needs of PID patients facing IG treatment choices would be valuable. Using a questionnaire specifically designed to measure the burden of Ig treatment from the patient\'s perspective is recommended in future research.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare, severe, otherwise fatal viral infection of the white matter of the brain caused by the polyomavirus JC virus, which typically occurs only in immunocompromised patients. One patient with dominant gain-of-function (GOF) mutation in signal transducer and activator of transcription 1 (STAT1) with chronic mucocutaneous candidiasis and PML was reported previously. We aim to identify the molecular defect in 3 patients with PML and to review the literature on PML in primary immune defects (PIDs).
METHODS: STAT1 was sequenced in 3 patients with PML. U3C cell lines were transfected with STAT1 and assays to search for STAT1 phosphorylation, transcriptional response, and target gene expression were performed.
RESULTS: We identified 3 new unrelated cases of PML in patients with GOF STAT1 mutations, including the novel STAT1 mutation, L400Q. These STAT1 mutations caused delayed STAT1 dephosphorylation and enhanced interferon-gamma-driven responses. In our review of the literature regarding PML in primary immune deficiencies we found 26 cases, only 54% of which were molecularly characterized, the remainder being syndromically diagnosed only.
CONCLUSIONS: The occurrence of PML in 4 cases of STAT1 GOF suggests that STAT1 plays a critical role in the control of JC virus in the central nervous system.