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Introduction and Hypothesis: Non-antibiotic regimens such as methenamine hippurate, D-mannose, and vaginal estrogen are often prescribed as prevention for recurrent urinary tract infections (rUTIs). The objective of our study was to describe adherence rates in women prescribed non-antibiotic prophylaxis for rUTI and to explore factors associated with adherence., Methods: This was an ambispective cohort study describing and comparing adherence to non-antibiotic prophylactic regimens for rUTIs. Adult women who sought care from a Urogynecology clinic at a tertiary care center for rUTIs or frequent UTIs between January 2020 and December 2021 were included if they were prescribed a non-antibiotic prophylactic regimen. The Medication Adherence Questionnaire (MAQ) was administered to all eligible patients prospectively and then their charts were reviewed retrospectively for demographic and clinical factors. A score of 0 on the MAQ defined medication adherence. Any score ≥ 1 defined medication non-adherence., Results: A total of 90 patients met the inclusion criteria and completed the MAQ, with 33 (37%) in the adherent group and 57 (63%) in the non-adherent group. Mean age was 64.7 (± 14.7) years. Vaginal estrogen (81.1%) was the most commonly prescribed prophylactic regimen, followed by methenamine hippurate (26.7%). 73.3% of patients met criteria for rUTI at the index visit as per the American Urogynecologic Society best-practice statement. No demographic or clinical factors were associated with adherence to non-antibiotic prophylactic regimens., Conclusions: Non-antibiotic prophylactic rUTI regimens are commonly prescribed; however, adherence remains low at 37%. There were no predictors associated with patient compliance. Clinicians should therefore inquire about adherence prior to escalating treatment., Competing Interests: Declarations. Ethical/Institutional Review Board: Approval was obtained from the Northwestern Institutional Review Board. Conflicts of Interest: None., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The industry's pursuit for higher antibody production has led to increased cell density cultures that impact the performance of subsequent product recovery steps. This increase in cell concentration has highlighted the critical role of solids concentration in centrifugation yield, while recent product degradation cases have shed light on the impact of cell lysis on product quality. Current methods for measuring solids concentration and cell lysis are not suited for early-stage high-throughput experimentation, which means that these cell culture outputs are not well characterized in early process development. This article describes a novel approach that leveraged the data from a widely-used automated cell counter (Vi-CELL™ XR) to accurately predict solids concentration and a common cell lysis indicator represented as lactate dehydrogenase (LDH) release. For this purpose, partial least squares (PLS) models were derived with k-fold cross-validation from the particle size distribution data generated by the cell counter. The PLS models showed good predictive potential for both LDH release and solids concentration. This novel approach reduced the time required for evaluating the solids concentration and LDH for a typical high-throughput cell culture system (with 48 bioreactors in parallel) from around 7 h down to a few minutes., (© 2023 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals LLC.)

The developed asymmetric monovalent bispecific IgG1 or Duet monoclonal antibody (Duet mAb) has two distinct fragment antigen-binding region (Fab) subunits that target two different epitope specificities sequentially or simultaneously. The design features include unique engineered disulfide bridges, knob-into-hole mutations, and kappa and lambda chains to produce Duet mAbs. These make it structurally and functionally complex, so one expects challenging developability linked to instability, degradation of products and pathways, and limited reports available. Here, we have treated the product with different sources of extreme stress over a lengthy period, including varying heat, pH, photo stress, chemical oxidative stress, accelerated stress in physiological conditions, and forced glycation conditions. The effects of different stress conditions on the product were assessed using various analytical characterization tools to measure product-related substances, post-translational modifications (PTMs), structural integrity, higher-order disulfide linkages, and biological activity. The results revealed degradation products and pathways of Duet mAb. A moderate increase in size, charge, and hydrophobic variants, PTMs, including deamidation, oxidation, isomerization, and glycation were observed, with most conditions exhibiting biological activity. In addition, the characterization of fractionated charge variants, including deamidated species, showed satisfactory biological activity. This study demonstrated the prominent stability of the Duet mAb format comparable to most marketed mAbs., Competing Interests: Declaration of competing interest All authors are or were employees of AstraZeneca and may hold stock ownership or interests in the company. Yasunori Watanabe and Lydia Dewis were employees of AstraZeneca during experiments and manuscript compilation., (Copyright © 2024 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Protein-based biopharmaceutical drugs, such as monoclonal antibodies, account for the majority of the best-selling drugs globally in recent years. For bioprocesses, key performance indicators are the concentration and aggregate level for the product being produced. In water NMR ( w NMR), the use of the water transverse relaxation rate [ R 2 ( 1 H 2 O)] has been previously used to determine protein concentration and aggregate level; however, it cannot be used to separate between them without using an additional technique. This work shows that it is possible to "decouple" these two key characteristics by recording the water diffusion coefficient [ D ( 1 H 2 O)] in conjunction with R 2 ( 1 H 2 O), even in the event of overlap in either D ( 1 H 2 O) or R 2 ( 1 H 2 O). This method is demonstrated on three different systems, following appropriate D ( 1 H 2 O) or R 2 ( 1 H 2 O) calibration data acquisition for a protein of interest. Our method highlights the potential use of benchtop NMR as an at-line process analytical technique.

Developing a knob-into-hole asymmetric bispecific IgG1 monoclonal antibody (mAb) poses manufacturing challenges due to the expression of chain pairing variants, also called mispaired species, in the desired product. The incorrect pairing of light and heavy chains could result in heterogeneous mispaired species of homodimers, heterodimers, light chain swapping, and low molecular weight species (LMWS). Standard chromatography, capillary electrophoretic, or spectroscopic methods poorly resolve these from the main variants. Here, we report a highly sensitive reverse-phase polyphenyl ultra-high-performance liquid chromatography (RP-UHPLC) method to accurately measure mispaired species of Duet mAb format, an asymmetric IgG1 bispecific mAb, for both process development and quality control analytical tests. Coupled with electrospray ionization mass spectrometry (ESI-MS), it enabled direct online characterization of mispaired species. This single direct assay detected diverse mispaired IgG-like species and LMWS. The method resolved eight disulfide bonds dissociated LMWS and three mispaired LMWS. It also resolved three different types of IgG-like mispaired species, including two homodimers and one heterodimer. The characterization and quantification simultaneously enabled the cell line selection that produces a lesser heterogeneity and lower levels of mispaired species with the desired correctly paired product. The biological activity assessment of samples with increased levels of these species quantified by the method exhibited a linear decline in potency with increasing levels of mispaired species in the desired product. We also demonstrated the utility of the technique for testing in-process intermediate materials to determine and assess downstream purification process capability in removing diverse mispaired IgG-like species and LMWS to a certain level during the downstream purification process. Our investigation demonstrates that adopting this method was vital in developing asymmetric bispecific mAb from the initial stage of cell line development to manufacturing process development. Therefore, this tool could be used in the control strategy to monitor and control mispaired species during manufacturing, thus improving the quality control of the final product., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘All authors are or were employees of AstraZeneca and may hold stock ownership or interests in the company. Yasunori Watanabe, Lydia Dewis, and Nikola Lonska were employees of AstraZeneca during experiments and manuscript compilation. reports financial support was provided by AstraZeneca UK Limited. All authors are or were employees of AstraZeneca and may hold stock ownership or interests in the company. Yasunori Watanabe, Lydia Dewis, and Nikola Lonska were employees of AstraZeneca during experiments and manuscript compilation. reports a relationship with AstraZeneca UK Limited that includes: employment. All authors are or were employees of AstraZeneca and may hold stock ownership or interests in the company. Yasunori Watanabe, Lydia Dewis, and Nikola Lonska were employees of AstraZeneca during experiments and manuscript compilation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.’., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cell line development is an essential stage in biopharmaceutical development that often lies on the critical path. Failure to fully characterise the lead clone during initial screening can lead to lengthy project delays during scale-up, which can potentially compromise commercial manufacturing success. In this study, we propose a novel cell line development methodology, referenced as CLD 4 , which involves four steps enabling autonomous data-driven selection of the lead clone. The first step involves the digitalisation of the process and storage of all available information within a structured data lake. The second step calculates a new metric referenced as the cell line manufacturability index ( MI CL ) quantifying the performance of each clone by considering the selection criteria relevant to productivity, growth and product quality. The third step implements machine learning (ML) to identify any potential risks associated with process operation and relevant critical quality attributes (CQAs). The final step of CLD 4 takes into account the available metadata and summaries all relevant statistics generated in steps 1-3 in an automated report utilising a natural language generation (NLG) algorithm. The CLD 4 methodology was implemented to select the lead clone of a recombinant Chinese hamster ovary (CHO) cell line producing high levels of an antibody-peptide fusion with a known product quality issue related to end-point trisulfide bond (TSB) concentration. CLD 4 identified sub-optimal process conditions leading to increased levels of trisulfide bond that would not be identified through conventional cell line development methodologies. CLD 4 embodies the core principles of Industry 4.0 and demonstrates the benefits of increased digitalisation, data lake integration, predictive analytics and autonomous report generation to enable more informed decision making., Competing Interests: Authors CL, NB, TS, DH, JK, MC, RT, and JS were employed by AstraZeneca. The remaining 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., (Copyright © 2023 Goldrick, Alosert, Lovelady, Bond, Senussi, Hatton, Klein, Cheeks, Turner, Savery and Farid.)

Data Integrity (DI) in the highly regulated biopharmaceutical sector is of paramount importance to ensure decisions on meeting product specifications are accurate and hence assure patient safety and product quality. The challenge of ensuring DI within this sector is becoming more complex with the growing amount of data generated given increasing adoption of process analytical technology (PAT), advanced automation, high throughput microscale studies, and managing data models created by machine learning (ML) tools. This paper aims to identify DI risks and mitigation strategies in biopharmaceutical manufacturing facilities as the sector moves towards Industry 4.0. To achieve this, the paper examines common DI violations and links them to the ALCOA+ principles used across the FDA, EMA, and MHRA. The relevant DI guidelines from the ISPE's GAMP5 and ISA-95 standards are also discussed with a focus on the role of validated computerised and automated manufacturing systems to avoid DI risks and generate compliant data. The paper also highlights the importance of DI whilst using data analytics to ensure the developed models meet the required regulatory standards for process monitoring and control. This includes a discussion on possible mitigation strategies and methodologies to ensure data integrity is maintained for smart manufacturing operations such as the use of cloud platforms to facilitate the storage and transfer of manufacturing data, and migrate away from paper-based records., (© 2022 The Authors. Biotechnology Journal published by Wiley-VCH GmbH.)

Background: Despite the prevalence of abortion stigma in the United States, few studies have examined the relationship between stigma and psychological well-being postabortion among women who undergo abortion for fetal anomalies., Materials and Methods: We conducted a cross-sectional study of women who underwent second-trimester abortion for pregnancy complications to assess the association between abortion stigma and psychological outcomes. We asked women to retrospectively report self-judgment and perceived community condemnation at the time of their abortion and evaluated present-day grief, post-traumatic stress, and self-reported mental health. We recruited participants using Facebook, Craigslist, and other public online forums. We used multivariable linear regression to evaluate relationships between abortion stigma and psychological outcomes. In adjusted models, we controlled for covariates that were associated with the outcome at a level of p  < 0.1., Results: Adjusted models, including 80 women, revealed that higher self-judgment at the time of abortion was significantly associated with increased postabortion grief ( β  = 2.5 and p  = 0.02). Self-judgment was not associated with statistically significant differences in post-traumatic stress or mental health. There was no association between perceived community condemnation and psychological outcomes., Discussion: Abortion stigma may be associated with increased postabortion grief, but does not appear to be associated with differences in post-traumatic stress or mental health. Investigating how different preprocedure counseling methods can impact self-judgment might inform future interventions aimed at improving psychological outcomes postabortion., Implications for Practice And/or Policy: Abortion providers should consider that women who display signs of self-judgment may be at higher risk for increased grief after pregnancy termination for fetal anomalies or maternal complications., Competing Interests: No competing financial interests exist., (© Jennifer Kerns et al., 2022; Published by Mary Ann Liebert, Inc.)

There are large amounts of data generated within the biopharmaceutical sector. Traditionally, data analysis methods labelled as multivariate data analysis have been the standard statistical technique applied to interrogate these complex data sets. However, more recently there has been a surge in the utilisation of a broader set of machine learning algorithms to further exploit these data. In this article, the adoption of data analysis techniques within the biopharmaceutical sector is evaluated through a review of journal articles and patents published within the last ten years. The papers objectives are to identify the most dominant algorithms applied across different applications areas within the biopharmaceutical sector and to explore whether there is a trend between the size of the data set and the algorithm adopted., (© 2021 The Authors.)

Background: Research on the impact of providers disclosing personal contraceptive experiences with patients is limited. In this study, we examine patient and provider perspectives about provider self-disclosure (PSD) of personal contraceptive experiences and its effects on contraceptive decision making and the provider-patient relationship., Methods: We conducted 18 one-on-one telephone interviews with clinicians who provide contraceptive services to young women and 17 patients seeking emergency contraception from three Bay Area community-based, youth-friendly clinics regarding their contraceptive counseling practices and experiences, respectively. After transcribing and coding all interviews, we summarized structural codes related to contraceptive counseling and PSD., Results: Although providers noted that PSD could help to build rapport and increase patient comfort, most did not report self-disclosing their contraceptive experiences, primarily owing to concerns that it might cross professional boundaries or compromise patient autonomy. All patients held positive attitudes toward and welcomed PSD practices, with many noting that it increased their comfort and trust in their provider., Conclusions: There were notable differences between patient and provider attitudes toward PSD of contraceptive method use, with patients expressing more positive feelings about the practice than providers. Community-based providers should consider that many young women welcome self-disclosure of provider contraceptive experiences and that more research is needed to understand the effects of PSD practices around contraception on the patient-provider relationship and autonomous contraceptive decision making., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Multivariate data analysis (MVDA) is a highly valuable and significantly underutilized resource in biomanufacturing. It offers the opportunity to enhance understanding and leverage useful information from complex high-dimensional data sets, recorded throughout all stages of therapeutic drug manufacture. To help standardize the application and promote this resource within the biopharmaceutical industry, this paper outlines a novel MVDA methodology describing the necessary steps for efficient and effective data analysis. The MVDA methodology is followed to solve two case studies: a "small data" and a "big data" challenge. In the "small data" example, a large-scale data set is compared to data from a scale-down model. This methodology enables a new quantitative metric for equivalence to be established by combining a two one-sided test with principal component analysis. In the "big data" example, this methodology enables accurate predictions of critical missing data essential to a cloning study performed in the ambr15 system. These predictions are generated by exploiting the underlying relationship between the off-line missing values and the on-line measurements through the generation of a partial least squares model. In summary, the proposed MVDA methodology highlights the importance of data pre-processing, restructuring, and visualization during data analytics to solve complex biopharmaceutical challenges., (© 2019 The Authors. Biotechnology Journal published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Chinese hamster ovary (CHO) cells are used for the production of the majority of biopharmaceutical drugs, and thus have remained the standard industry host for the past three decades. The amino acid composition of the medium plays a key role in commercial scale biologics manufacturing, as amino acids constitute the building blocks of both endogenous and heterologous proteins, are involved in metabolic and non-metabolic pathways, and can act as main sources of nitrogen and carbon under certain conditions. As biomanufactured proteins become increasingly complex, the adoption of model-based approaches become ever more popular in complementing the challenging task of medium development. The extensively studied amino acid metabolism is exceptionally suitable for such model-driven analyses, and although still limited in practice, the development of these strategies is gaining attention, particularly in this domain. This paper provides a review of recent efforts. We first provide an overview of the widely adopted practice, and move on to describe the model-driven approaches employed for the improvement and optimization of the external amino acid supply in light of cellular amino acid demand. We conclude by proposing the likely prevalent direction the field is heading towards, providing a critical evaluation of the current state and the future challenges and considerations.

The original version of this article unfortunately contained a mistake in the order of authors. The co-author "Sarah Benatar" should be the second author and "Brigette Courtot" should be the third author of the article.

Objectives Strategies to prevent preterm birth are limited. 17 Alpha-Hydroxyprogesterone Caproate (17P) injections have been shown to be effective, but the intervention is under-used. This mixed methods study investigates barriers and facilitators to 17P administration among Medicaid and CHIP participants enrolled in Strong Start for Mothers and Newborns, a federal preterm birth prevention program. Methods Twenty-seven awardees with more than 200 sites in 30 states, the District of Columbia, and Puerto Rico enrolled approximately 46,000 women in Strong Start from 2013 to 2016. Participant data, including data on preterm birth and 17P, was collected for each woman. Intensive interviews (n = 211) conducted with Strong Start program staff and providers (n = 314) included questions about 17P provision. Results Of women whose data included a valid response regarding 17P initiation, 3919 had a prior preterm birth and current singleton pregnancy; 14.95% received 17P. Barriers to 17P administration include late entry to prenatal care, administrative burden of preauthorization, cost risks to providers, limits in scope of practice for non-physician providers, and social barriers among participants. Facilitators for provision include streamlined work flows and the option of home administration. Conclusions for Practice A universal insurance authorization process could mitigate many barriers to 17P use. Providers need continuing education regarding the effectiveness of 17P, and expanding scope of practice for non-physician prenatal care providers would increase access. Targeted program interventions can help to overcome social barriers Medicaid participants face in accessing care. Streamlined work processes and the option of home health services are two effective program-based facilitators for providing 17P to a Medicaid population.

Background: Closely spaced, unintended pregnancies are common among Medicaid beneficiaries and create avoidable risks for women and infants, including preterm birth. The Strong Start for Mothers and Newborns Initiative, a program of the Center for Medicare and Medicaid Innovation, intended to prevent preterm birth through psychosocially based enhanced prenatal care in maternity care homes, group prenatal care, and birth centers. Comprehensive care offers the opportunity for education and family planning to promote healthy pregnancy spacing., Methods: As of March 30, 2016, there were 42,138 women enrolled in Strong Start and 23,377 women had given birth. Individual-level data were collected through three participant survey instruments and a medical chart review, and approximately one-half of women who had delivered (n = 10,374) had nonmissing responses on a postpartum survey that asked about postpartum family planning. Qualitative case studies were conducted annually for the first 3 years of the program and included 629 interviews with staff and 122 focus groups with 887 Strong Start participants., Results: Most programs tried to promote healthy pregnancy spacing through family planning education and provision with some success. Group care sites in particular established protocols for patient-centered family planning education and decision making. Despite program efforts, however, barriers to uptake remained. These included state and institutional policies, provider knowledge and bias, lack of protocols for timing and content of education, and participant issues such as transportation or cultural preferences., Conclusions: The Strong Start initiative introduced a number of successful strategies for increasing women's knowledge regarding healthy pregnancy spacing and access to family planning. Multiple barriers can impact postpartum Medicaid participants' capacity to plan and space pregnancies, and addressing such issues holistically is an important strategy for facilitating healthy interpregnancy intervals., (Published by Elsevier Inc.)

Histidine-tagged lentiviral vectors were separated from crude cell culture supernatant using labscale monolithic adsorbents by immobilized metal affinity chromatography. The capture capacity, concentration factor, purification factor, and elution efficiency of a supermacroporous cryogel monolith were evaluated against the BIA Separations convective interaction media (CIM) disc, which is a commercial macroporous monolith. The morphology of the polymeric cryogel material was characterised by scanning electron microscopy. Iminodiacetic acid was used as the metal chelating ligand in both monoliths and the chelating capacity for metal ions was found to be comparable. The CIM-IDA-Ni(2+) adsorbent had the greatest capture capacity (6.7 x 10(8) IU/ml of adsorbent), concentration factor (1.3-fold), and elution efficiency (69%). Advantages of the cryogel monoliths included rapid, low pressure processing as well low levels of protein and DNA in the final purified vector preparations.

We investigated the effect of smaller dose, weight-adjusted heparin with earlier monitoring of activated partial thromboplastin time on the incidence of ischemic and hemorrhagic complications in patients with ST-elevation myocardial infarction treated with full-dose tenecteplase. We compared the outcomes of patients enrolled in the Second Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-2; n = 8,461) who received heparin stratified by weight (patients weighing >67 kg received a 5,000-U bolus plus infusion at 1,000 U/hour; those weighing < or =67 kg received a 4,000-U bolus plus infusion at 800 U/hour) with patients in ASSENT-3 who received weight-adjusted heparin (60-U/kg bolus, maximum 4,000 U/hour, followed by a 12-U/kg/hour infusion, maximum 1,000 U/hour). Compared with patients in ASSENT-2, those in ASSENT-3 had similar rates of 30-day mortality, recurrent infarction, and intracranial hemorrhage, less major bleeding (2.2% vs 4.7%, p <0.001), and less refractory ischemia (6.5% vs 8.6%, p <0.001). After adjustment for baseline characteristics, patients in ASSENT-3 had similar rates of 30-day mortality (odds ratio [OR] 0.96, 95% confidence interval [CI] 0.77 to 1.19) and intracranial hemorrhage (OR 1.02, 95% CI 0.61 to 1.69) but less major bleeding (OR 0.49, 95% CI 0.35 to 0.67) than did patients in ASSENT-2. These findings support the use of smaller dose, weight-adjusted heparin in patients with ST-elevation myocardial infarction treated with tenecteplase.

A rare complication of the knee-chest position used for lumbar disk surgery is reported. Central retinal artery occlusion resulted in permanent loss of vision secondary to direct ocular pressure. Prevention is the only rational treatment for this unfortunate condition.

Compression of the spinal cord secondary to disc disorders in Scheuermann's kyphosis is rare. This review reports an unusual case emphasizing mechanisms of compression of the spinal cord from this disc disorder. Contrasts and comparisons with previously published cases are included.

A retrospective review of 99 cases of stable and unstable femoral shaft fractures treated with Grosse-Kempf intramedullary fixation is presented. Despite minor complications and technical problems, the procedures resulted in union with acceptable alignment in 98% of cases. Details of the complications and technical problems are reviewed. There was no incidence of deep infection despite 16 open fractures. The two cases of nonunion were salvaged with revision internal fixation and bone grafting. Grosse-Kempf interlocking intramedullary fixation is a technically demanding procedure, but offers excellent results in the management of stable and unstable, open and closed fractures of the femoral shaft.

A case of nonglucocorticoid-induced lumbar epidural lipomatosis in a middle-aged black woman with neurogenic claudication is presented. The etiology, diagnosis, management, and outcome are discussed in detail.