Real-World Effectiveness of Primary Series and Booster Doses of Inactivated Coronavirus Disease 2019 Vaccine Against Omicron BA.2 Variant Infection in China: A Retrospective Cohort Study.

BACKGROUND: China has been using inactivated coronavirus disease 2019 (COVID-19) vaccines as primary series and booster doses to protect the population from severe to fatal COVID-19. We evaluated primary and booster vaccine effectiveness (VE) against Omicron BA.2 infection outcomes. METHODS: This was a 13-province retrospective cohort study of quarantined close contacts of BA.2-infected individuals. Outcomes were BA.2 infection, COVID-19 pneumonia or worse, and severe/critical COVID-19. Absolute VE was estimated by comparison with an unvaccinated group. RESULTS: There were 289 427 close contacts ≥3 years old exposed to Omicron BA.2 cases; 31 831 turned nucleic acid amplification test-positive during quarantine, 97.2% with mild or asymptomatic infection, 2.6% with COVID-19 pneumonia, and 0.15% with severe/critical COVID-19. None died. Adjusted VE (aVE) against any infection was 17% for primary series and 22% when boosted. Primary series aVE in adults >18 years was 66% against COVID-19 pneumonia or worse and 91% against severe/critical COVID-19. Booster dose aVE was 74% against pneumonia or worse, and 93% against severe/critical COVID-19. CONCLUSIONS: Inactivated COVID-19 vaccines provided modest protection from infection, very good protection against pneumonia, and excellent protection against severe/critical COVID-19. Booster doses are necessary to provide strongest protection.

The Influence of Small Biomolecules, Salts and Buffers on the Molecular Recognition of Amide Naphthotube in Aqueous Solutions.

We found the binding affinities of amide naphthotube to neutral organic molecules in water are not influenced by most of small biomolecules, inorganic salts, and PBS and Tris buffers but are reduced in HEPES buffer through competitive binding. Nevertheless, salts do change the binding affinities of amide naphthotube to charged molecules through a screening effect.

Single-cell RNA-seq reveals altered NK cell subsets and reduced levels of cytotoxic molecules in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune disease with unknown aetiology. To unravel the mechanisms mediating AS pathogenesis, we profiled peripheral blood mononuclear cells (PBMCs) from AS patients and healthy subjects using 10X single-cell RNA sequencing. The frequencies of immune cell subsets were evaluated by flow cytometry. NK cells were purified from PBMCs using isolation kit and were examined for gene expression by RT-qPCR. Plasma levels of cytolytic molecules were examined by enzyme-linked immunosorbent assay. Compared to healthy controls, AS patients showed a significant decrease in total NK cells as well as CD56dim NK subset, whereas CD56bright NK cells were increased. Additionally, impaired expression of cytotoxic genes in NK cells of AS patients was observed by bioinformatics algorithm and verified by RT-qPCR and flow cytometry. Consistent with changes in transcriptomics, we found decreased plasma levels of granzymes, but not granulysin, in AS patients. Furthermore, Pearson correlation analysis revealed a negative correlation between plasma GZMB levels and disease activity (r = -0.5275, p = 0.0358). No correlation was observed between plasma cytolytic molecules and biochemical indexes (ESR and CRP). Our findings uncover altered NK cell subsets and cytotoxic profiles in peripheral circulation of AS patients at single-cell resolution.

Stabilization of Imines and Hemiaminals in Water by an Endo-Functionalized Container Molecule.

Stabilizing water-sensitive reaction intermediates is challenging but desirable for guiding reactions to desired products in water. Herein, we report that labile imine and hemiaminal functional groups can be stabilized inside a synthetic container compound, a water-soluble naphthotube. The naphthotube features a primary amine group anchored in a cavity with both hydrogen bonding sites and hydrophobic surfaces. Aldehydes in bulk aqueous solution are trapped in the cavity by the amine to form hemiaminals stabilized through hydrogen bonding and hydrophobic effects. Dehydration of the hemiaminal to the imine is favored by the release of water from the hydrophobic microenvironment. Both the hemiaminals and imines can be detected at room temperature by NMR spectroscopy and mass spectrometry.

How government health insurance coverage of novel anti-cancer medicines benefited patients in China - a retrospective analysis of hospital clinical data.

BACKGROUND: China started to cover novel medicines for the treatment of major cancers, such as trastuzumab for breast cancer by the government health insurance programs since 2016. Limited data have been published on the use of cancer medications and little is known about how government health insurance coverage of novel anti-cancer medicines benefited patients in the real world. This study aimed to generate evidence to inform the health security authorities to optimize the government health insurance coverage of novel anti-cancer medicines as a more inclusive and equal policy, through which each of the needed patient can get access to the novel anti-cancer medicines regardless of the ability to pay. METHODS: The study targeted one of the government health insurance newly covered novel medicines for breast cancer and the breast cancer patients. The analyses were based on the data collected from one tertiary public hospital in Fujian province of China. We conducted interrupted time series analysis with a segmented regression model and multivariate analyses with a binary logistic regression model to analyze the impact of the government health insurance coverage on medicines utilization and the determinants of patient's medication choice. RESULTS: The average proportion of patients who initiated medication with novel medicines increased from 37.4% before the government health insurance coverage to 69.2% afterwards. Such an increase was observed in all patient sub-groups. The monthly proportion of patients who initiated medication with novel medicines increased sharply by 18.3 % (95 %CI,10.4-34.0 %, p = 0.01) in September 2017, the afterwards trend continuously increased (95 %CI,1.03-3.60, p = 0.02). The critical determinants of patient's medication choice were mostly connected with the patient's health insurance benefits packages. CONCLUSIONS: The government health insurance coverage of novel anti-breast-cancer medicines benefited the patients generally. The utilization of novel medicines such as trastuzumab continuously increased. The insurance coverage benefited well the patients in the high-risk age groups. However, rural patients, patients enrolled in the "resident program", and patients from low-income residential areas and non-local patients benefited less from this policy. Improving the benefits package of the low-income patients and the "resident program" beneficiary would be of considerable significance for a more inclusive and equal health insurance coverage of novel anti-cancer medicines.

Training non-native vowel perception: In quiet or noise.

Noise makes speech perception much more challenging for non-native listeners than for native listeners. Training for non-native speech perception is usually implemented in quiet. It remains unclear if background noise may benefit or hamper non-native speech perception learning. In this study, 51 Chinese-native listeners were randomly assigned into three groups, including vowel training in quiet (TIQ), vowel training in noise (TIN), and watching videos in English as an active control. Vowel identification was assessed before (T1), right after (T2), and three months after training (T3) in quiet and various noise conditions. Results indicated that compared with the video watching group, the TIN group improved vowel identification in both quiet and noise significantly more at T2 and at T3. In contrast, the TIQ group improved significantly more in quiet and also in non-speech noise conditions at T2, but the improvement did not hold at T3. Moreover, compared to the TIQ group, the TIN group showed significantly less informational masking at both T2 and T3 and less energetic masking at T3. These results suggest that L2 speech training in background noise may improve non-native vowel perception more effectively than TIQ background only. The implications for non-native speech perception learning are discussed.

Molecular Imaging of Brown Adipose Tissue Mass.

Brown adipose tissue (BAT), a uniquely thermogenic tissue that plays an important role in metabolism and energy expenditure, has recently become a revived target in the fight against metabolic diseases, such as obesity, diabetes, and non-alcoholic fatty liver disease (NAFLD). Different from white adipose tissue (WAT), the brown adipocytes have distinctive features including multilocular lipid droplets, a large number of mitochondria, and a high expression of uncoupling protein-1 (UCP-1), as well as abundant capillarity. These histologic characteristics provide an opportunity to differentiate BAT from WAT using imaging modalities, such as PET/CT, SPECT/CT, MRI, NIRF and Ultrasound. However, most of the reported imaging methods were BAT activation dependent, and the imaging signals could be affected by many factors, including environmental temperatures and the states of the sympathetic nervous system. Accurate BAT mass detection methods that are independent of temperature and hormone levels have the capacity to track the development and changes of BAT throughout the lifetime of mammals, and such methods could be very useful for the investigation of potential BAT-related therapies. In this review, we focus on molecular imaging modalities that can detect and quantify BAT mass. In addition, their detection mechanism and limitations will be discussed as well.

Pharmaceutical care in Chinese public tertiary hospitals: findings from the 4th National Healthcare Improvement Initiative Survey.

BACKGROUND: Pharmaceutical care has been playing an increasingly critical role in Chinese hospitals. However, evidence about the most recent development of pharmaceutical care in China is limited. This study analyzed the current situation of pharmaceutical care and the capacities of pharmacists in Chinese public tertiary hospitals. METHODS: All on-duty pharmacists of 143 public tertiary hospitals responded to the Likert-5 pre-set online questionnaire about their pharmaceutical care capacities in eight aspects, and their respective hospitals valued pharmaceutical care in clinical practice from March 18 to 31, 2019. This study measured the appraisals of the responding pharmacists as positive ("strongly agree" and "agree") or negative ("neither agree nor disagree," "strongly disagree," and "disagree") results. The study performed a descriptive analysis of the responding pharmacists and unconditional multivariate binary logistic regression analysis to predict the influencing factors of the pharmacists' appraisals of pharmaceutical care. The dependent variable was transformed into binary categories and assigned 1 = positive response and 0 = negative response. The independent variables included the identifications of sample hospitals and the characteristics of the responding pharmacists. RESULTS: The survey retrieved 10 815 valid responded questionnaires. 74.5%, 67.5%, and 65.0% of the responding pharmacists made a positive self-appraisal of their abilities of communication with patients and doctors, reviewing prescriptions, and communication with particular patients, respectively. 65.5% had a positive appraisal of their respective hospitals to conduct active monitoring of the clinical use of new medicines, and 68.9% admitted that their respective hospitals valued the clinical pharmaceutical care. The doctor's degree and senior academic rank of the responding pharmacists, as well as maternal and child hospitals, were predictors of higher appraisals of the responding pharmacists about their pharmaceutical care capacities, and their respective hospitals valued pharmaceutical care (all ORs > 1.5, P < 0.05). CONCLUSIONS: The study suggested that there is a need to strengthen the pharmacy education, training, and staffing of pharmacists with improved professional skills to offer value-added specialized pharmaceutical care in Chinese public hospitals. Patient-centered and inter-disciplinary interactions in medical practice should be promoted. There is also a need for public hospitals to provide a platform for the achievement of the professional values of high-quality pharmacists at different carrier development stages.

The risk of Helicobacter pylori infection for adverse pregnancy outcomes: A systematic review and meta-analysis.

OBJECTIVE: To estimate the current evidence regarding the association between Helicobacter pylori infection during pregnancy and adverse pregnancy outcomes. MATERIALS AND METHODS: A systematic literature search for relevant publications was conducted using PubMed, EMBASE, Cochrane Library, and Web of science databases through November 17th, 2018. The pooled odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were selected as the effect size. Subgroup analysis and sensitivity analysis were performed. RESULTS: Thirty-one studies with a total of 22 845 participants were identified. There was significant association of H pylori infection with preeclampsia (OR: 2.51; 95% CI: 1.88-3.34; P < 0.001), fetal growth restriction (OR: 2.28; 95% CI: 1.21-4.32; P = 0.01), gestational diabetes mellitus (OR: 2.03; 95% CI: 1.56-2.64; P < 0.001), spontaneous abortion (OR: 1.50; 95% CI: 1.05-2.14; P = 0.024), and birth defect (OR: 1.63; 95% CI: 1.05-2.54; P = 0.03). Sensitivity analysis showed the significant association between H pylori infection and low birthweight (OR: 1.59; 95% CI: 1.05-2.40; P = 0.03). CONCLUSION: The present meta-analysis offers proof to support that H pylori infection during pregnancy can increase the risk on adverse pregnancy outcomes. Screening and treating for H pylori infection before pregnancy should be taken into account.

Molecular Recognition of Hydrophilic Molecules in Water by Combining the Hydrophobic Effect with Hydrogen Bonding.

During the last half a century, great achievements have been made in molecular recognition in parallel with the invention of numerous synthetic receptors. However, the selective recognition of hydrophilic molecules in water remains a generally accepted challenge in supramolecular chemistry but is commonplace in nature. In an earlier Communication [ Huang et al. J. Am. Chem. Soc. 2016 , 138 , 14550 ], we reported a pair of endo-functionalized molecular tubes that surprisingly prefer highly hydrophilic molecules over hydrophobic molecules of a similar size and shape. The hydrophobic effect and hydrogen bonding were proposed to be responsible, but their exact roles were not fully elucidated. In this Article, we present a thorough study on the binding behavior of these molecular tubes toward 44 hydrophilic molecules in water. Principal component analysis reveals that the binding strength is weakly correlated to the hydrophobicity, volume, surface area, and dipole moment of guests. Furthermore, molecular dynamics simulations show the hydrophobic effect through releasing the poorly hydrogen-bonded cavity water contributes to the binding of all the hydrophilic molecules, while hydrogen bonding differentiates these molecules and is thus the key to achieve a high selectivity toward certain hydrophilic molecules over other molecules with a similar size and shape. Therefore, a good guest for these molecular tubes should meet the following criteria: the hydrogen-bonding sites should be complementary, and the molecular volume should be large enough to expel all the cavity water but not too large to cause steric hindrance. This rule of thumb may also be used to design a selective receptor for certain hydrophilic molecules. Following these guidelines, a "best-fit" guest was found for the syn-configured molecular tube with a binding constant as high as 106 M-1.

DBU-Promoted Cascade Annulation of Nitroarylcyclopropane-1,1-dicarbonitriles and 3-Aryl-2-cyanoacrylates: An Access to Highly Functionalized Cyclopenta[ b]furan Derivatives.

A DBU-promoted cascade annulation of nitroarylcyclopropane-1,1-dicarbonitriles and 3-aryl-2-cyanoacrylates for the synthesis of highly functionalized cyclopenta[ b]furan derivatives is described. High stereoselectivity, fused cyclopentane and furan can be established in a single reaction, highlighting the high efficiency and step-economy of this protocol. This reaction offers a novel and straightforward protocol to the synthesis of cyclopenta[ b]furans featuring the [3 + 2] cycloadditions of nitroarylcyclopropane-1,1-dicarbonitriles with 3-aryl-2-cyanoacrylates.

Otic drug delivery systems: formulation principles and recent developments.

Disorders of the ear severely impact the quality of life of millions of people, but the treatment of these disorders is an ongoing, but often overlooked challenge particularly in terms of formulation design and product development. The prevalence of ear disorders has spurred significant efforts to develop new therapeutic agents, but perhaps less innovation has been applied to new drug delivery systems to improve the efficacy of ear disease treatments. This review provides a brief overview of physiology, major diseases, and current therapies used via the otic route of administration. The primary focuses are on the various administration routes and their formulation principles. The article also presents recent advances in otic drug deliveries as well as potential limitations. Otic drug delivery technology will likely evolve in the next decade and more efficient or specific treatments for ear disease will arise from the development of less invasive drug delivery methods, safe and highly controlled drug delivery systems, and biotechnology targeting therapies.

Auditory detection of non-speech and speech stimuli in noise: Native speech advantage.

Detection thresholds of Chinese vowels, Korean vowels, and a complex tone, with harmonic and noise carriers were measured in noise for Mandarin Chinese-native listeners. The harmonic index was calculated as the difference between detection thresholds of the stimuli with harmonic carriers and those with noise carriers. The harmonic index for Chinese vowels was significantly greater than that for Korean vowels and the complex tone. Moreover, native speech sounds were rated significantly more native-like than non-native speech and non-speech sounds. The results indicate that native speech has an advantage over other sounds in simple auditory tasks like sound detection.

Evolutionary and ontogenetic changes in RNA editing in human, chimpanzee, and macaque brains.

Adenosine-to-inosine (A-to-I) substitutions are the most common type of RNA editing in mammals. A-to-I RNA editing is particularly widespread in the brain and is known to play important roles in neuronal functions. In this study we investigated RNA-editing changes during human brain development and maturation, as well as evolutionary conservation of RNA-editing patterns across primates. We used high-throughput transcriptome sequencing (RNA-seq) to quantify the RNA-editing levels and assess ontogenetic dynamics of RNA editing at more than 8000 previously annotated exonic A-to-I RNA-editing sites in two brain regions--prefrontal cortex and cerebellum--of humans, chimpanzees, and rhesus macaques. We observed substantial conservation of RNA-editing levels between the brain regions, as well as among the three primate species. Evolutionary changes in RNA editing were nonetheless evident, with 40% of the annotated editing sites studied showing divergent editing levels among the three species and 16.5% of sites displaying statistically significant human-specific editing patterns. Across lifespan, we observed an increase of the RNA-editing level with advanced age in both brain regions of all three primate species.

Anthelmintic efficacy of cinnamaldehyde and cinnamic acid from cortex cinnamon essential oil against Dactylogyrus intermedius.

Utilization of chemical pesticide to control monogenean diseases is often restricted in many countries due to the development of pesticide resistance and concerns of chemical residues and environmental contamination. Thus, the use of antiparasitic agents from plants has been explored as a possible way for controlling monogenean infections. Extracts from Cinnamomum cassia were investigated under in vivo conditions against Dactylogyrus intermedius in goldfish. The two bioactive compounds, cinnamaldehyde and cinnamic acid, were identified using nuclear magnetic resonance and electrospray ionization mass spectrometry. The 48 h median effective concentrations (EC(50)) for these compounds against D. intermedius were 0·57 and 6·32 mg L(-1), respectively. The LD(50) of cinnamaldehyde and cinnamic acid were 13·34 and 59·66 mg L(-1) to goldfish in 48 h acute toxicity tests, respectively. These data confirm that cinnamaldehyde is effective against D. intermedius, and the cinnamaldehyde exhibits potential for the development of a candidate antiparasitic agent.

Widespread splicing changes in human brain development and aging.

While splicing differences between tissues, sexes and species are well documented, little is known about the extent and the nature of splicing changes that take place during human or mammalian development and aging. Here, using high-throughput transcriptome sequencing, we have characterized splicing changes that take place during whole human lifespan in two brain regions: prefrontal cortex and cerebellum. Identified changes were confirmed using independent human and rhesus macaque RNA-seq data sets, exon arrays and PCR, and were detected at the protein level using mass spectrometry. Splicing changes across lifespan were abundant in both of the brain regions studied, affecting more than a third of the genes expressed in the human brain. Approximately 15% of these changes differed between the two brain regions. Across lifespan, splicing changes followed discrete patterns that could be linked to neural functions, and associated with the expression profiles of the corresponding splicing factors. More than 60% of all splicing changes represented a single splicing pattern reflecting preferential inclusion of gene segments potentially targeting transcripts for nonsense-mediated decay in infants and elderly.

The COVID-19 Vaccines Evaluation Program: Implementation, Management, and Experiences, 2021-2023.

In 2021, China's domestically produced coronavirus disease 2019 (COVID-19) vaccines received approval from regulatory bodies and were administered worldwide. Due to a low number of infections within China during that period, it became imperative to evaluate the vaccines' real-world effectiveness through international studies. To facilitate this, China CDC launched the COVID-19 Vaccines Evaluation Program (COVEP). This program formed research collaboration agreements with health institutes across five World Health Organization regions, addressing key questions about vaccine performance through ten cooperative agreements. The findings from COVEP projects reinforced confidence, both domestically and globally, in the effectiveness of the vaccines produced in China. Moreover, the outcomes observed internationally were frequently mirrored by later studies conducted within China. COVEP thus pioneered a novel approach for fostering cross-national research collaborations, addressing significant public health issues and exemplifying a framework for international cooperation. This approach is in line with the strategic objectives and other development efforts of China CDC's national disease control and prevention initiatives.

The efficacy of statins in the treatment of rheumatoid arthritis: A systematic review and meta-analysis.

BACKGROUND: A large body of research has investigated the use of statins in rheumatoid arthritis (RA); however, the therapeutic effects of statins remain uncertain. Thus, we designed a systematic review and meta-analysis to evaluate the role of statins in patients with RA. METHODS: Databases searched to detect clinical randomized controlled trials or clinical controlled trials on the interaction between statins and RA before January 2020 included PubMed, Web of Sciences, Embase, Cochrane Library, CNKI, Wan Fang Database. Efficacy was measured by Disease Activity Score in 28 Joints (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tenderness of the joint (TJ), swelling of the joint (SJ), and interleukin-6. The level of blood lipid was also evaluated. STATA 12.0 was used for the meta-analysis. The Cochrane method was used for quality assessment. Heterogeneity was considered to determine fixed effects or random effects models. RESULTS: Nineteen clinical trials with a total of 22,906 subjects were included in the meta-analysis. Sixteen studies reported a change in DAS28 after statin treatment. The pooled analysis showed that statins reduced DAS28 in RA patients. Change in ESR after statin treatment was reported in 9 studies. The summary analysis showed that statins lowered ESR in RA patients. Twelve studies reported a change in CRP after statin treatment. The results of the entire analysis showed that statins lowered CRP in RA patients. Seven studies reported a change in TJ after statin treatment. The combined analysis showed that statins reduced TJ at RA patients. Six studies reported changes in IL6 after statin therapy. The results showed that statins failed to reduce IL6 in RA patients. Seven studies reported changes in SJ after statin therapy, which showed that statins failed to reduce SJ in RA patients. We also found that statins can reduce blood lipid levels in RA patients. CONCLUSION: In conclusion, statins were able to reduce DAS28, ESR, CRP, TJ, and blood lipids. It indicated that stains can benefit patients with RA by inhibiting the expression of inflammatory factors and reducing the levels of lipids in the blood. Our study may offer a new perspective on the treatment of RA and provide research ideas for future larger multi-center clinical trials.

Extraction of soybean plant trait parameters based on SfM-MVS algorithm combined with GRNN.

Soybean is an important grain and oil crop worldwide and is rich in nutritional value. Phenotypic morphology plays an important role in the selection and breeding of excellent soybean varieties to achieve high yield. Nowadays, the mainstream manual phenotypic measurement has some problems such as strong subjectivity, high labor intensity and slow speed. To address the problems, a three-dimensional (3D) reconstruction method for soybean plants based on structure from motion (SFM) was proposed. First, the 3D point cloud of a soybean plant was reconstructed from multi-view images obtained by a smartphone based on the SFM algorithm. Second, low-pass filtering, Gaussian filtering, Ordinary Least Square (OLS) plane fitting, and Laplacian smoothing were used in fusion to automatically segment point cloud data, such as individual plants, stems, and leaves. Finally, Eleven morphological traits, such as plant height, minimum bounding box volume per plant, leaf projection area, leaf projection length and width, and leaf tilt information, were accurately and nondestructively measured by the proposed an algorithm for leaf phenotype measurement (LPM). Moreover, Support Vector Machine (SVM), Back Propagation Neural Network (BP), and Back Propagation Neural Network (GRNN) prediction models were established to predict and identify soybean plant varieties. The results indicated that, compared with the manual measurement, the root mean square error (RMSE) of plant height, leaf length, and leaf width were 0.9997, 0.2357, and 0.2666 cm, and the mean absolute percentage error (MAPE) were 2.7013%, 1.4706%, and 1.8669%, and the coefficients of determination (R2) were 0.9775, 0.9785, and 0.9487, respectively. The accuracy of predicting plant species according to the six leaf parameters was highest when using GRNN, reaching 0.9211, and the RMSE was 18.3263. Based on the phenotypic traits of plants, the differences between C3, 47-6 and W82 soybeans were analyzed genetically, and because C3 was an insect-resistant line, the trait parametes (minimum box volume per plant, number of leaves, minimum size of single leaf box, leaf projection area).The results show that the proposed method can effectively extract the 3D phenotypic structure information of soybean plants and leaves without loss which has the potential using ability in other plants with dense leaves.

Data-driven engineering framework with AI algorithm of Ginkgo Folium tablets manufacturing.

Smart manufacturing still remains critical challenges for pharmaceutical manufacturing. Here, an original data-driven engineering framework was proposed to tackle the challenges. Firstly, from sporadic indicators to five kinds of systematic quality characteristics, nearly 2,000,000 real-world data points were successively characterized from Ginkgo Folium tablet manufacturing. Then, from simplex to the multivariate system, the digital process capability diagnosis strategy was proposed by multivariate Cpk integrated Bootstrap-t. The Cpk of Ginkgo Folium extracts, granules, and tablets were discovered, which was 0.59, 0.42, and 0.78, respectively, indicating a relatively weak process capability, especially in granulating. Furthermore, the quality traceability was discovered from unit to end-to-end analysis, which decreased from 2.17 to 1.73. This further proved that attention should be paid to granulating to improve the quality characteristic. In conclusion, this paper provided a data-driven engineering strategy empowering industrial innovation to face the challenge of smart pharmaceutical manufacturing.